               In the United States Court of Federal Claims
                                OFFICE OF SPECIAL MASTERS
                                       Filed: August 31, 2017 1
                             Refiled in Redacted Form: February 7, 2018

                                                      PUBLISHED
    J.M. and V.M., in their Own Right and as
    Best Friends of their Son, V.J.M.,                No. 02-10V

                      Petitioners,                    Chief Special Master Dorsey
    v.
                                                      Denial of Entitlement; Measles, Mumps
    SECRETARY OF HEALTH AND                           & Rubella (“MMR”) Vaccine; Hepatitis
    HUMAN SERVICES,                                   A (“Hep A”) Vaccine; Varicella Vaccine;
                                                      Autistic Disorder (“AD”); Residual
                     Respondent.                      Human DNA Fragments; HERV-K
                                                      Fragments; Insertional Mutagenesis;
                                                      Autoimmunity.


John F. McHugh, Law Office of John McHugh, New York, NY, for petitioners.
Ann Donohue Martin, U.S. Department of Justice, Washington, DC, for respondent.

                                            DECISION

         I.   Introduction

        On January 4, 2002, J.M. and V.M. (“petitioners”) brought a claim pursuant to the
National Vaccine Injury Compensation Program (“the Program”) 2 on behalf of their son, V.J.M.,
in which they alleged that the measles, mumps and rubella (“MMR”) vaccine that he received on
January 19, 1999, caused his pervasive developmental disorder (“PDD”), not otherwise
specified, autism. Amended Petition (“Am. Pet.”) at ¶¶ 10, 12, 15. V.J.M. was one year old at

1
  When this decision was originally filed, I advised the parties of my intent to post it on the
United States Court of Federal Claims’ website, in accordance with the E-Government Act of
2002. 44 U.S.C. §3501 note (2012) (Federal management and Promotion of Electronic
Government Services). In accordance with Vaccine Rule 18(b), petitioners filed a motion to
redact certain information. This decision is being reissued with minimal changes, including
redaction of the petitioners’ name in the case caption and text to initials and redaction of
V.J.M.’s date and place of birth. Except for those changes and this footnote, no other substantive
changes have been made.
2
 The Program comprises Part 2 of the National Childhood Vaccine Injury Act of 1986, 42
U.S.C. §§ 300aa-10 et seq. [hereinafter “Vaccine Act” or “the Act”]. Hereafter, individual
section references will be to 42 U.S.C. § 300aa of the Act.


                                                 1
the time of the vaccination, and thereafter, petitioners allege he failed to either gain or maintain
his verbal and social skills. Id. at ¶¶ 1, 6.

        This case is the lead case for a mini-omnibus proceeding comprised of 23 cases. 3
Petitioners in each of these cases have agreed to be bound by the decision in this case, which will
be filed in each of the cases in the mini-omnibus.

        As their theory of causation, petitioners assert that V.J.M. had an adverse reaction to
human DNA found in the rubella portion of the MMR 4 vaccine, which triggered his autism. 5
Am. Pet. at ¶¶ 15-16; Pet. Ex. 10 at ¶¶ 3, 17. Respondent argues against awarding compensation,
stating that petitioners failed to provide adequate evidence that V.J.M.’s MMR vaccination, or
any other vaccinations, caused him to suffer from autism.

       After carefully analyzing and weighing all of the evidence and testimony filed and
presented in this case in accordance with applicable legal standards, I find that petitioners have
not met their legal burden under Prong One of Althen v. Sec’y of Health & Human Servs., 418
F.3d 1274, 1278 (Fed. Cir. 2005). Petitioners have not demonstrated preponderant evidence that
the MMR or any other vaccinations that V.J.M., or the children in the other related proceedings,
received can cause autism. Therefore, this case, and the other cases, must be dismissed. 6



3
  The 23 cases in the mini-omnibus include: J.M. et al. (02-010V), J.K.R. et al. (09-143V),
Fuesel (02-095V), E.H. et al. (09-206V), Arranga (02-1616V), B.W. (14-375V), J.H.R. et al.
(03-1156V), M.P. et al. (07-750V), Coiro-Lorusso (04-258V), S.O. et al. (08-125V), Young (05-
207V), Graddy (08-416V), C.B. et al. (05-1168V), Eworonsky (04-992V), C.B. et al. (08-131V),
King (05-717V), F.J.D. et al. (08-254V), P.R. et al. (10-096V), F.J.D. et al. (08-253V), Torres
(15-561V), N.P. et al. (08-388V), M.J. et al. (16-434V), and A.E.R. (17-470V). This Decision
applies to all of these cases.
4
 The MMR vaccine at issue is occasionally referenced as “MMR II” in petitioners’ exhibits,
expert reports, and medical literature, as this distinction is material to Dr. Deisher’s theory. For
purposes of this decision, the term “MMR vaccine” is used with no distinction drawn between
MMR vaccine and MMR II vaccine, except when discussing Dr. Deisher’s change point study.
See section VIII(a).
5
  While the minor child in J.M. et al. received only the MMR vaccine, the petitioners in the other
cases joined in this proceeding had one or more of the vaccines at issue: MMR, “Varivax, Vaqta,
Havrix and Pentacel.” See Pet. Prehearing Memorandum at n.1. This decision applies to these
additional vaccines as well. Varivax is indicated for vaccination against varicella zoster virus in
individuals 12 months of age and older. Vaqta (by Merck) and Havrix (by GlaxoSmithKline)
vaccinate against hepatitis A. Pentacel is indicated for diphtheria, tetanus, pertussis, and polio
(DTaP-IPV).
6
    A decision dismissing each of the mini-omnibus cases will issue following this decision.



                                                  2
no developmental or behavioral concerns were noted. The varicella vaccine was offered and
refused. Id. at 17. V.J.M. presented to his physician for his 18 month well-child visit on July 20,
1999, at which time no behavioral or developmental concerns were noted. Id. at 17-18. During
this visit, he received the DPT and the oral polio vaccine (“OPV”) vaccinations. Id. at 18.

        On April 6, 2000, V.J.M. visited his primary care doctor for an ear checkup, where
residual otitis media was noted. Pet. Ex. A at 22. He had fluid in his left ear and his right ear
was infected; he was prescribed Bactrim. Id. On June 21, 2000, a primary care note states that
V.J.M. was pulling on both of his ears, and while he did not have a fever, he was cranky. Id.
During that visit, he was referred to an early intervention program for a speech, hearing, and
behavioral evaluation. 10 Id. At his next well-child visit on July 18, 2000, V.J.M. was noted to
be a well-child with no developmental or behavioral concerns. Id. at 18. He received the
Prevnar vaccination during this visit. Id. On September 26, 2000, he was given a neurological
referral for “questionable pervasive developmental disorder (“PDD”).” Id. at 23.

        On July 21, 2000, when he was two and a half years old, V.J.M. underwent a
psychological evaluation at the Programs for Special Children. Pet. Ex. B at 27. His evaluation
indicated that he did not suffer from any significant medical problems at birth or thereafter, with
the exception of repeated ear infections. 11 Id. at 28. The report further indicated that while his
developmental milestones were within normal limits during his first year, his speech
development did not progress as expected. Id.

        Based on his psychological evaluation, it was recommended that V.J.M. receive an
intensive early intervention program with an emphasis on developing his social and
communication skills. Pet. Ex. B at 31. On September 5, 2000, V.J.M. began an intensive multi-
modal therapeutic program at the New York City Early Intervention Program, which included 20
hours of behavioral therapy, one hour of daily speech and language therapy, and occupational
therapy three times weekly. Pet. Ex. C at 33; Pet. Ex. F at 20. Notes from October 31, 2000,
show that V.J.M. initially made great progress in therapy, though he continued to show speech
and language delay. Pet. Ex. F at 20. Therapy notes reflect that his eye contact improved, he
began responding to his name, and he was able to identify common objects. Id. at 19. While
V.J.M.’s speech and language skills showed significant initial improvement, his progress
plateaued, resulting in the need for neurological evaluation. Pet. Ex. C at 33. V.J.M. had no
family history of neurological disorders, and his two month old sister had no behavioral
abnormalities. Id.



10
   The doctor’s note from the visit on June 21, 2000, does not include an explanation as to why
V.J.M. was referred to early intervention. See Pet. Ex. A at 22. However, this appears to be the
first mention of any developmental issue in the medical records, which occurred approximately
one year and five months after the January 19, 1999 MMR vaccination.
11
   V.J.M. went to the doctor for otitis media (recurrent ear infections) on the following dates:
August 19, 1998, September 4, 1998, February 13, 1999, March 3, 1999, November 30, 1999,
March 23, 2000, April 6, 2000, June 21, 2000, July 16, 2001, and December 4, 2001. Pet. Ex. A
at 20-24.
                                                 4
        On May 24, 2001, Dr. Arnold Gold, a neurologist, evaluated V.J.M. Pet. Ex. C at 32.
During the evaluation, V.J.M. was irritable and fussy, apparently because he had been wakened
from a nap. Id. at 33. Dr. Gold reported that V.J.M.’s one year milestones were considered age-
appropriate by his parents. He was able to sit on his own at the age of six months and was able
to walk unassisted by the age of 14 and a half months. V.J.M.’s parents did not express concern
about his development until he was approximately 14 to 15 months old. Id. at 32. Although he
uttered his first word, “car,” at the age of 12 months, there was only limited improvement in his
speech and language development. Id.

        During Dr. Gold’s evaluation, V.J.M. exhibited self-stimulatory behaviors such as
spinning repetitively in a circle while seated. Pet. Ex. C at 32. The spinning eventually resolved,
but V.J.M. then began jumping up and down and jumping across the room while grinding his
teeth. Id. at 32-33. Additionally, he would frequently scatter and gather objects, such as blocks,
and would at times rock in a repetitive manner. Id. at 33. He had no dysmorphic features or
cutaneous lesions suggestive of a neurocutaneous disorder. His gait was normal and he had no
difficulty walking, running, or jumping. Id. He did not like to have his head touched and could
be occasionally physically aggressive by hitting. Id. Dr. Gold stated that V.J.M.’s behaviors
were consistent with ASD. Id. An etiology could not be established, but Dr. Gold reported that
he “would question any relationship to the MMR vaccination.” Id. at 35. There was no evidence
of a seizure disorder or progressive encephalopathy. Id. at 34.

             b. Petitioners’ Affidavit 12

        Along with their petition, petitioners also filed an affidavit from J.M., in which she
averred that V.J.M. was healthy at birth and developed normally until his first birthday. Pet.
Affidavit at 6. By his first birthday, he could stand up, say several words, and use words to
identify the objects that he was holding. Id. On January 19, 1999, after receiving the MMR,
Hib, and hepatitis B vaccinations, V.J.M. fell asleep in the car on the way home. Id. at 7. He did
not wake up when being transferred from the car to his crib, which was unusual. Id. J.M. avers
that V.J.M. awoke several hours later and was cranky and clingy, and when she put him on the
floor, he began to spin himself around. Id. J.M. stated that sometimes he would fall silent and
sit and stare for several minutes.13 Id.

        Two days after his vaccinations, J.M. took V.J.M. back to the doctor with a chief
complaint of a sore throat. Pet. Affidavit at 8. Although she described V.J.M.’s symptoms to his
pediatrician, J.M. stated that she did not alert his doctor to the spinning or staring because she did
not know that either was a significant symptom. Id. V.J.M.’s pediatrician diagnosed him with
an ear infection and a sore throat. Id.




12
   Petitioners filed an affidavit from J.M. along with their petition. They did not attend or testify
at the hearing in this matter.
13
     The medical records do not contain any mention of these behaviors after vaccination.


                                                  5
        After January 21, 1999, J.M. stated that V.J.M.’s development halted, and he stopped
attempting to use words. Pet. Affidavit at 8. He began repetitive activities and stopped sleeping
through the night. Id. V.J.M. became more easily cranky, he stopped trying to speak, and when
he resumed speaking, he was incessantly repetitive. Id. J.M. stated that she began reporting her
observations of V.J.M. to his pediatrician beginning on January 21, 1999, but was told that there
was nothing wrong. Id. at 9. Although she stated that her reports to his pediatrician became
more frantic, the medical records do not reflect her concerns. Id. Specifically, she noted that
when she took V.J.M. to his pediatrician on July 18, 2000, she reported her concerns about his
lack of development, but her concerns were not recorded by the pediatrician. Id. She stated that
V.J.M.’s health problems began immediately after he received his vaccinations on January 19,
1999, and that he is permanently disabled and in need of assistance. Id. at 10-11.

     III.   Procedural History

            a. Omnibus Autism Proceeding

        This case is one of more than 5,400 cases filed under the Program in which petitioners
alleged that conditions known as “autism” or “autism spectrum disorders” (“ASD”) 14 were
caused by one or more vaccinations. A special proceeding known as the Omnibus Autism
Proceeding (“OAP”) was developed to manage these cases within the Office of Special Masters
(“OSM”). A detailed history of the controversy regarding vaccines and autism, along with a
history of the development of the OAP, was set forth in the six entitlement decisions issued as
“test cases” for two theories of causation litigated in the OAP (see cases cited below), and will
only be summarized here.

        A group called the Petitioners’ Steering Committee (“PSC”) was formed in 2002 by the
many attorneys who represented Vaccine Act petitioners who raised autism-related claims.
About 180 attorneys, including petitioners’ counsel, Mr. McHugh, participated in the PSC. Their
responsibility was to develop any available evidence indicating that vaccines could contribute to
causing autism, and eventually present that evidence in a series of “test cases,” exploring the
issue of whether vaccines could cause autism, and, if so, under what circumstances. Ultimately,
the PSC selected groups of attorneys to present evidence in two different sets of “test cases”
during many weeks of trial in 2007 and 2008. In the six test cases, the PSC presented two
separate theories concerning the causation of ASDs. The first theory alleged that the measles
portion of the MMR vaccine could cause ASDs. That theory was presented in three separate
Program test cases during several weeks of trial in 2007. The second theory alleged that the
mercury contained in thimerosal-containing vaccines could directly affect an infant’s brain,



14
  ASD is a general classification, which as of 2010 included five different specific disorders:
Autistic Disorder (“AD”), Childhood Disintegrative Disorder, Asperger’s syndrome, Rett
syndrome, and Pervasive Developmental Disorder Not Otherwise Specified (“PDD-NOS”). Pet.
Ex. 27; Pet. Ex. 34 at 2; King v. Sec’y of Health & Human Servs., No. 03-584V, 2010 WL
892296, at *5 (Fed. Cl. Spec. Mstr. Mar. 12, 2010). The term “autism” is often utilized to
encompass all of the types of disorders falling within the autism spectrum. Id.


                                                6
thereby substantially contributing to the causation of ASD. That theory was presented in three
additional test cases during several weeks of trial in 2008.

        Decisions in each of the three test cases pertaining to the PSC’s first theory rejected the
petitioners’ causation theories. Cedillo v. Sec’y of Health & Human Servs., No. 98-916V, 2009
WL 331968 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), mot. for rev. denied, 89 Fed. Cl. 158 (2009),
aff’d, 617 F.3d 1328 (Fed. Cir. 2010); Hazlehurst v. Sec’y of Health & Human Servs., No. 03-
654V, 2009 WL 332306 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), mot. for rev. denied, 88 Fed. Cl.
473 (2009), aff’d, 604 F.3d 1343 (Fed. Cir. 2010); Snyder, 2009 WL 332044, mot. for rev.
denied, 88 Fed. Cl. 706 (2009). Decisions in each of the three “test cases” pertaining to the
PSC’s second theory also rejected the petitioners’ causation theories, and the petitioners in each
of those three cases chose not to appeal. Dwyer v. Sec’y of Health & Human Servs., No. 03-
1202V, 2010 WL 892250 (Fed. Cl. Spec. Mstr. Mar. 12, 2010); King, 2010 WL 892296; Mead
v. Sec’y of Health & Human Servs., No. 03-215V, 2010 WL 892248 (Fed. Cl. Spec. Mstr. Mar.
12, 2010).

        The “test case” decisions were comprehensive, analyzing in detail all of the evidence
presented on both sides. The three test case decisions concerning the PSC’s first theory totaled
more than 600 pages of detailed analysis, and were solidly affirmed in many more pages of
analysis in three different rulings by three different judges of the United States Court of Federal
Claims, and in two rulings by two separate panels of the United States Court of Appeals for the
Federal Circuit. The three special master decisions concerning the PSC’s second theory were
similarly comprehensive.

        All told, the 11 lengthy written rulings by the special masters, the judges of the U.S.
Court of Federal Claims, and the panels of the U.S. Court of Appeals for the Federal Circuit
unanimously rejected the petitioners’ claims, finding no persuasive evidence that either the
MMR vaccine or thimerosal-containing vaccines could contribute in any way to the causation of
autism.

         The proceedings in the six “test cases” concluded in 2010. Thereafter, the petitioners in
this case, and the petitioners in other cases within the OAP, were instructed to decide how to
proceed with their own claims. The vast majority of those autism petitioners elected either to
withdraw their claims or to request that the special master file a decision denying their claim on
the written record, resulting in a decision rejecting the petitioner’s claim for lack of support.
However, a small minority of the autism petitioners elected to continue to pursue their cases,
seeking other causation theories and/or other expert witnesses. A few such cases have gone to
trial before a special master, and in the cases of this type decided thus far, all have resulted in
rejection of petitioners’ claims that vaccines played a role in causing their child’s autism. See,
e.g., Henderson v. Sec’y of Health & Human Servs., No. 09-616V, 2012 WL 5194060 (Fed. Cl.
Spec. Mstr. Sept. 28, 2012) (autism not caused by pneumococcal vaccination); Franklin v. Sec’y
of Health & Human Servs., No. 99-855V, 2013 WL 3755954 (Fed. Cl. Spec. Mstr. May 16,
2013) (MMR and other vaccines found not to contribute to autism); Coombs v. Sec’y of Health
& Human Servs., No. 08-818V, 2014 WL 1677584 (Fed. Cl. Spec. Mstr. Apr. 8, 2014) (autism
not caused by MMR or Varivax vaccines); Blake v. Sec’y of Health & Human Servs., No. 03-
31V, 2014 WL 2769979 (Fed. Cl. Spec. Mstr. May 21, 2014) (autism not caused by MMR

                                                 7
vaccination); Long v. Sec’y of Health & Human Servs., No. 08-792V, 2015 WL 1011740 (Fed.
Cl. Spec. Mstr. Feb. 19, 2015) (autism not caused by influenza vaccine); Brook v. Sec’y of
Health & Human Servs., No. 04-405V, 2015 WL 3799646 (Fed. Cl. Spec. Mstr. May 14, 2015)
(autism not caused by MMR or Varivax vaccines); Holt v. Sec’y of Health & Human Servs., No.
05-136V, 2015 WL 4381588 (Fed. Cl. Spec. Mstr. June 24, 2015) (autism not caused by
hepatitis B vaccine); Lehner v. Sec’y of Health & Human Servs., No. 08-554V, 2015 WL
5443461 (Fed. Cl. Spec. Mstr. July 22, 2015) (autism not caused by influenza vaccine); Miller v.
Sec’y of Health & Human Servs., No. 02-235V, 2015 WL 5456093 (Fed. Cl. Spec. Mstr. Aug.
18, 2015) (ASD not caused by combination of vaccines); Allen v Sec’y of Health & Human
Servs., No. 02-1237V, 2015 WL 6160215 (Fed. Cl. Spec. Mstr. Sept. 26, 2015) (autism not
caused by MMR vaccination); R.K. v. Sec’y of Health & Human Servs., No. 03-632V, 2015 WL
10911950 (Fed. Cl. Spec. Mstr. Sept. 28, 2015) (autism not caused by influenza vaccine), mot.
for rev. denied, 125 Fed. Cl. 57 (2016); Hardy v. Sec’y of Health & Human Servs., No. 08-108V,
2015 WL 7732603 (Fed. Cl. Spec. Mstr. Nov. 3, 2015) (autism not caused by several vaccines);
Sturdivant v. Sec’y of Health & Human Servs., No. 07-788V, 2016 WL 552529 (Fed. Cl. Spec.
Mstr. Jan. 21, 2016) (autism not caused by Hib and Prevnar vaccines); R.V. v. Sec’y of Health &
Human Servs., No. 08-504V, 2016 WL 3882519 (Fed. Cl. Spec. Mstr. Feb. 19, 2016) (autism not
caused by influenza vaccine), mot. for rev. denied, 127 Fed. Cl. 136 (2016); Murphy v. Sec’y of
Health & Human Servs., No. 05-1063V, 2016 WL 3034047 (Fed. Cl. Spec. Mstr. Apr. 25, 2016)
(autism not caused by DTaP or MMR vaccines).

        In addition, some autism causation claims have been rejected without trial, at times over
the petitioner’s objection, in light of the failure of the petitioner to file plausible proof of
vaccine-causation. See, e.g., Waddell v. Sec’y of Health & Human Servs., No. 10-316V, 2012
WL 4829291 (Fed. Cl. Spec. Mstr. Sept. 19, 2012) (autism not caused by MMR vaccination);
Fester v. Sec’y of Health & Human Servs., No. 10-243V, 2016 WL 1745436 (Fed. Cl. Spec.
Mstr. Apr. 7, 2016) (autism not caused by measles, mumps, rubella, and varicella (“MMRV”)
vaccine); Fresco v. Sec’y of Health & Human Servs., No. 06-469V, 2013 WL 364723 (Fed. Cl.
Spec. Mstr. Jan. 7, 2013) (autism not caused by multiple vaccines); Fesanco v. Sec’y of Health &
Human Servs., No. 02-1770V, 2010 WL 4955721 (Fed. Cl. Spec. Mstr. Nov. 9, 2010) (autism
not caused by multiple vaccines); Miller v. Sec’y of Health & Human Servs., No. 06-753V, 2012
WL 12507077 (Fed. Cl. Spec. Mstr. Sept. 25, 2012) (autism not caused by DTaP or MMR
vaccines); Pietrucha v. Sec’y of Health & Human Servs., No. 00-269V, 2014 WL 4538058 (Fed.
Cl. Spec. Mstr. Aug. 22, 2014) (autism not caused by multiple vaccines); Bushnell v. Sec’y of
Health & Human Servs., No. 02-1648V, 2015 WL 4099824 (Fed. Cl. Spec. Mstr. June 12, 2015)
(autism not caused by multiple vaccines); Bokmuller v. Sec’y of Health & Human Servs., No.
08-573V, 2015 WL 4467162 (Fed. Cl. Spec. Mstr. June 26, 2015) (autism not caused by multiple
vaccines); Canuto v. Sec’y of Health & Human Servs., No. 04-1128V, 2015 WL 9854939 (Fed.
Cl. Spec. Mstr. Dec. 18, 2015) (autism not caused by DTP and DTaP vaccines); Valle v. Sec’y of
Health & Human Servs., No. 02-220V, 2016 WL 2604782 (Fed. Cl. Spec. Mstr. Apr. 13, 2016)
(autism not caused by DTaP vaccine). Judges of this court have affirmed the practice of
dismissal without trial in such cases. E.g., Fesanco v. Sec’y of Health & Human Servs., 99 Fed.
Cl. 28 (2011) (Chief Judge Braden affirming).




                                               8
        In none of the rulings since the test cases has a special master or judge found any merit in
an allegation that any vaccine can cause autism. 15

           b. Procedural History Specific to This Case

       Petitioners filed their petition on January 4, 2002. The initial status conference was held
on February 6, 2002, and respondent filed a Rule 4(b) Report on June 3, 2002. 16 Respondent
requested additional medical records, and petitioners were ordered to file those records. Resp. R.
4(b) Rept. at 2-3. A Rule 5 conference was held on June 20, 2002.

       Petitioners filed additional exhibits on November 27, 2002, including an expert report
from Dr. Harold Buttram and additional medical records. Notice of Filing dated November 27,
2002 (ECF No. 17). On December 16, 2002, respondent filed an expert report from Dr. Arnold
Gale, and petitioners filed a supplemental expert report from Dr. Buttram on February 19, 2003.
Respondent filed a supplemental expert report from Dr. Gale on April 1, 2003. 17 During a status


15
  I note that during the years since the “test cases” were decided, Vaccine Act compensation was
granted in only two cases involving vaccinees suffering from ASDs. But in neither of those
cases did respondent concede, nor did a special master find, that there was any causation-in-fact
connection between a vaccination and the vaccinee’s ASD. Instead, in both cases it was
conceded or found that the vaccinee displayed the symptoms of a Table Injury within the Table
time frame after vaccination and causation under the Act was presumed.

In Poling, the presiding special master clarified that the family was compensated because the
respondent conceded that the Poling child had suffered a Table Injury – not because respondent
or the special master had concluded that any vaccination had contributed to causing or
aggravating the child’s ASD. See Poling v. Sec’y of Health & Human Servs., No. 02-1466V,
2011 WL 678559, at *1 (Fed. Cl. Spec. Mstr. Jan. 28, 2011) (a fees decision noting specifically
that the case was compensated as a Table Injury).

Second, in Wright v. Sec’y of Health & Human Servs., No. 12-423V, 2015 WL 6665600 (Fed.
Cl. Spec. Mstr. Sept. 21, 2015), Special Master Vowell concluded that a child, later diagnosed
with ASD, suffered a Table Injury after a vaccination. However, she stressed that she was not
finding that the vaccinee’s ASD in that case was caused-in-fact by the vaccination – to the
contrary, she specifically found that the evidence in that case did not support a causation-in-fact
claim, going so far as to remark that the petitioners’ causation-in-fact theory in that case was
“absurd.” Id. at *2. The compensation of these two cases thus does not afford any support to the
notion that vaccinations can contribute to the causation of autism.
16
  Respondent stated in her Rule 4(b) Report that because the medical records were not complete,
she could not provide a full evaluation of the merits of petitioners’ case. Resp. R. 4(b) Rept.
dated June 3, 2002 (ECF No. 8) at 9, 12.
17
  The reports of Drs. Buttram and Gale were superseded when petitioners later introduced and
pursued a theory by Dr. Theresa Deisher. In their Joint Prehearing Submission, the parties


                                                 9
conference on March 27, 2003, petitioners requested that the case be stayed pending the
completion of the OAP. 18 See Order dated April 15, 2003 (ECF No. 25) at 1. On May 16, 2003,
a formal notice was filed to inform the parties that the statutory time period for the special
master’s issuance of a decision in the case had expired. Petitioners filed a response to the formal
notice on June 24, 2003, stating that they wished to remain in the Program. Resp. to Formal
Notice dated June 24, 2003 (ECF No. 27). Petitioners further stated that they wished for their
case to be “consolidated with the omnibus autism litigation for initial determination of
causation.” Id. at 2.

         After June 24, 2003, no filings were made in the case until January 15, 2008, on which
date petitioners were ordered to file the remainder of the medical records and a statement of
whether their claim should proceed in an omnibus proceeding. Order dated January 15, 2008
(ECF No. 29). The order provided an overview of the OAP to date, and petitioners were ordered
to file completed records in anticipation of the forthcoming OAP rulings. Id. at 1-2. The Order
also explained the two-stage approach for filing medical records. First, petitioners were required
to provide evidence that the “first symptom or manifestation of onset” occurred within 36
months of the vaccine. Id. at 3; see also 42 U.S.C. § 300aa-16(a)(2). Assuming this first
requirement could be met, petitioners would then proceed to gather and file all medical records
from V.J.M.’s birth through either the date of the petition’s filing or the date of V.J.M.’s initial
diagnosis of autism, whichever was later. Order dated Jan. 15, 2008 (ECF No. 29) at 5.

        On March 17, 2008, respondent filed a Statement Regarding Jurisdiction and
Appropriateness of Proceeding within the Court’s OAP. Resp. Statement dated Mar. 17, 2008
(ECF No. 31). Respondent stated that after an initial review of the record, petitioners’ claims
appeared to have met the 36 month onset requirement. Id. at 2. On April 21, 2009, petitioners
filed a Notice of Compliance that phase one medical records production was complete. Notice of
Compliance dated Apr. 21, 2009 (ECF No. 35). Petitioners also filed a statement that
“[V.J.M.’s] claim is that he became autistic following an MMR vaccination. This action belongs
in the Omnibus Autism Proceeding.” Statement dated Apr. 27, 2009 (ECF No. 36). This case
was converted to electronic case filing (“ECF”) on March 24, 2011.

        Petitioners filed an amended petition on June 10, 2011, which included additional details
regarding V.J.M.’s medical history and diagnosis. Am. Pet. dated June 10, 2011 (ECF No. 42).
The petition states that V.J.M. was diagnosed with PDD by Dr. Ruben Rosenblatt on July 20,
2000. Id. at 3. Petitioners claimed that V.J.M. had an adverse reaction to one or more of the
vaccines he received on January 19, 1999, which caused him to develop autism. Id. at 4. They
also alleged that the MMR and varicella vaccines contained human embryonic tissue. Id. at 5.
Petitioners claimed that the human DNA contained in these vaccines played a role in V.J.M.’s


confirmed that “[t]he parties agree that the sole issue to be resolved through the upcoming
hearing is whether Dr. Deisher’s theory of vaccine-caused autism meets petitioners’ burden
under [P]rong [O]ne of Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed.
Cir. 2005).” See Joint Prehearing Submission (ECF No. 223) at 1.
18
     For a full explanation of the OAP, see supra Omnibus Autism Proceeding at 6-9.


                                                10
development of ASD. Id. Petitioners filed a status report on October 26, 2011, which listed
several other Program cases alleging the same medical theory of causation. Status Report dated
Oct. 26, 2011 (ECF No. 44) at 1.

         On January 3, 2012, petitioners filed an expert report and supporting materials by
Theresa Ann Deisher, Ph.D.19 On February 3, 2012, petitioners filed their first motion to compel
access to the Vaccine Safety Datalink (“VSD”). Pet. Mot. to Compel dated Feb. 3, 2012 (ECF
No. 46). Petitioners sought access to data contained in the VSD in order to perform research
related to their medical theory of causation. Petitioners argued that access to the VSD would
allow their expert witness to independently corroborate her statistical data. Id. at 3. Dr. Deisher
testified that she made several unsuccessful attempts to gain access to the VSD, and some of her
efforts pre-dated her involvement in this case. Tr. 245. After she became involved in the case, in
2011, she made another unsuccessful attempt to access the VSD. Id. Further, her team applied
for an NIH grant to help fund her research on the VSD, but the application was denied. Id. She
also stated that she applied for access to government maintained databases on ASD in two
European countries but that her team was denied access to these databases as well. Tr. 97.

        Petitioners filed a second motion to compel on March 2, 2012, further seeking
“documents in the custody and control of the respond [sic] which are reasonable and necessary to
a fair and informed determination on the merits of this matter.” Mot. to Compel dated Mar. 2,
2012 (ECF No. 50) at 1. Respondent and other non-party managed care organizations (“MCOs”)
filed responses opposing petitioners’ motions on March 30, 2012. Resp. to Mot. to Compel
dated Mar. 30, 2012 (ECF No. 58); Resp. to Mot. to Compel dated March 30, 2012 (ECF No.
60). Respondent and the non-party MCOs made three essential arguments against petitioners’
motions to compel. First, they argued that the proposed research investigation for which the data
was requested was a litigation-driven and results-oriented study. Next, they argued that Dr.
Deisher was not an independent and disinterested researcher, because her hypothesis was
informed by an anti-stem cell research agenda. Third, respondent stated that Dr. Deisher’s
proposed study did not meet criteria for institutional board review and thus would not be reliable.
Scheduling Order dated Feb. 24, 2012 (ECF No. 49) at 2. Petitioners filed a reply to respondent
and the MCOs’ responses on April 13, 2012. Pet. Reply dated Apr. 13, 2012 (ECF No. 63).

         Respondent filed a response to petitioners’ second motion to compel on June 14, 2012.
Resp. to Mot. to Compel dated June 14, 2012 (ECF No. 65). Respondent argued that petitioners’
requests were not reasonable or necessary, in accordance with the standards of the Program. Id.
at 3. Respondent further argued that the discovery was irrelevant to petitioners’ medical theory.
Id. at 5. Petitioners filed a reply on July 14, 2012. Pet. Reply dated July 14, 2012 (ECF No. 69).
The litigation over petitioners’ motions to compel continued throughout the remainder of 2012
and 2013. The presiding special master denied petitioners’ motion to compel access to the VSD,
their motion for authority to issue subpoenae to the MCOs, and their motion to compel
production of Food and Drug Administration (“FDA”) documents. [redacted] v. Sec’y of Health
& Human Servs., No. 02-10V, 2013 WL 3368236 (Fed. Cl. Spec. Mstr. June 12, 2013).



19
 Petitioners’ Notice of Intent to File on CD was previously filed on December 20, 2011. See
ECF No. 45.
                                                11
Petitioners’ motion for reconsideration of the special master’s Order was also denied. [redacted],
2013 WL 6038670 (Fed. Cl. Oct. 24, 2013).

        Petitioners filed a supplemental report from Dr. Deisher on December 20, 2013. Notice
of Filing dated Dec. 20, 2013 (ECF No. 95). On March 14, 2014, petitioners filed a status report
in which they identified 13 other Program cases which alleged the same medical theory of
causation. Status Rept. dated Mar. 14, 2014 (ECF No. 106). Petitioners filed an expert report
from Dr. William Toffler on March 31, 2014, and a supplemental letter from Dr. Toffler on May
9, 2014. 20 Notice of Compliance dated Mar. 31, 2014 (ECF No. 110); Notice of Filing dated
May 9, 2014 (ECF No. 113). I held a status conference in the case on February 9, 2015, during
which petitioners identified J.M. et al. as the lead case in the mini-omnibus. Scheduling Order
dated Feb. 10, 2015 (ECF No. 130) at 2. Due to conflicts in Dr. Deisher’s schedule, the hearing
originally scheduled for late 2015 was rescheduled for March 2016. Status Rept. dated May 15,
2015 (ECF No. 134). Petitioners filed a number of medical records and additional medical
literature throughout the remainder of 2015. Petitioners also filed an expert report from Dr.
Karin Burkhard on January 15, 2016. Petitioners also filed a motion for interim fees, and I
issued a decision partially granting that request. [redacted] v. Sec’y of Health & Human Servs.,
No. 02-10V, 2016 WL 720969 (Fed. Cl. Spec. Mstr. Feb. 4, 2016).

       Petitioners filed their prehearing submissions on January 15, 2016. Pet. Prehearing Brief
(“Prehrg Br.”) dated Jan. 15, 2016 (ECF No. 202). Respondent filed her prehearing submissions
on February 8, 2016. Prehrg Submissions dated Feb. 8, 2016 (ECF No. 222). An entitlement
hearing was held on March 7-8, 2016, in Seattle, Washington. The hearing continued in
Washington, D.C. on March 10-11, 2016. I heard rebuttal testimony from Dr. Deisher and Dr.
Burkhard in Washington, D.C. on May 6, 2016.

        On May 5, 2016, the day before the hearing on May 6, 2016, petitioners filed a motion to
issue subpoena to obtain the testimony of Dr. William Thompson, an epidemiologist employed
by the CDC, and to recall Dr. Fallin, one of respondent’s expert witnesses. Pet. Mot. dated May
5, 2016 (ECF No. 261). Respondent filed a response opposing the motion on June 16, 2016,
arguing that such testimony was unnecessary and irrelevant to the determination of vaccine
causation. Resp. Res. dated June 16, 2016 (ECF No. 264). Petitioners filed a reply on July 7,
2016. Pet. Reply dated July 7, 2016 (ECF No. 268). On August 30, 2016, I issued an Order
denying petitioners’ motion to issue subpoena but granting petitioners’ motion to file
documentation. [redacted], 2016 WL 5362878 (Fed. Cl. Aug. 30, 2016).

        On August 1, 2016, respondent filed a supplemental expert report from Dr. Arking in
response to the rebuttal testimony presented by Dr. Deisher and Dr. Burkhard. Notice of Filing
dated Aug. 1, 2016 (ECF No. 270). Petitioners then filed a reply to Dr. Arking’s supplemental
report on September 9, 2016. The parties agreed that post hearing briefs were not necessary, and
the evidentiary record was closed on September 9, 2016.



20
  Petitioners did not call Dr. Toffler to testify at the hearing in this case. See Order dated March
28, 2016 (ECF No. 254). Although not discussed herein, I have nonetheless reviewed his written
opinion, and I do not find it to offer support to petitioners’ causation theories. See Pet. Ex. 263.
                                                12
           The case is now ripe for adjudication.

     IV.      Issue to be Decided

        The sole issue to be decided in this mini-omnibus proceeding is whether Dr. Deisher’s
theory of vaccine-caused autism meets petitioners’ burden under Prong One of Althen, 418 F.3d
at 1278. Joint Prhrg Submission dated Feb. 8, 2016 (ECF No. 223), at 1. This Decision is
therefore limited to an evaluation of whether petitioners have met their burden under Althen
Prong One.

     V.       Standards for Adjudication

        The Vaccine Act established the Program to compensate vaccine-related injuries and
deaths. 42 U.S.C. § 300aa-10(a). “Congress designed the Vaccine Program to supplement the
state law civil tort system as a simple, fair and expeditious means for compensating vaccine-
related injured persons. The Program was established to award ‘vaccine-injured persons quickly,
easily, and with certainty and generosity.’” Rooks v. Sec’y of Health & Human Servs. 35 Fed.
Cl. 1, 7 (1996) (quoting H.R. REP. No. 99-908, at 3 (1986), as reprinted in 1986 U.S.C.C.A.N.
6287, 6344).

        To receive compensation under the Program, petitioners must prove either: (1) that
V.J.M. suffered a “Table Injury”—i.e., an injury listed on the Vaccine Injury Table—
corresponding to a vaccine that he received, 21 or (2) that V.J.M. suffered an injury that was
actually caused by the vaccine (or vaccines) he received. See §§ 300aa-13(a)(1)(A) and
11(c)(1); Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1319-20 (Fed. Cir.
2006).



21
  Although petitioners have not contended that V.J.M. suffered a Table encephalopathy, out of
an abundance of caution, I have thoroughly analyzed the issue and concluded that V.J.M.’s
symptoms cannot properly be classified as a Table encephalopathy. As explained in Waddell,
2012 WL 4829291, “[t]he scope of the medical term ‘encephalopathy’ is more expansive than
the narrower, statutory definition set forth in the Table.” Id.*12 (referencing Hazelhurst, 2009
WL 332306, at *26-29). The Qualifications and Aids to Interpretation (“QAI”) definition of
acute encephalopathy simply does not encompass every type of brain dysfunction to which the
broader meaning of “encephalopathy” applies.

To establish an MMR-Table encephalopathy, petitioners would have to demonstrate that V.J.M.
suffered an “encephalopathy” as defined by the QAI section to the Vaccine Injury Table within
five to 15 days of his MMR vaccination. 42 C.F.R. § 100.3(b). According to the QAI, a
vaccinee is considered to have suffered a Table encephalopathy if the vaccine manifests an injury
encompassed in the definition of an acute encephalopathy within the appropriate time period, and
if a chronic encephalopathy is present for more than six months after the immunization. 42
C.F.R. § 100.3(b)(2). I note that V.J.M.’s medical records fail to demonstrate evidence of such
an encephalopathy.


                                                    13
       Because petitioners cannot show that V.J.M. suffered a Table injury, they must prove that
a vaccine that he received caused his injury. To do so, petitioners must establish, by
preponderant evidence, a medical theory causally connecting a vaccine and V.J.M.’s injury
(“Althen Prong One”). Althen, 418 F.3d at1278; § 300aa–13(a)(1) (requiring proof by a
preponderance of the evidence).

     VI.   Expert Opinions

           a. Experts’ Education, Background, and Experience

                   i. Petitioners’ Experts

                          1. Dr. Theresa Deisher, Ph.D.

      Dr. Theresa Deisher holds a Bachelor of Arts in Human Biology and a Ph.D. in
Molecular and Cellular Physiology, both from Stanford University. Pet. Ex. 12 at 2. She also
completed a post-doctoral fellowship in Pathology/Hematology at the University of Washington.
Id.

         Dr. Deisher’s career has been predominantly focused on commercial biotechnology, and
her research has led to the development of 22 patents. Pet. Ex. 12 at 2. From 1988 to 1990, she
worked as a research associate for Genentech, Inc., in the area of cardiovascular pharmacology.
Id. at 4. From 1993 to 1995, she worked as a research scientist for Repligen Corporation in the
Inflammation Department. Id. From 1995 to 1998, Dr. Deisher worked as a scientist and
project leader for ZymoGenetics, Inc., where she directed a research program focused on the
discovery of cardioprotective compounds for ischemic or cytotoxic damage. Id. at 3. 22 From
October 2000 to July 2002, Dr. Deisher worked as a senior staff scientist in the Vascular Biology
Department at Immunex Corporation, where she acted as a project leader on anti-thrombotics
and inflammation/myocardial repair. In July 2002, after Amgen, Inc. acquired Immunex, she
began working as a principal scientist in the Inflammation Department of Amgen, where part of
her work focused on the use of stem cell therapies for myocardial regeneration. Id. While there,
Dr. Deisher was the lead inventor on a patent for the use of stem cells in cardiac repair. Id.
From September 2006 to October 2007, she served as the Vice President of Research and
Development for CellCyte Genetics Corporation. Id.

       Dr. Deisher is currently the President of Sound Choice Pharmaceutical Institute (“Sound
Choice”), which she founded in January 2008. Pet. Ex. 12 at 2. She is also the CEO, Founder,
and Research and Development Director of AVM Biotechnology, LLC (“AVM”).23 Id. The


22
  Dr. Deisher’s work with ZymoGenetics in the areas of catecholamine or anthracycline
administration led “to the discovery of a novel regenerative growth factor (licensed to Serono for
development) and to the identification of adult cardiac stem cells.” Pet. Ex. 12 at 3.
23
  According to Dr. Deisher, AVM is “[d]edicated to safe, effective, affordable and ethical
human therapeutics, focusing initially on regenerative medicine and vaccinations.” Pet. Ex. 12 at


                                               14
initial focus of AVM “was to develop drugs that optimized the activity of stem cells outside of
the blood-forming cells.” 24 Tr. 34. According to Dr. Deisher, Amgen was already selling stem
cell optimization drugs at that time, but AMV was formed to create drugs that would improve
stem cell effectiveness for heart, pancreatic, or liver repairs. Id. at 35. AMV’s future business
plan also included developing an alternative to vaccines that use human cell lines.25 Id. The
company’s mission statement is focused on doing research “that would not exploit or harm
another human being,” including human fetuses.

        Sound Choice Pharmaceuticals is a non-profit organization “whose purpose is to inform
… pediatricians about the human exploitation that goes on in biomedical research and in the
name of biomedical progress, and to conduct research into the autism human-fetal-manufactured
contaminants in vaccines link.” Tr. 45. 26 Dr. Deisher decided to form Sound Choice due to the
“compelling association” between autism and vaccines. Id. She states, “The association was so
compelling, and the known biology of the potential dangers accumulated over decades from
different scientific fields was so well established that it would be unconscionable to ignore this
association.” Id.

        Dr. Deisher testified, “The publication of the articles we pursued largely at your [John
McHugh’s] insistence. You … definitely wanted that data to be published, and so we did pursue
that.” Id. Dr. Deisher has written papers focused on various aspects of stem cell treatments and
research. 27 Pet. Ex. 12 at 5-8. She has also given speeches and lectures to religious, political,


2.
24
  Dr. Deisher testified that while she was working at ZymoGenetics, she was involved in a
research project to develop heart muscle cell lines that could be continuously cultured. Tr. 23.
At that time, researchers at ZymoGenetics were using mice to try to develop these cell lines. Dr.
Deisher testified that she was the first to isolate pluripotent stem cells from adult mouse hearts –
something which had previously been thought as impossible. Id. at 25-26. She further defined
pluripotent stem cells as “a stem cell that can give rise to any type of cell in the body.” Id. Dr.
Deisher stated that her discovery resulted in a “huge controversy,” because scientists previously
believed that adult stem cells did not exist outside of the blood-forming cells. Id.
25
  To date, AVM has not produced any such alternative vaccines. Tr. 312. AVM was
unsuccessful in developing vaccines that did not use human cell lines, and thus this goal was
dropped from its business plan by 2011. Id. at 229; 312.
26
  Sound Choice Pharmaceutical Institute is “[c]ommitted to providing education, scientific
research, development and resources to encourage safe and moral medicines and therapeutics.”
Pet. Ex. 12 at 2.
27
   Dr. Deisher did not disclose a conflict of interest in her 2015 article in the Journal of Public
Health regarding the potential for vaccines derived from human fetal stem cell lines to cause
ASD. Tr. 225. Dr. Deisher testified that at the time the article was published, she was attending
to urgent personal family business and that the potential conflict of interest between her research


                                                 15
and student-led organizations regarding the use of stem cells in scientific manufacturing and
research. Id.

                           2. Dr. Karin Burkhard, M.D.

        Dr. Karin Burkhard testified on behalf of petitioners during the hearing in Washington,
D.C., on March 10-11, 2016, and she also offered rebuttal testimony on May 6, 2016. Dr.
Burkhard has a Bachelor of Arts from the New School for Social Research in New York, New
York, and a M.D. from Dartmouth Medical School in Hanover, New Hampshire. Pet. Ex. 475 at
1. 28 She completed her post graduate adult psychiatry residency at Beth Israel Medical Center
from 1984-1987, and afterward completed a Child Psychiatry Fellowship from 1987-1989 at the
Long Island Jewish Medical Center.

        From 1988-1990, Dr. Burkhard worked as a staff psychiatrist and consultant at Pride of
Judea Mental Health Center in Douglaston, New York. Pet. Ex. 475 at 1. In 1989, she began
working as a staff psychiatrist and consultant at St. Mary’s Children and Family Services in
Syosset, New York, where she worked until 1993. Id. In 1989, she also entered private practice
in child, adolescent, and adult psychiatry, where she has worked ever since. Id.

                   ii. Respondent’s Experts

                           1. Dr. M. Daniele Fallin, Ph.D.

       Dr. M. Daniele Fallin testified on behalf of respondent during the hearing in Washington,
D.C., on March 11, 2016, as an expert in autism epidemiology. Dr. Fallin received her Bachelor
of Science in Zoology at the University of Florida, and she was also a doctoral student in the
genetic epidemiology of Alzheimer’s disease at the University of South Florida from 1995-1998.
Resp. Ex. K at 1. She received her Ph.D. in Genetic Epidemiology from Case Western Reserve
University in Cleveland, Ohio. Id.

       Dr. Fallin is a professor at Johns Hopkins University in both the School of Medicine and
the Bloomberg School of Public Health. She holds a joint appointment in the Departments of
Medicine, Biostatistics, and Epidemiology, and she is the Director of the Wendy Klag Center for
Autism and Developmental Disabilities. Resp. Ex. K at 1-2. She also serves on the advisory
board for Autism Speaks and as a committee co-chair for the International Society for Autism
Research. Id. at 3. She co-organized the Autism Speaks Conference on Epigenetics in Autism in
2011, and she has spoken on a number of panels on autism and genetics. Id. at 3-4.




on alternatives to fetal cell manufactured vaccines and her ownership of AVM pharmaceuticals
was not apparent to her or her research team. She stated that the team pursued the research
independent of any legal claims. Id. However, Dr. Deisher further stated that “theoretically,
[there] is a potential conflict of interest [that] probably should have been disclosed.” Id. at 226.
28
     Dr. Burkhard’s CV was filed on December 29, 2015, at CM/ECF No. 198-1.
                                                 16
        Dr. Fallin is an editor for numerous medical journals, including Epidemiology, Genetic
Epidemiology, and the American Journal of Human Genetics. Id. at 4. She has published over
160 articles in the areas of genetics, epigenetics, Alzheimer’s disease, and autism, and she has
co-authored several book chapters. Id. at 4-24. Dr. Fallin also has extensive teaching experience
and serves as an advisor for Ph.D. students, public health masters’ students, and post-doctoral
fellows. Id. at 25-27. She has taught courses on Public Mental Health, Autism Spectrum
Disorder and Public Health, Introduction to Genetic Epidemiology, and Genetic Epidemiology in
Populations, just to name a few. Id. at 33. Dr. Fallin has received a number of grants to do
genetic research on autism. She has received awards to do research as part of the Study to
Explore Early Development (“SEED”), as well as the Early Autism Risk Longitudinal
Investigation (“EARLI”) network. Resp. Ex. K at 37-41.

        Dr. Fallin described two autism epidemiology studies for which she is the main
investigator, which are funded by the Centers for Disease Control (“CDC”) and the National
Institutes of Health (“NIH”), respectively. Tr. 652. The first study is called SEED, which is a
national case control study. Dr. Fallin explained, “There are six sites nationally that go out and
recruit children between ages two and five who have autism, and then also recruit children who
have a non-autistic developmental disability, as well as children from the same birth cohorts and
geographic regions who are typically developing.” Id. at 652-53. Researchers collect bio
samples from parents and children in an effort to understand both environmental as well as
genetic components of autism. Id. at 653.

        The second autism study which Dr. Fallin leads is EARLI, which is a pregnancy cohort 29
study. Tr. 653. The study follows pregnant women and fetuses in four different sites around the
country in an effort to look at the interplay between genetics and the environment in a child’s
risk for developing autism. Id.

                           2. Dr. Neal Halsey, M.D.

        Dr. Neal Halsey testified on behalf of respondent during the hearing in Washington, D.C.,
on March 10, 2016. Dr. Halsey received his Bachelor of Science and a Doctor of Medicine
from the University of Wisconsin. Resp. Ex. M at 1. He completed an internship in pediatrics at
the Center for Health Sciences in Madison, Wisconsin, and he completed a residency in
pediatrics at the University of Colorado Medical Center in Denver, Colorado. Id. From 1975 –
1978, he worked at the CDC in Atlanta, Georgia, first as an epidemic intelligence service officer
and then as a preventive medicine resident. Id. Dr. Halsey also completed a fellowship at the
University of Colorado Medical Center in pediatric infectious diseases from 1978-1980. He is
licensed to practice medicine in the State of Maryland, and he was licensed by the National
Board of Medical Examiners in 1972. Id. He is board certified by the American Board of
Pediatrics and a Diplomat in Pediatric Infectious Diseases. Id.



29
  In epidemiology, a “cohort” is a “group of individuals who share a common characteristic,
e.g., all of the individuals born in one year (a birth cohort) …. The term [ ] indicates observation
of the individuals over time.” DORLAND’S ILLUSTRATED MEDICAL DICTIONARY 382 (32d ed.
2012).
                                                 17
        Dr. Halsey is a professor in the Department of International Health at Johns Hopkins
University, Bloomberg School of Public Health, in Baltimore, Maryland, and the Director of the
Institute for Vaccine Safety at the Bloomberg School of Public Health. Resp. Ex. M at 1. From
1999 to 2011, he served as the Co-Director for the Center for Disease Studies and Control in
Guatemala City, Guatemala, and he was the Director of the Division of Disease Control at Johns
Hopkins from 1985-2002. Id. at 2. He has served on a number of advisory panels and
committees, including the Advisory Board of the Albert B. Sabin Vaccine Foundation, the
Scientific Advisory Committee at the Johns Hopkins Autoimmune Disease Center, and the
Advisory Board for the Immunization Action Coalition. Id. at 3. Dr. Halsey has served as editor,
advisor, and committee chair for five books, he has been on the editorial board of four medical
journals, and he has participated in a number of manuscript reviews since 1981. Id. at 5-6. In
2015, he received the Stanley A. Plotkin Lecture in Vaccinology Award from the Pediatric
Infectious Disease Society. Id. at 6. He has also published over 230 articles in the areas of
pediatrics, immunization, and infectious diseases. Id. at 8-28. Dr. Halsey was admitted as an
expert in the fields of pediatric medicine, pediatric infectious disease, medical epidemiology, and
vaccine safety. Tr. 431.

                          3. Dr. Dan Arking, Ph.D.

       Dr. Dan Arking testified on behalf of respondent during the hearing in Washington, D.C.,
on March 10-11, 2016. Dr. Arking has a Bachelor of Science in Molecular Biology and Genetics
from the University of Maryland in College Park, Maryland. Resp. Ex. I at 1. He holds a Ph.D.
in Human Genetics from the Johns Hopkins University School of Medicine in Baltimore,
Maryland, and he completed a post-doctoral fellowship in complex disease genetics in the
McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. Id.

        From 2007-2011, Dr. Arking served as an assistant professor at the McKusick-Nathans
Institute of Genetic Medicine and Department of Medicine, Institute of Cardiology at Johns
Hopkins. Resp. Ex. I at 1. He is currently an associate professor at the McKusick-Nathans
Institute, and he also serves as affiliated faculty for the Johns Hopkins Institute for Data-
Intensive Engineering and Science. Id. He is a faculty member of the Wendy Klag Center for
Autism and Developmental Disabilities at the Johns Hopkins Bloomberg School of Public
Health. Id. Dr. Arking has published over 100 articles in the areas of genetics, genetic variation,
and autism, and he has made contributions to several patents and copyrights. Id. at 1-14. He has
received a number of research grants for various studies, including grants from the Autism
Center of Excellence, the American Heart Association, and the Simons Foundation Autism
Research Initiative. Id. at 14-15. Dr. Arking serves as the Co-Director of the Johns Hopkins
Claude D. Pepper Older Americans Independence Center Biological Mechanisms Core, and he
has served as a member of a number of institutional committees. Id. at 16-18. He also currently
serves as an editor for two academic journals and participates in a number of advisory
committees, including the Simons Foundation Autism Research Initiative Gene Advisory Board
and the Scientific Review Board. Id. at 18-19.

       Dr. Arking conducts large-scale genetic studies to identify and distinguish particular
genetic traits for autism. Tr. 563. His research team at Johns Hopkins focused on mapping the



                                                18
entire genome 30 of autistic patients to look at gene variances. Id. He testified, “When I started
up my own lab, I wanted to incorporate more than just genetics, so one of the things we focused
on is getting access to brains from autistic individuals and match controls.” Id. The lab he began
at Johns Hopkins in 2005 focuses on combining “traditional genetics” with the study of the brain,
including gene expression. Id. at 563-64. 31

     VII.   Autism Spectrum Disorders

        The terms “autism” and “autism spectrum disorders” are used to describe a set of
“complex neurodevelopmental disorders characterized by a combination of deficits in
communication and social interaction and repetitive, stereotyped behavior and interest.” Pet. Ex.
14 at 2; 32 Pet. Ex. 27; 33 Pet. Ex. 34 at 2. 34 There is no definitive diagnostic test, and thus,
diagnosis is based on behavior, using the various criteria, tests, 35 and the Diagnostic and
Statistical Manual of Mental Disorders (“DSM”). 36 See, e.g. Snyder, 2009 WL 332044, at *39


30
  The genome is defined as “the entirety of the genetic information encoded by the nucleotide
sequence of an organism, cell, organelle, or virus; it is DNA in eukaryotes and prokaryotes, and
DNA or RNA in viruses. In a human being, the genome size is approximately [three] billion
base pairs of DNA and approximately 25,000 genes.” DORLAND’S at 771.
31
  Dr. Arking’s lab performs research on ASD as well as in the areas of cardiovascular genetics
and frailty in aging. Tr. 564.
32
  Hjoris O. Alottodir, Association of Family History of Autoimmune Disease and ASDs, 124
PEDIATRICS 687-94 (2009) [Pet. Ex. 14].
33
  Michael E. McDonald & John F. Paul, Timing of Increased Autistic Disorder Cumulative
Incidence, 44 ENVIRON. SCI. TECHNOL. 2112 (2010) [Pet. Ex. 27, 432].
34
  Helen V. Ratajczak, Theoretical Aspects of Autism: Causes – A Review, 8 J.
IMMUNOTOXICOLOGY 68-79 (2011) [Pet. Ex. 34].
35
   Such tests include the Childhood Autism Rating Scale (“CARS”), a tool used to identify
autism in children that includes classifying their symptoms on a numbered scale. See, e.g.
Emanuela Rellini et al., Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist
(ABC) Correspondence and Conflicts with DSM-IV Criteria in Diagnosis of Autism, 34 J.
AUTISM AND DEV. DISORDERS 703 (Dec. 2004) [Pet Ex. 461]; But cf. Synder, 2009 WL 332044,
at *39 (noting that CARS “has been used for many years,” but also noting more recent rating
systems such as the Autism Diagnostic Interview-Revised (“ADI-R”) and the Autism Diagnostic
Observational Schedule–Generic (“ADOS-G”)).
36
  The DSM is published by the American Psychiatric Association. It comprises “a classification
of mental disorders with associated criteria designed to facilitate more reliable diagnoses of these
disorders.” AMERICAN PSYCHIATRIC ASSOCIATION, DIAGNOSTIC AND STATISTICAL MANUAL OF
MENTAL DISORDERS xli (5th ed. 2013). First published in 1952, the DSM “has become a


                                                19
(noting that “specialized checklists and interview instruments are used to evaluate ASD” and that
“most autism specialists use one or more of the checklists in making a diagnosis.”); Hazlehurst,
2009 WL 332306, at *29 (noting that “[a]n evaluating clinician may select the method of
assessing a child's symptoms, choosing either a clinical examination or one of the standardized
checklists that afford a more standardized observation or measure, or a developmental interview
that guides the clinician in the collection of informative symptoms and then can be used to apply
DSM–IV criteria in an algorithmic manner to reach a diagnostic conclusion. The diagnosis of an
ASD is based entirely on abnormalities in behavior and development observed by clinicians and
reported by parents. There are no biological markers or medical tests that are diagnostic of an
ASD.” (internal citations omitted).)

        Despite extensive investigation, the causes of autism remain elusive. Generally, autism 37
is thought to be a “disruption of brain development caused by a combination of genes and
environment.” Pet. Ex. 15 at 2. 38 Well-funded, large scale and highly technical studies have
revealed considerable information on the genetic causes. Id. Current research suggests that
1,000 genes, or more, may contribute to the cause of ASDs. Resp. Ex. J47 at 9. 39
Approximately 50-56 percent of ASDs are due to inherited genetics, five to 10 percent are due to
de novo genetic mutations,40 and the other 40 percent of cases have unknown causes. Tr. 572,
613.

        As for environmental causes, research in neuroanatomy based on autopsies and imaging
studies suggest that the prenatal time frame is the “window of susceptibility” for causation. Tr.
660-61. See also Resp.’s Ex. J3 at 1.41 Environmental factors are believed to affect the fetus
during the prenatal period. Tr. 661. In addition to neuroanatomical evidence, genetic research
supports the prenatal period as important with regard to causation. Id. at 663.


standard of reference for clinical practice in the mental health field.” Id.
37
   Petitioner’s expert, Dr. Deisher, characterizes autism as “an encephalopathy.” See Pet Ex. 10
at 3; Pet Ex. 76 at 41. V.J.M. received the MMR vaccine at issue on January 19, 1999, and his
medical records do not reveal any signs or symptoms consistent with any brain injury after
vaccination. The first mention of any developmental issue was not until June 21, 2000. Pet. Ex.
B at 27, 30-31. There is no evidence to support a finding that V.J.M. suffered either a Table or
non-Table encephalopathy.
38
     Nature Publishing Group, The Mind’s Tangled Web, 479 NATURE 1 (2011) [Pet. Ex. 15].
39
   Jeremy A. Willsey et al., Coexpression Networks Implicate Human Midfetal Deep Cortical
Projection Neurons in the Pathogenesis of Autism, 155 CELL 997 (2013) [Resp. Ex. J47].
40
   De novo mutations are defined as “a mutation observed in a child that is not observed in the
parent.” Tr. 573.
41
  Margaret L. Bauman, & Thomas L. Kemper, Neuroanatomic Observations of the Brain in
Autism: A Review and Future Directions, 23 INT. J. DEVL. NEUROSCIENCE 183 (2005) [Resp. Ex.
J3].


                                                 20
     VIII. Petitioners’ Theory of Causation 42

    Petitioners posit that residual human DNA 43 and/or retroviral fragments 44 found in three
vaccines, MMR II, varicella, and hepatitis A, serve as environmental triggers, and that exposure
to these vaccines accounts for the increase in the prevalence of autism. To develop her theory,
Dr. Deisher performed a study in which she purports to identify change points 45 as to autism


42
  Though this decision does not discuss every medical article that petitioners filed, I have
carefully reviewed and considered all of petitioners’ medical literature, as well as all other
documents filed in this case. See § 300aa-13(a)(1) (stating that the special master should
consider the “record as a whole”).
43
   Most biologicals, including vaccines, are produced within living cells in cell substrates,
typically resulting in final products that contain some residual cellular constituents. Ivana
Knezevic, et al., WHO Study Group on Cell Substrates for Production of Biologicals, Geneva,
Switzerland, 11-12 June 2007, 36 BIOLOGICALS 203 (2008) [Pet Ex. 136]. These residual
constituents include DNA from the substrate, which may be referred to variously as “residual
cellular DNA,” “cell contaminating residual DNA,” “anomalous DNA,” or simply as “cellular,”
or “residual” DNA. See, e.g., Pet Ex. 136 at 2; Pet. Ex. 34 at 1; Resp. Ex. L at 2; Pet. Ex. 42 at
3; Pet Ex. 10 at 13. Cell substrates can be used from a number of different sources. Cell
substrates commonly used in U.S. vaccine manufacturing include primary cells of avian or
monkey origin as well as primate diploid cell strains and a continuous cell line called the Vero
cell line. Pet Ex. 34 at 1. “Residual human fetal DNA,” refers to petitioner’s specific contention
that certain vaccines manufactured using human cell lines contain residual DNA originating from
human fetal material. See Pet Ex. 10 at 13; Tr. 239-40. At various points in her testimony Dr.
Deisher also referenced “human-fetal-manufactured contaminants,” (Tr. 45) “residual fetal
cellular debris,” (Tr. 79) “contaminating human fetal DNA,” (Tr. 80) “fetal DNA contaminants,”
(Tr. 102) and “fetal DNA fragments” (Tr. 121).
44
   A retrovirus is any virus belonging to the retroviridae family of viruses, which are a family of
single strand RNA viruses. DORLAND’S at 1636. A human endogenous retrovirus (“HERV”) is
a retrovirus-like sequence found in the human genome and believed to be the remains of true
retroviruses previously absorbed through evolution. Id. HERVs, which make up at least eight
percent of the human genome, have been associated with several human diseases, including HIV
infection, autoimmune diseases and malignancies. Derek Dube, et al., Genomic Flexibility of
Human Endogenous Retrovirus Type K, 88 J. VIROLOGY 9673 (2014) [Resp. Ex. L4]. Human
endogenous retrovirus type K (“HERV-K”) is the most recent family of HERVs to be
incorporated into the human genome, integration having occurred as recently as 200,000 years
ago. Id. In her expert reports, Dr. Deisher cites HERV-K fragments as a vaccine contaminant.
See, e.g., Pet. Ex. 10 at 20-21; Pet. Ex. 76 at 5.
45
  According to Dr. Deisher, a change point indicates that “autism was rising at a lower rate in
children” prior to the date of the change point, than after it. Pet. Ex. 26 at 8. For example, with
regard to the change point in 1988, “this means that autism was rising at a lower rate in children
born prior to 1988 than in children born after 1988.” Id.


                                                 21
prevalence. The change points relevant to the United States are 1980.9, 1988.4, and 1996. 46 Dr.
Deisher opines that these change points correspond to “the introduction of or increased doses of”
the three vaccines manufactured using human DNA. Pet. Ex. 265 at 1. Dr. Deisher offers two
broad causal mechanisms as to how these vaccines cause ASD: insertional mutagenesis and
autoimmunity.

        Petitioners’ theory of causation is discussed in two parts. Dr. Deisher’s change point
research and the criticisms brought against it are discussed first, followed by a discussion of
petitioners’ two causal mechanisms: insertional mutagenesis and autoimmunity.

           a. Dr. Deisher’s Change Point Study47

        The goal of Dr. Deisher’s change point study was to “investigate a previously
overlooked, universally introduced environmental factor, fetal and retroviral contaminants in
childhood vaccines, absent prior to change points in autistic disorder prevalence…and known
pathologic mechanisms of action.” Pet. Ex. 265 at 1. Data was obtained from the United States,
Australia, United Kingdom, and Denmark. Vaccines included MMR II, varicella and hepatitis
A, given to children ages 19 to 35 months of age at the time of vaccination. Dr. Deisher
identified birth year change points 1980.9, 1988.4 and 1996 for the United States (“U.S.”) data.
In the United Kingdom, one change point, 1987, was identified. Change points of 1990.4, for
Australia, and 1987.5 for Denmark were also identified. Dr. Deisher asserts that these change
points “corresponded to introduction of or increased doses of human fetal cell line-manufactured
vaccines.” Pet. Ex. 265 at 1. She opined that the change points were not due to other factors
such as paternal age or to changes in diagnostic criteria due to revisions of the DSM. She
concluded that “rising autistic disorder prevalence is directly related to vaccines manufactured
utilizing human fetal cells.” 48 Id.


46
  Dr. Deisher referred to the second change point as occurring between “approximately 1988 to
1989.” Tr. 67. Dr. Deisher’s valuation of the third change point is not entirely clear. She
occasionally referred to this change point as occurring in 1995, but later, she testified that it
occurred in 1996. Compare Tr. 67 with Tr. 817.
47
  Dr. Deisher’s change point study, “Impact of environmental factors on the prevalence of
autistic disorder after 1979,” was published in the Journal of Public Health and Epidemiology in
2014. Theresa A. Deisher et al., Impact of Environmental Factors on the Prevalence of Autistic
Disorders After 1979, 6 J. PUBLIC HEALTH & EPIDEMIOLOGY 9, 271 (. 2014) [Pet. Ex. 265].
Follow-up articles were published in Issues in Law & Medicine at Mr. McHugh’s behest (Tr.
227) in November of 2015. See Theresa Deisher & Ngoc Doan, Sociological Environmental
Causes are Insufficient to Explain Autism Change Points of Incidence, 30 ISSUES IN LAW &
MEDICINE 1, 25 (2015) [Pet Ex. 419]; and Theresa A. Deisher et al., Epidemiologic and
Molecular Relationship Between Vaccine Manufacture and Autism Spectrum Disorder, 30
ISSUES IN LAW & MEDICINE 47 (2015) [Pet Ex. 675].
48
  In an earlier draft of the study, Dr. Deisher is much more restrained and circumspect in stating
the conclusions. She does not conclude that an increase in autism prevalence is related to


                                                22
        Prior to Dr. Deisher’s study, in 2010, McDonald and Paul (“McDonald”) co-authored a
study in which they calculated a change point in 1988-1989 associated with the increased
incidence of AD. Pet. Ex. 27 at 2112. The purpose of their study was to identify one or more
change points so as to focus the time frame required for researching possible environmental
exposures associated with autism. Id. Using data from California and Denmark, McDonald
identified a change point, or increase in the cumulative incidence of AD, occurring in 1987.5.
Id. Based on a worldwide data set, the change point was estimated to be 1988.7. Id. The
McDonald study, and the use of change points relative to researching environmental factors that
may contribute to autism, provided a model and frame of reference for Dr. Deisher’s change
point study. However, McDonald did not identify any environmental causes associated with
their change point of 1988-1989. In fact, McDonald specifically stated that “studies on MMR
vaccine…did not support a relationship with autism.” Pet. Ex. 27 at 2. Further, McDonald did
not identify the additional two change points noted by Dr. Deisher for 1980.0 and 1996 (US). Id.
No other researcher or publication has referenced the two additional change points found in
Deisher’s study for 1980.9 and 1996. Tr. 236-37. Moreover, there is no evidence suggesting
that any other researcher or publication has associated any autistic disorder change points as
being associated with vaccines.

         Like the change point in McDonald, Dr. Deisher’s autism prevalence change points are
reported based on birth year cohorts. Tr. 62. Data on autism prevalence are also typically
reported by birth year, rather than the year symptoms become evident or the year of diagnosis,
because children are diagnosed with autism at different stages of life. Id. Dr. Deisher “focused
on autistic disorder…the more severe form of autism,” because of its “relatively constant
diagnostic criteria over the past [five] decades.” 49 Id. at 48-49. Dr. Deisher used the print dates
for DSM editions, and its revisions, to “indicate the rapidity with which changes in diagnostic
criteria were disseminated to the professional community.” Id. Autistic disorder data was
obtained from a number of sources, including the California Department of Developmental
Services and Individuals with Disabilities Educations Act program. Birth data were obtained
from the CDC, the U.S. Census Bureau and similar agencies. 50 Linear regression and R
statistical software were used for analysis. Id. at 75.




vaccines. Instead she states, “our results…place emphasis on identifying environmental or other
factors that are temporally associated with specific AD [birth year] change points of 1981, 1988,
and 1996. Further research on other environmental factors is clearly warranted.” Pet. Ex. 26 at
20.
49
  The terms “autism” and “autism spectrum disorder” are used interchangeably to refer to the
entire group of disorders within the broad PDD category. The specific term “autistic disorder,”
(“AD”) on the other hand, refers to the subcategory of PDD, consistent with Dr. Deisher’s use
described above.
50
     For a full discussion of methodology and data sources, see Pet. Ex. 265 at 2.



                                                  23
       Vaccines manufactured from human cell lines referenced in Dr. Deisher’s study included
Meruvax (Rubella), the rubella component of MMR II,51 and HAVRIX (hepatitis A). Meruvax
and MMR II are manufactured using fetal cell line WI-38 and were approved for use in 1979.
Pet. Ex. 265 at 9; Pet. Ex. 30. Varivax vaccine is manufactured using fetal cell line MRC-5, and
was licensed for use in 1995. Pet. Ex. 265 at 9. Havrix is also manufactured using cell line
MRC-5, and while it was initially approved for use in 1995, it was not made part of the
immunization schedule for children at that time. Pet. Ex. 29 at 3. In 2005, it was included in the
childhood immunization schedule for children 12 months and older. Id. Each of these vaccines
contain residual DNA from the cell lines used for their production. Safety guidance published by
the U.S. Department of Health and Human Services, the Food and Drug Administration, and
Center for Biologics Evaluation and Research specified that residual DNA from “widely used
human diploid cell strains, such as MRC-5 and WI-38 cells,” did not present a safety concern.
Pet. Ex. 90 at 42.

        The graph below 52 represents a summary of Dr. Deisher’s data on AD prevalence in the
United States among children born between 1975 and 2002. Tr. 66. The x-axis represents birth
years from 1970 to 2005; the y-axis represents the prevalence of ASD per 10,000 children. Pet.
Ex. 76 at 14, fig. 1. The arrows show the change points and the vaccine(s) or vaccine event
associated with each change point which Dr. Deisher opines are associated with an increase in
AD prevalence. 53




51
   The MMR vaccine was licensed for use in the United States in 1971, and MMR II vaccine was
licensed for use in 1979. Dr. Halsey explained that MMR was renamed MMR II in 1979
because the rubella portion was changed from strain HPV 77, which was not manufactured using
human cell lines, to RA27/3, which was manufactured using human cell lines. Resp. Ex. L at 4-
5. Dr. Halsey further explained that after 1979, RA27/3 was the only strain of rubella
manufactured in MMR vaccines in the United States. Id. Presumably only MMR II was
available after 1981-1982. According to Dr. Deisher, however, the shelf life of the earlier HPV
77-containing MMR was two years, suggesting that uptake of the MMR II vaccine would not
have been immediate. Tr. 60-61. This assertion factors into her analysis associating a 1980.9
change point to the introduction of the MMR II vaccine. The Proquad vaccine, which was first
licensed for use in 2005, also contains the RA27/3 strain of the rubella vaccine. Resp. Ex L at 4;
see also Food and Drug Administration, CBER Clinical Review of Studies Submitted in Support
of Licensure of Proquad, available at
https://www.fda.gov/downloads/BiologicsBloodVaccines/vaccines/.../ucm123800.pdf (2005)
(last visited August 30, 2017).
52
  Reproduced from “Human Fetal DNA and Retrovirus Contaminants in Vaccines Coincide
with Autism Change points.” Pet. Ex. 76 at 14, fig. 1. These vaccines include MMR II, polio,
varicella, and hepatitis A.
53
     “Chickenpox” in this graph refers to the varicella vaccine, Varivax.



                                                  24
       The first change point is approximately 1980, which Dr. Deisher attributes to the 1979
approval of Meruvax and MMR II. See Pet. Ex. 265 at 6. The second change point occurs in
“approximately 1988,” which Dr. Deisher attributes to three events. First, a polio vaccination
manufactured in human cell lines, Poliovax, was released in 1987. Second, the CDC and
Advisory Committee on Immunization Practices (“ACIP”) recommended a second dose, or
“booster,” of the MMR II vaccination for children. Id. at 7. The third event was an MMR II
compliance campaign. 54 Pet. Ex. 265 at 7; Tr. 68, 824.

        The third change point occurs in 1995, which Dr. Deisher associates with the introduction
of the varicella vaccine, Varivax, which was licensed by the FDA and recommended for routine
use in 1995. Pet. Ex. 265 at 7. Rather than leveling off, however, as would be expected over
time, autism rates continued to increase after birth year 1998, 55 which Dr. Deisher attributes to

54
   A measles outbreak led to an MMR II compliance campaign, which according to Dr. Deisher,
“increased compliance” from ≤62.2 to 82percent between birth years 1987 and 1989. Tr. 68;
Pet. Ex. 10 at 17. CDC data, however, show slightly different numbers. MMR vaccine coverage
in the U.S. was 61.2percent in 1985 and increased to 82percent in 1991. Pet. Ex. 35 at 2. “No
national coverage data [for the MMR vaccine] were collected from 1986 through 1990,” so it is
not possible to confirm Dr. Deisher’s numbers. Id.

Vaccine coverage was not uniform and immunization levels of pre-school age children were
often low. The “increased incidence of measles in preschoolers living in densely populated
urban areas reflect[ed] low vaccination levels in these populations” (relevant to 1988 to 1989).
Pet. Ex. 66 at 2. “[I]mmunization levels in some inner cities [were] as low as 49percent in
children [two] years of age.” Id.
55
  Dr. Deisher agrees that, from birth year 1998 forward, sociological factors could explain the
continued increase in prevalence after the uptake of varicella leveled off. These sociological


                                                25
the approval and introduction of the hepatitis A vaccine, Havrix. Havrix was approved in 1995,
but was not included in the schedule of vaccines recommended for use until 1999 and later. 56 In
2005, it was recommended for children 12 months and older. Id.

                    i. Limitations and Criticism of Dr. Deisher’s Change Point Analysis

        There are a number of limitations to Dr. Deisher’s study which call into question her
conclusion that rising rates of AD are “directly related to vaccines manufactured utilizing human
fetal cells.” To be fair, Dr. Deisher acknowledges several shortcomings of her study. In an
earlier draft of the study, 57 she acknowledges that “the main shortcoming of our analysis stems
from the original autism prevalence or incidence data: the diagnosis of autism is behaviorally
based and there are currently no biomarkers available to validate diagnosis.” Pet. Ex. 26 at 19.
She also recognizes that AD reporting systems may have contributed to “erroneous diagnoses.”
Pet. Ex. 265 at 12; see also Pet. Ex. 419 at 3. Respondent’s experts also identified a number of
weaknesses of the study, including the ecological study design, the reliance on faulty
assumptions, and the study’s overreaching conclusions. Resp. Ex. J at 1.

       Dr. Deisher’s change point study does not present reliable evidence of vaccine-caused
AD. First, as best explained by Dr. Fallin, the study design, even if perfectly executed, does not
allow for an inference of causation. Second, there are concerns about the accuracy of the
underlying data. Third, Dr. Deisher assumes that vaccines containing residual human DNA
fragments, rather than other sociologic or environmental factors, are causing an increase in AD.
Fourth, the statistical software used in the study may have been a poor fit for the data analysis.
These criticisms are more fully discussed below.


                           1. Ecological Study Design

       Dr. Deisher’s change point study uses an ecological study design. The goal of an
ecological study58 is to identify differences between groups that may explain the outcomes or


factors include: (1) funding for special education approved in 1995; (2) awareness due to
availability of the internet; and (3) an increase in scientific publications. Pet Ex. 61 at 12-13.
56
  Dr. Deisher states that in 1999, 17 states recommended the hepatitis A vaccine for children
two years and older. In 2005, the ACIP recommended it for children 12 months and older.
Compliance was not uniform, and public tracking data for the vaccine was not available until
2006. See Pet. Ex. 265 at 7.
57
  Marissa LaMadrid, et al., U.S. Autistic Disorder (1970-2002) Change Points Do Not Coincide
with Change Points for Suspected Sociologic and Environmental Causes, unpublished
manuscript on file with John Wiley & Sons (Mar. 16, 2011) [Pet. Ex. 26].
58
  An ecological study is a type of observational epidemiologic study which analyzes exposure
and disease data at a population, rather than at an individual level. Federal Judicial Center, REF.


                                                  26
risk of illness or disease seen in the groups. Federal Judicial Center, REFERENCE MANUAL ON
SCIENTIFIC EVIDENCE (“REF. MAN. SCI. EV.”) at 561 (3d ed. 2011). That is, ecological studies
examine disease trends in a population and try to infer relationships based on the co-occurrence
of trends. Tr. 667. One cannot, however, assume that the relationships seen in a population
group are true or accurate at the individual level. Id. at 671. What may appear to be a cause and
effect relationship at the aggregate level may be misleading when examined in individuals. Id.
The name for this phenomenon is “ecological fallacy.” Id.

        Consider Dr. Fallin’s example of an ecological fallacy using the introduction of
computers in the 1970s and 1980s. During this time frame, there was an increase in asthma. An
ecological study could be designed to examine the frequency of computer use and the frequency
of asthma. If data were gathered and plotted in a graph format, the study would likely show an
association between computer use and an increase in asthma. Tr. 674. It would be erroneous,
however, to assume that the use of computers caused an increase in the prevalence of asthma.
This is because causation cannot by shown by an ecological study, even if the study is perfectly
executed. 59 Id. at 672, 696.

        Dr. Deisher’s change point study used “specific discrete time points based on [ ] trends
for autism,” and “discrete time points based on [ ] trends in vaccine utilization,” to see if the
numbers, or time frames, were the same. Tr. 697. The ecological fallacy is Dr. Deisher’s
conclusion “that vaccines using fetal cell DNA are a cause of autism.” Id. at 695. Like the
example concluding that computer use causes asthma because computer use is seen in
relationship to an increase in asthma, the assumption that there is a causal relationship between
vaccines and autism is an ecological fallacy.




MAN. SCI. EV. at 556-57, 561 (3d ed. 2011). Ecological studies are designed to collect data from
defined groups and compare it to other groups, with the objective of identifying and explaining
their differences. Id. at 561. While ecologic studies are useful for identifying associations
between exposure and disease, “they rarely provide definitive causal answers.” Id.; see also
Resp. Ex. L15.
59
   Unlike ecological studies, randomized control trial studies are considered the “experimental
gold standard” for measuring causal associations. Researchers randomly assign participants to
different groups in order to measure disease exposure. Tr. 666. Control groups that are not
exposed to disease are compared with those who are exposed. Id. 665-66. Observational
epidemiology is another study design which allows researchers to observe a cohort of individuals
over a certain period of time. Id. at 666. Case control studies identify those with a particular
disease and compare them to an appropriate control group. Id. Case control studies are often
considered retrospective studies, because individuals are recruited and evaluated for potential
risk factors and causes after they have been identified as having the disease. Id. Cross-sectional
studies look at exposure to a disease and the outcome over a certain period of time, taking a
“cross-section” of the information. Id. at 667.



                                                27
                           2. Incidence and Prevalence Data

        Another significant problem with Dr. Deisher’s change point study derives from the
inherent difficulty in accurately measuring the incidence 60 and prevalence 61 of AD data, birth
data, population data, and the other data used in the study were collected from numerous
sources. 62 It is “incredibly difficult” to calculate accurate and reliable data as to rates of AD for
several reasons. Tr. 678. These reasons include changes in the diagnostic criteria, changes in
disease reporting practices, changes in clinician and parental awareness of autism, and
confounding factors 63 such as access to services and stigma, the decreasing age at diagnosis, and


60
  Incidence is defined as the number of new cases of disease that occur during a specific period
of time. Tr. 665. For example, in a total group of 100 people, 10 have disease A. Over the next
year, four more develop disease A. The incidence for the year is 4 people. Id.
61
   Prevalence is defined as the total count of people with the disease in a given period. Id. In the
example above, prevalence is measured by adding the 10 who already have the disease with the
four who developed it, for a total of 14 out of 100 who have disease A. See Tr. 665. When
measuring prevalence, it is important to know not only how many total disease cases there are
(i.e. the “numerator” of a prevalence measure) but also the total number of people in the
population who are eligible to get the disease (i.e. the “denominator” of a prevalence measure).
Resp. Ex. J at 4.
62
   “For the U.S., autistic disorder data were obtained from the California Department of
Developmental Services (DDS) (McDonald 2010; Cavagnaro 2003; Schechter and Grether
(2008) and from the Individuals with Disabilities Education Act (IDEA) program website of the
Department of Education (IDEA 2012). Live birth data were extracted from the CDC’s ‘Annual
[R]eports of the Vital Statistics of the United States, (Centers of [sic] Disease Control and
Prevention 2012a; Centers of [sic] Disease Control and Prevention 2012b) and birth year autistic
disorder prevalence per 10,000 was then calculated. Male population data were obtained from
the U.S. Census Bureau website (U.S. Census Bureau 2012a) for data prior to 2000 and the ‘fact
finder’ website for data after 2000 (U.S. Census Bureau 2012b). Birth rates by age of father
were obtained from the National Vital Statistics Reports: ‘Birth Final Data’ (Centers of [sic]
Disease Control and Prevention 2012). Varicella and hepatitis A immunization coverage for
children 19 to 35 months of age was obtained from the CDC National Immunization Survey
(“NIS”) (Centers of [sic] Disease Control and Prevention 2012).” Pet. Ex. 265 at 2.
63
   “Confounding occurs when another causal factor (the confounder) confuses the relationship
between the agent of interest and the outcome of interest.” REF. MAN. SCI. EV. at 591. For
example, a study could find that individuals with gray hair have a higher rate of death than those
with other hair colors. “Instead of hair color having an impact on death, the results might be
explained by the confounding factor of old age …. Researchers must separate the relationship
between gray hair and risk of death from that of [old] age and risk of death.” Id. Thus, when a
relationship is found between a disease and a potential agent, it is important to recognize and
eliminate confounding factors. Id.


                                                  28
an increase in paternal age. All of these problems make it difficult to determine whether a true
increase in AD has occurred, and if so, the amount of the increase. See id. at 679, 689. As stated
by McDonald, “Distinguishing between whether the observed increases are real increases in the
incidence of autism or simply an increase attributable to changes in reporting, clinical
definitions, or the kinds of services offered continues to be a source of controversy. The impacts
of these issues have been discussed extensively…but without definitive clarification of the
overall reason for the increase.” Pet. Ex. 27 at 4.

                                   a. Changes in Diagnostic Criteria

         Over time, the name or label, as well as the diagnostic criteria, for the underlying
construct that we now call autism has changed. Tr. 678-79. In particular, the diagnostic criteria
set forth in the DSM, which is used to diagnose autism by psychiatrists and psychologists, have
changed with successive revisions. Id. at 681.

       Since the original DSM was published in 1952, there have been six major revisions, the
most recent in 2013. In her study, Dr. Deisher discusses five of the six revisions, including
DSM-II (1968), DSM-III (1980), DSM-III-R (1987), DSM-IV (1994), and DSM-IV-TR (2000).
Pet. Ex. 265 at 3, 6. Not addressed in Dr. Deisher’s study, the DSM-5 (2013) made further
substantive changes to the diagnostic criteria for ASDs. Charles B. Nemeroff, et al., DSM-5: A
Collection of Psychiatrist Views on the Changes, Controversies, and Future Directions, 11 BMC
MEDICINE 202 (2013) [Resp. Ex. J31]. Dr. Deisher’s change point study encompasses the years
1975 to 2002, spanning the DSM-II to the DSM-IV-TR.

        DSM-II included autistic behaviors under the diagnostic category of “schizophrenia,
childhood type,” which was manifested by “autistic, atypical, and withdrawn behavior; failure to
develop identity separate from the mother’s; and general unevenness, gross immaturity and
inadequacy in development.” Onset was identified as “before puberty.” AM. PSYCHIATRIC
ASS’N, DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS (“DSM-II”) 35 (2d ed.
1968). Significantly, in its third edition (1980), the DSM differentiated autism from
schizophrenia and included a category for “infantile autism.” Diagnostic criteria for infantile
autism required the following: onset before 30 months of age; pervasive lack of responsiveness
to other people; gross deficits in language development; peculiar speech patterns (if speech is
present); “bizarre” responses to various aspects of the environment; and absence of delusions,
hallucinations, loosening of associations, and incoherence as in schizophrenia. AM.
PSYCHIATRIC ASS’N, DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS (“DSM-
III”) 89-90 (3d ed. 1980).

        Under DSM-III-R (1987), the diagnostic criteria for autism – now listed as “autistic
disorder” rather than “infantile autism” – were expanded significantly. Individuals were
assessed using 16 criteria divided into three lettered categories. These categories related to: (a)
“qualitative impairment in reciprocal social interaction,” (b) “qualitative impairment in verbal
and nonverbal communication, and in imaginative activity,” and (c) a “markedly restricted
repertoire of activities and interests.” To be considered autistic, a person would demonstrate
eight of the listed criteria, with at least two impairments in reciprocal social interaction and
communication and imaginative play (i.e., categories (a) and (b)) and at least one relating to a

                                                 29
restricted repertoire of activities and interests (category c). DSM-III-R at 38-39. Specific
criteria demonstrating impairment in reciprocal social interaction included marked lack of
awareness of the existence or feelings of others; no or abnormal seeking of comfort at time of
distress; no or impaired imitation; no or abnormal social play; and gross impairment in the ability
to make peer friendships. Specific criteria demonstrating impairment in communication and
imaginative play included having no mode of communication, such as babbling, facial
expression, gesture, mime, or spoken language; markedly abnormal nonverbal communication;
absence of imaginative activity; marked abnormalities in the form or content of speech; and
marked impairment in the ability to initiate or sustain conversation with others. Specific criteria
demonstrating a restricted repertoire of activities and interests included stereotyped body
movements; persistent preoccupation with part of objects; marked distress over changes in trivial
aspects of the environment; unreasonable insistence on following routines in precise detail; and a
markedly restricted range of interests and a preoccupation with one narrow interest. An
additional diagnostic category (d) called for onset prior to 36 months. AM. PSYCHIATRIC ASS’N,
DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS (“DSM-III-R”) 38-39 (3d ed.
1987).

         Under DSM-IV (1994), the three categories for autistic disorder were adjusted to the
following numbered categories: (1) “qualitative impairment in social interaction;” (2)
“qualitative impairments in communication;” and (3) “restricted repetitive and stereotyped
patterns of behavior, interests, and activities.” Specific criteria demonstrating impairment in
social interaction included marked impairment of the use of multiple nonverbal behaviors; failure
to develop peer relationships appropriate to developmental level; a lack of spontaneous seeking
to share enjoyment, interest, or achievements with others; and lack of social or emotional
reciprocity. Specific criteria demonstrating impairments in communication included delay in, or
total lack of, the development of spoken language; in individuals with adequate speech, marked
impairment in the ability to initiate or sustain conversation with others; stereotyped and
repetitive use of language or idiosyncratic language; and lack of varied, spontaneous make-
believe play or social imitative play appropriate to developmental level. Specific criteria
demonstrating restricted repetitive or stereotyped patterns of behavior included an encompassing
preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal
either in intensity or focus; apparently inflexible adherence to specific nonfunctional routines or
rituals; stereotyped and repetitive motor mannerisms; and persistent preoccupation with parts of
objects. To be considered autistic, an individual would demonstrate a total of six or more of
these criteria, with at least two relating to impaired social interaction (category 1) and at least
one each relating to impaired communication and restricted repetitive behavior (categories 2 and
3) respectively. In addition to demonstrating these traits, additional criteria required delays or
abnormal functioning prior to age 3 in at least one of the following categories: social interaction,
language as used in social communication; or symbolic or imaginative play. Additionally, the
DSM-IV distinguished autistic disorder from Rett syndrome and Childhood Disintegrative
Disorder, requiring that “the disturbance is not better accounted for” by either of those
conditions. AM. PSYCHIATRIC ASS’N, DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL
DISORDERS (“DSM-IV”) 75 (4th ed. 1994). There were no changes to the above diagnostic
criteria in DSM-IV-TR. AM. PSYCHIATRIC ASS’N, DIAGNOSTIC AND STATISTICAL MANUAL OF
MENTAL DISORDERS (“DSM-IV-TR”) 70-71 (4th ed. Text Revision 1994).



                                                30
        In an attempt to discern whether changes in DSM diagnostic criteria accounted for the
increase in incidence and prevalence of AD, Dr. Deisher studied the dissemination of DSM
revisions after publication by analyzing the DSM’s printing dates. See Pet. Ex. 419 at 15, tbl. 4.
By looking at these dates, Dr. Deisher attempted to gauge how quickly diagnosing professionals
were using the DSM changes. Tr. 49. She then used these dates to predict expected birth year
change points. Pet. Ex. 419 at 13. When her calculated change points for the DSM revisions did
not correspond to her autistic disorder prevalence change points, Dr. Deisher concluded that the
changes in the diagnostic criteria set forth in the DSM did not account for the increase in
incidence and prevalence of AD. Tr. 50; see also Pet. Ex. 419 at 12-13. However, AD is a
subjective diagnosis, and Dr. Deisher assumed that the newest diagnostic criteria are uniformly
used by all diagnosing clinicians. Dr. Fallin explained that it is not possible to identify discrete
dates corresponding to DSM revisions, because the uptake of the new criteria for AD across
DSM revisions was not instantaneous or discrete. Tr. 712. Instead, the revised criteria are
implemented by healthcare providers over time. Moreover, clinicians do not unanimously or
uniformly follow the most recent DSM criteria when diagnosing AD. Id.

        As explained by McDonald, changes in the diagnostic criteria, and a “broadening of the
definition of autism to PDD occurred during data collection relevant to the Danish and California
data used for the study. Pet. Ex. 27 at 4. Even using only the diagnosis of autistic disorder,
which has had fairly “consistent diagnostic criteria since about 1978” does not resolve the
problem. A review of the California date from the 1990s to 2006 “suggests that changing
diagnostic criteria may account for about a 2.2 fold higher cumulative incidence of autism,
relative to the [seven]-fold increase observed over 11 birth cohorts.” Id.

        In addition to the changes and revisions to diagnostic criteria, there is the issue of how
practitioners apply the criteria. Although autistic disorder has had relatively consistent criteria,
“this does not necessarily mean that the diagnostic criteria have been consistently applied in
practice over this time.” Pet. Ex. 27 at 4. Diagnostic practices are not only based on criteria
from the DSM, but also on physician training, diagnostic tests, awareness, and the relationship
between certain diagnoses and available services for particular diagnostic categories. Id. In her
study, Dr. Deisher acknowledges that “[the] impact of DSM revisions on the diagnosis of autism
depends on the significance of changes to diagnostic criteria and on the rapidity with which the
DSM revisions are disseminated and applied.” Pet. Ex. 265 at 3. However, Dr. Fallin believes
that Dr. Deisher did not accurately consider all of these factors and that nuances in diagnostic
“classification rubrics” and training used by different professions (e.g., developmental
psychologists versus pediatric neurologists) may also account for changes in diagnoses over
time. Tr. 681-82.

                                  b. Reporting Practices

       Not only have diagnostic criteria changed over time, but so too have reporting practices,
which affect how researchers count children who have autism. Tr. 682. Some countries, like
Denmark, have a registry system which uses diagnostic reporting codes. Initially, Denmark
reported and captured autism diagnoses only on inpatients. When Denmark began including



                                                 31
outpatient data for children diagnosed with autism, the number of reported cases significantly
increased. Id. at 683-84.
         Dr. Fallin cited a paper by Hansen et al., 64 in which the authors address how changes in
Denmark’s reporting practices affected prevalence estimates. Resp. Ex. J12; Tr. 703. Hansen
concluded that up to 42 percent of the increase in AD prevalence in Denmark in 1995 was due to
the inclusion of outpatient data. Resp. Ex. J12 at 56. When including changes in diagnostic
criteria and changes in reporting practices, the increase was 60 percent. Id. Hansen uses
“sophisticated statistical methods to try to estimate the actual proportion of increase in autism
prevalence [in Denmark] that could be attributed to this change … in reporting by including the
outpatient data.” Tr. 703. Dr. Fallin cited Hansen’s paper as an example of why trend data like
that presented in Dr. Deisher’s change point study must be used with hesitation. Id. at 703-04.
One must question whether the data reflects an increase in the true prevalence of autism or
changes in the reporting of diagnoses. Id.

                                  c. Access to Services and Stigma

        Lack of access to health and educational services may also affect autism prevalence data.
Dr. Fallin explained that younger children, not yet in preschool or any other educational system,
who have little or no access to healthcare, may not be reported. Tr. 686-87. Autism prevalence
data are calculated in the United States through surveillance programs tied to children’s health
and educational records. 65 Clinicians examine school and health records to determine whether
children meet the criteria for ASD. Id. at 682. If a child with autism has not yet been diagnosed
due to a lack of access to care, prevalence numbers are not accurate. Additionally, in settings or
communities where there is a negative stigma attached to an autism diagnosis, families may not
seek out care. Id. at 688.

        Dr. Deisher disagreed that lack of access to services impacts prevalence estimates. 66 She
also disagreed that there was an increase in the diagnosis of autism due to an increase in federal




64
  Stefan Hansen et al., Explaining the Increase in the Prevalence of Autism Spectrum Disorders:
The Proportion Attributable to Changes in Reporting Practices, 169 JAMA PEDIATR. 56 (2015)
[Resp. Ex. J12].
65
  Dr. Fallin explained that in the United States, access to services is connected to reporting
practices because most of the data about ASD is collected from children enrolled in ASD
services. Tr. 686.
66
  Dr. Deisher acknowledged a study that showed an increase in autism rates correlated to the
approval of special services. Pet. Ex. 419 at 2. She addressed the issue of federal funds for
special education in one of her papers and identified a change point of 1998.7 for federal
funding, and thus rejected this as a factor influencing the increase in autism diagnoses. Pet. Ex.
419 at 9.



                                                32
funding67 for special education, because federal funding for autistic children did not become
available until 1995, and her change points precede that date. Tr. 52; Pet. Ex. 419 at 8.
        However, data may be “prone to diagnostic substitution” where certain diagnoses allow a
child to receive administrative services. Pet. Ex. 27 at 4. For example, in “British Columbia
[and] Canada, changes in the assignment of special education codes may account for at least one-
third of the increase in autism prevalence from 1996 to 2004.” Id. While data from Canada were
not used by Dr. Deisher, the issue remains. Diagnosis may be driven based on access to services.

                                  d. Physician and Parental Awareness of Autism

        Another factor that impacts prevalence is knowledge and awareness of autism. Tr. 684.
Family advocacy efforts and social media have been instrumental in increasing parental and
clinician awareness. Tr. 685. Increased parental and clinical awareness of autism impacts the
number of children who are diagnosed; as awareness of the disease increases, previously
undiagnosed children may now be diagnosed. See Tr. 51, 684-85.

        Dr. Deisher discounts the effect of parental awareness as it relates to the prevalence of
autism. To measure parental awareness, she studied Yahoo chat group messages from 1990 to
2008, totaling the number of messages sent about autism and the number of messages sent about
children’s health generally for each year. Tr. 51; Pet. Ex. 419 at 4. She then compared the two
numbers and calculated a change point that “follows all of the U.S. autism disorder change
points.” Tr. 51. Dr. Deisher claimed that the autism chat group data mirrored the prevalence
change points for 1980, 1988, and 1995. However, she acknowledged that Yahoo messaging
was not available until 1994 and that the numbers of messages prior to 1998 were very small
compared to the total. Pet. Ex. 419 at 4. Thus, her data do not account for the 1980 and 1988
change points. Because the Internet was not available in 1980, the date of her first change point,
it “cannot possibly have artificially elevated autistic disorder levels” at that time. Id. Dr.
Deisher discounted other avenues for physician and parental awareness when she concluded that
“rising autism levels were responsible for increased parental concern about autism.” Tr. 51-52.

        To address the issue of professional awareness of autism as a cause of increased
prevalence, Dr. Deisher reviewed trends in the number of medical professionals qualified to
diagnose autism. Pet. Ex. 419 at 3. Using data published by the U.S. Census Bureau, Dr.
Deisher calculated the number of psychiatrists, neurologists, pediatricians, and clinical
psychologists with office practices in the United States. Id. at 4. “The annual numbers of all
professionals qualified to diagnose autism were then added and normalized to the annual U.S.
population.” Id. (see also id. at 5, tbl. 1). Dr. Deisher reported that the number of physicians
qualified to diagnose autism slightly decreased after the 1995 prevalence change point, and thus




67
  Dr. Deisher referenced the Individuals with Disabilities Education Act (“IDEA”) as federal
law that provides educational funding for children with autism. She stated that the Act began
providing funding for autistic disorder in 1992. Pet. Ex. 419 at 8.



                                                33
she concluded that an increase in physician awareness was not responsible for the increase in
disease prevalence.68 Tr. 51-52.
        Dr. Fallin disagreed with Dr. Deisher’s conclusions and explained that increased
awareness of AD could very well have impacted prevalence numbers. Tr. 684-85. Over the last
several decades, awareness of AD has spread through various mediums. Id. at 684. Increased
awareness of the disease has caused stigma to decrease, and thus parents are more likely to seek
a diagnosis for their child. Id. at 688. If parents know that good services are available for their
autistic children, there is an incentive to go to the doctor and get their child diagnosed so that the
child can receive treatment. 69 Id.

        The findings in McDonald and other studies agree with Dr. Fallin that “wider awareness
of autism, greater motivation of parents to seek services, and increased funding for services []
may contribute to increasing cumulative AD incidence, but these factors [can] not be
documented or quantified.” Pet. Ex. 27 at 4-5. With regard to data from North East London,
researcher Lingam noted that the prevalence of autism increased from 1979 and then plateaued at
1992. This suggests that the earlier increase was not a true increase in prevalence but was
probably due to “factors such as increased recognition, [and] a greater willingness on the part of
educationalists and families to accept the diagnostic label, and better recording systems.” Pet.
Ex. 287 at1.

                                   e. Paternal Age

        Change or increase in the underlying risk factors for autism may also affect incidence.
Evidence has established that paternal age is a risk factor for autism, and that children born to
older fathers are more likely to be diagnosed with the disorder. Tr. 716-17. A Swedish study by
Idring et al.70 used registry-based information to follow children based on birth year and identify
those who developed autism. Id. The results demonstrated that children born to older fathers
had an increased risk of developing ASD. Resp.’s Ex. J17 at 1.

       Dr. Deisher agrees that paternal age “provides an underlying risk,” but she does not
believe it accounts for a rise in autism prevalence. Tr. 166. Her research, based on absolute


68
  Specifically, Dr. Deisher calculated a change point of 1997.4 for the number of autism-
diagnosing professionals. Pet. Ex. 419 at 12, tbl. 2. Dr. Deisher also studied “the number of
scientific publications referring to autism,” and calculated a change point of 1997.5, and thus,
concluded that “sociological factors such as awareness of autism disorder among parents and
professionals,” were not responsible for the increase in autism diagnoses. See Pet. Ex. 419 at 8.
69
  For example, the “increasing prevalence and incidence rates (in Denmark) during the 1990s
may well be explained by changes in the registration procedures and more awareness of the
disorders.” Resp. Ex. J24 at 1339.
70
  Selma Idring et al., Parental Age and the Risk of Autism Spectrum Disorders: Findings from a
Swedish Population-Based Cohort, 43 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 107 (2014)
[Resp. Ex. J17].


                                                  34
numbers, shows that older fathers have just as many children today as they did back in 1960,
when the prevalence of autism was lower. See Pet. Ex. 278 at 8, panel A. Although currently
men may become fathers at a later age, statistics from the U.S. Census Bureau show that “older
fathers had just as many absolute numbers of children back in the 1960s” as they do now. Tr.
166. Dr. Deisher thus reasoned that “if older age was the trigger for autistic disorder, we would
have seen equivalent numbers of children with autistic disorder who were born to older fathers
back in the 1960s.” Id.

       Dr. Fallin disputes Dr. Deisher’s conclusion that paternal age has no impact on the
increase in autism prevalence. Tr. 713. She further opined that whether paternal age is a
contributor to the rise in autism prevalence is not a question that can be answered by the data
provided in Dr. Deisher’s change point study. Id. at 714. Dr. Fallin explained that Dr. Deisher’s
conclusions are not reliable because she relies on the absolute number of live births when she
should be looking at proportions of children born to older fathers. Id. at 715. If, for example,
200 total children were born in 1960, but only 10 were born to older dads, then the proportion of
children born to older fathers would be five percent. Id. In 2016, if 100 total children are born
and 10 are born to older dads, then the same absolute number (10) now gives way to a different
proportion (10 percent). Id. Because the absolute number of live births is different today than in
1960, Dr. Fallin opines that Dr. Deisher’s analysis is misleading. Id. at 716.

                                  f. Decreasing Age at Diagnosis

       The average age at diagnosis continues to decrease with the ongoing goal of early
intervention. Tr. 686. This change affects prevalence data. For example, if you have 10 autistic
children, only three may be diagnosed at age three. By age seven, however, all 10 children will
have the autism diagnosis. Thus, reporting at age three versus age ten results in a different
prevalence measure. 71 Id.

      The findings of McDonald and others agree with Dr. Fallin and have reported that
“changes in diagnostic criteria and earlier age at diagnosis do contribute to some of the observed




71
  In “Sociological Environmental Causes are Insufficient to Explain Autism Change Points of
Incidence,” Dr. Deisher did acknowledge a study which showed that as much as 12 percent of
the increase in the California autism rate could be due to an earlier age at the time of diagnosis.
Pet. Ex. 419 at 2 (referencing Irva Hertz-Picciotto & Lora Delwiche, The Rise in Autism and the
Role of Age at Diagnosis, 20 EPIDEMIOLOGY 84 (2009)). Ultimately, however, she disclaimed
any direct assessment of this factor, stating that “[b]ecause of the known difficulties with autism
ascertainment, no attempt is made in this work to quantify these sociologic factors relative to
autism trends.” Id. at 3. Instead, Dr. Deisher indicated that “[s]ociologic factors are represented
by quantitative data such as the number of Yahoo groups discussing autism, the number of
scientific publications referring to autism, and the number of professionals qualified to diagnose
autism.” Id.



                                                35
increase in cumulative AD incidence in the California database for 1990-2006.” 72 Pet. Ex. 27 at
2114.

        Although research shows that more children have been diagnosed with autism in the last
thirty years, all of the above factors make it difficult to determine whether there has been a true
increase in prevalence, and if so, how to quantify that increase. Tr. 689. If Dr. Deisher’s
prevalence numbers are not accurate, then her change points are also inaccurate.

                                  g. Vaccine Uptake and Change Points

        Even assuming that her autism prevalence data are accurate, Dr. Deisher’s assumptions
regarding the availability and uptake of vaccines are equally problematic since vaccinations are
not widely administered as soon as they become licensed by the FDA. 73 After a vaccine is
approved by the FDA, the ACIP must decide whether to recommend its use. The
recommendation is then reviewed by the CDC, after which the vaccine may be added to the
official childhood immunization schedule.74 This process can cause a delay in the widespread
use of the vaccine. 75 For example, Dr. Deisher assumed that the 1988 change point was
attributable, in part, to the CDC’s recommendation that children between the ages of four and six
receive a second dose of MMR. Tr. 458-59. Dr. Halsey testified that this recommendation was
delayed, however, because the American Academy of Pediatrics (“AAP”) disagreed with the
CDC and instead recommended a second dose of MMR for adolescents between 11 and 16 years
old. Id. at 459. Dr. Halsey testified that the AAP’s advice was more widely followed and that
the “vast majority” of children received the second dose of MMR at adolescence, years after they
would have received an autism diagnosis. Id.


72
   With regard to the California data (1990-2006), the “changing age at diagnosis,” accounted for
a 12 percent increase in autism incidence, while “inclusion of milder cases,” accounted for a 56
percent increase.” Resp. Ex. J14 at 84.
73
   For the purposes of this decision, FDA licensure and approval are synonymous terms. For
further information regarding the licensing of vaccines by the FDA, see Vaccine Product
Approval Process, U.S. FOOD & DRUG ADMINISTRATION, available at
https://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/BiologicsLicenseA
pplicationsBLAProcess/ucm133096.htm (last updated Aug. 24, 2015).
74
  The Journey of Your Child’s Vaccine, CENTERS FOR DISEASE CONTROL AND PREVENTION,
available at https://www.cdc.gov/vaccines/parents/infographics/journey-of-child-vaccine-
text.html (last updated Dec. 28, 2015).
75
  Even though a vaccine is added to the immunization schedule, it may take years to achieve
compliance. For 1967 and 1985, coverage for the MMR vaccine was only 60 percent and 61.2
percent respectively. Pet. Ex. 35 at 2. Children ages two to four years old are “a weak link” in
vaccine coverage because of the difficulty in targeting children before they are school-age. See
Pet. Ex. 26 at 6. Preschoolers living in densely populated urban areas may have low vaccination
levels. Pet. Ex. 66 at 2.



                                                 36
        As for Dr. Deisher’s third autism change point in 1995, Dr. Halsey testified that it bears
no relevance to the use of the hepatitis A vaccine. 76 Dr. Deisher incorrectly assumed that the
hepatitis A vaccination “could have affected autistic disorder rates for children born in 1997 or
later….” Pet. Ex. 265 at 7. Dr. Halsey explained that although the hepatitis A vaccine was first
approved in 1996, it was not widely administered until 2006, when the CDC approved it for use
at age 12 months and older. Tr. 463-64; Resp.’s Ex L at 5. Thus, Dr. Deisher’s 1995 prevalence
change point could not be associated with the hepatitis A vaccine because the vaccine was not
widely used at that time. 77 Tr. 464.

        Similarly, there was a delay in the uptake of the varicella vaccine due to different
recommendations by the AAP and the ACIP at the CDC, which also makes it irrelevant to Dr.
Deisher’s change point study. Tr. 460. Although the AAP recommended administration of the
vaccine in 1995, the ACIP did not recommend it for children until 1996, and uptake of the
vaccine was slow. Id.; Resp.’s Ex L at 5 (illustrating the slow uptake of the varicella vaccine by
year and showing a gradual increase).78 Dr. Halsey testified that one “would [not] see a change
point in the diagnosis of autism in the same year that [the ACIP] make[s] the recommendation
…. [I]f there were to be a causative association, which there isn’t, there would be a delay.” Tr.
460. Because the uptake of the varicella vaccination was slow and AAP and ACIP
recommendations were different, a change point associated with the varicella vaccine in 1995 is
impossible. Id. at 461.

                          3. Use of R Software

       In addition to challenging the change point study’s design and the assumptions upon which
it is based, respondent’s experts also criticized Dr. Deisher’s use of the R software to calculate



76
   Dr. Deisher responds to Dr. Halsey’s criticism by stating that Dr. Halsey did not accurately
read her study because her change point occurred in 1996, and not 1995. See Tr. 817. However,
while describing her change point study during the hearing on March 7, 2016, Dr. Deisher
testified that “the third change point is approximately 1995.” Id. at 67. Even if the relevant
change point is 1996, this does not matter since hepatitis A vaccine was not widely used until
2006.
77
   Significantly, although Dr. Deisher postulated that “[b]ased on approval dates and
recommendation dates, hepatitis A could have affected autistic disorder rates for children born in
1997 or later,” she acknowledged that “there is no[] public data tracking vaccination rates prior
to 2006.” Pet. Ex. 265 at 277.
78
  Dr. Halsey cited 2003, 2009, and 2015 data published by the CDC which estimated the
coverage rate of the varicella vaccine. Resp. Ex. L at 5. “[I]n 1995, when the recommendation
was made, there were no data on coverage, because … no children were really immunized. It
took the manufacturer a while to get the vaccine out there.” Tr. 461.



                                                37
her change points. 79 Both Dr. Arking and Dr. Fallin opined that Dr. Deisher’s graphs do not
accurately portray the data, calling into question the accuracy of the change points. Moreover,
Dr. Deisher’s statistical analyses and graphs drawn using the R software are incorrect because
the prevalence numbers upon which they are based are flawed, as described above.

      The R program used by Dr. Deisher is a statistical software package that is used to draw
graphs and visualize data. If used incorrectly, it can yield incorrect results. Tr. 596, 98. Dr.
Arking opined that the segmented line fitting package in the R software program used by Dr.
Deisher did not yield accurate change point results because it was not appropriate for the type of
data she analyzed. Tr. 598. The lines in Dr. Deisher’s graphs are drawn over data points that are
all zero, causing Dr. Arking to question whether the data points were correctly calculated. Tr.
596-97. 80 For example, in the figure entitled “Denmark, Autism Disorders, 1964-1995,”
pictured below, data points from 1965 through 1980 are all zero value. Pet. Ex. 265 at 5. Dr.
Arking explained that “[t]his is not how you analyze data that has lots of zeros,” and based on
these concerns, Dr. Arking concluded that the graph is an incorrect application of the R program
software. Tr. at 598.




79
   During the hearing on March 8, 2016, Ms. Ngoc Doan testified about her work on the change
point study. Ms. Doan is employed by Sound Choice Pharmaceutical Institute as a research
associate and was involved in the data collection process for Dr. Deisher’s research. Tr. 334-35.
Her duties involved copying ASD prevalence data from government websites, published papers,
and other publicly available sources and analyzing it with the R software. Id. at 335-36. She
testified that she did not modify the data during the collection process and that Dr. Deisher
validated the results in the R program. Id. at 337.
80
     Dr. Arking specifically criticized the bottom two graphs found at Pet. Ex. 265 at 4. Tr. 596.


                                                  38
       Dr. Arking also questioned the calculated slope for the lines in many of Dr. Deisher’s
graphs because they contain lines that are above, rather than through, the middle of the data
points. Tr. 596. For example, in the figure entitled “US Autism, 1973-2002, 8 and 19 Years
Old,” pictured below, almost all of the data points between 1980 and 1990 are below the line of
best fit. Tr. 597; Pet. Ex. 265 at 4. Similarly, the majority of the data points in the figure entitled
“UK, Childhood Autism, 1979-1995, < 10 Years Old,” are also below Dr. Deisher’s line of best
fit. Tr. 597. Dr. Arking opined that lines like those shown below are “a very poor fit,” and that
the resulting change points are not reliable. Id. at 598 (referencing Pet. Ex. 265 at 5). There are
better and more specific methods, including zero-inflated statistical models, which should be
used to more accurately analyze this kind of data. Id.




       Dr. Fallin agreed with Dr. Arking that several of Dr. Deisher’s graphs did not appear to
reflect a correct use of the R software program, specifically with respect to the appropriate use of
a linear model. Tr. 705. For example, with regard to the figure above entitled “US Autism,
1973-2002, 8 and 19 Years Old,” Dr. Fallin testified that an “exponential or curved model”
would have been a better fit for the data because these data “do not overlap well with the line
drawn on top of them,” meaning that the change points in the graph are likely inaccurate. Id. at
707-08 (referencing Pet. Ex. 265 at 4).

                   ii. Other Epidemiological Studies

         In contrast to Dr. Deisher’s ecological study, a number of well-designed observational
studies 81 have tested and rejected Dr. Deisher's hypothesis that the MMR vaccination is causally
81
  An observational study is an analytic epidemiologic study in which the investigator “observes
and assesses the strength of the relationship between an exposure and disease variable. Three
types of observational studies include cohort studies, case-control studies, and cross-sectional
studies.” Jae Song & Kevin Chung, Observational Studies: Cohort and Case Control Studies,


                                                  39
associated with ASD. One of these studies, Jain et al.,82 is especially relevant to petitioners’
theory, as Jain studied patients born in the United States between January 1, 2001, and December
31, 2007, and the children in the study received the MMR II vaccination at issue in this case.
Resp. Ex J18 at 1534; Resp. Ex. L at 4.

         Jain performed a retrospective cohort study on 95,727 children in the Optum Research
Database, a database of privately insured individuals and Medicare patients across the United
States. Resp. Ex. J18 at 1534. The purpose of the study was to determine whether siblings of
children with ASD were at increased risk of developing autism due to the MMR vaccination.
Research identified these children to be at increased risk for ASD due to the fact that they had a
known sibling with ASD. Tr. 756-57. Siblings of children who have autism have a risk of one
in five of developing autism, as compared with one in 68. Id. Despite being at an increased risk
for autism, the authors concluded that “[r]eceipt of the MMR vaccine was not associated with the
risk of ASD, regardless of whether older siblings had ASD.” Id.

         A large retrospective study of all children born in Denmark from 1991 through 1998 was
done by Madsen, et al. 83 using Danish Registry data. In Denmark, children are assigned a civil
registry number at birth, and their data are then input into the Danish Civil Registration System.
Madsen obtained the children’s vaccination information from the National Board of Health and
collected autism diagnosis information from another central registry. Resp. Ex. J26 at 1477. A
total of 537,303 children were studied. Id. Of these, 440,655 received the MMR vaccine, and
the remaining 96,648 did not. Id. The risk of autism was no different between the vaccinated
and unvaccinated groups. The authors found "no association between [ ] age at the time of the
vaccination, the time since vaccination, or the date of vaccination and the development of autistic
disorder." Id. 84


126 PLAST. RECONSTR. SURG. 2234 (2010).
82
  Anjali Jain et al., Autism Occurrence by MMR Vaccine Status Among U.S. Children With
Older Siblings With and Without Autism, 313 JAMA 1534 (2015) [Resp. Ex. J18].
83
 Kreesten Madsen et al., A Population-Based Study of Measles, Mumps, and Rubella
Vaccination and Autism, 347 N. ENG. J. MED. 1477 (2002) [Resp. Ex. J26].
84
   Dr. Deisher criticized the Madsen paper because the authors did not publish their raw data and
because the immunization rate reported in the paper (82 percent) was lower than the rate which
Dr. Deisher independently obtained from the Danish Board of Health's website (85.88
percent). Tr. 154-56; 220. Dr. Fallin persuasively addressed both criticisms. First, she
explained that Denmark is very strict about sharing data of its private citizens contained within
its registries and does not allow the data to leave its system. Id. 750-51. In order to access the
data for research, one must be willing to travel to Denmark. Id. at 751. As for Dr. Deisher's
criticism of the discrepancy between the percentage of children vaccinated with MMR described
in the study as compared with the numbers provided on the government website, Dr. Fallin
explained that the difference was likely due to inclusion and exclusion criteria used in the study.
The government website numbers may be slightly higher, as it would not exclude those children


                                                40
       Other persuasive epidemiologic research has studied and rejected the MMR vaccine-
autism causal association. In Taylor et al., 85 researchers studied whether the incidence of autism
was associated with the introduction of the MMR vaccine in the United Kingdom in
1988. Children diagnosed with autism who were born from 1979 through 1998 were identified
and trends examined. Resp. Ex. J44 at 2026. As Special Master Hastings noted in Cedillo:

       The [Taylor] study took advantage of the fact that the MMR vaccine was first
       introduced in Britain in 1988, so that one could compare children born in earlier
       years who did not receive MMR vaccine with later-born children who did receive
       that vaccine. The study found that while there was a steady increase in autistic
       diagnoses throughout the study period, which was consistent with the world-wide
       pattern, the introduction of the MMR vaccine did not result in any significant
       “step-up” in that steady trend; one would have expected a clear “step-up” if the
       MMR vaccine were in fact contributing to autism in any significant way. 2009
       WL 331968, at *85.

The study did not support a causal association between the MMR vaccine and autism. Id.

         An impressive study was undertaken by The Cochrane Collaboration, a recognized world
leader in performing systematic reviews of epidemiology and medical science studies, with the
goal of providing a “summary conclusion” based on knowledge about MMR vaccine across
different studies. Tr. 753. The authors, Demicheli et al., 86 reviewed 139 articles related to
adverse events observed following MMR vaccination and identified 31 that met their strict
criteria for review. Resp. Ex. J8 at 2. Based upon a review of the 31 articles, the authors
concluded that MMR vaccination 87 was not likely to be associated with autism. Id.; see also Tr.
753-55.

        Specifically, Dr. Deisher opines that fetal DNA in vaccines is the environmental trigger
responsible for the “regressive” form of autism. Tr. 246. “There is no standard definition of
what is meant by regression. When [it] is reported, parents recall the loss of a few words or


that would have been excluded from the study due to death, or moving out of the country. Id. at
751-52. For a more detailed explanation, see Dr. Fallin's complete discussion on this point at Tr.
751-52.
85
  Brent Taylor et al., Autism and Measles, Mumps, and Rubella Vaccine: No Epidemiological
Evidence for a Causal Association, 353 LANCET 2026 (1999) [Resp. Ex. J44].
86
 Vittorio Demicheli et al., Vaccines for Measles, Mumps and Rubella in Children, Cochrane
Database of Systematic Reviews, Wiley & Sons Publishing, Ltd. (2005) [Resp. Ex. J8].
87
  The 31 studies in Demicheli’s review included studies published as early as 1975 up until
2004. Presumably, because MMR II was not introduced in the United States until 1979, some of
these early studies assessed by Dimicheli et al. were based on the MMR vaccine, not MMR II.
See Resp. Ex. J8 at 5.


                                                41
phrases acutely or over a period of time. Sometimes, the loss of language is accompanied by
decreased social play or increased irritability.” Resp. Ex. L6 at 4; see also Cedillo, 2009 WL
331968, at *89. “Evidence from multiple centers indicates that regression does occur in
approximately one third of children with autism.” Resp. Ex. L6 at 5. Although she believes her
causal mechanism applies to the regressive form of autism, Dr. Deisher’s change point study
does not apply only to regressive autism.

        Of note, in Cedillo, 2009 WL 331968, petitioners argued that epidemiologic studies were
irrelevant because they did not distinguish between regressive and nonregressive autism. Id. at
*89. Special Master Hastings found as follows:

       It is true that most of the epidemiologic studies discussed [in Cedillo] generally
       did not make any distinction between regressive and nonregressive autism. Thus,
       it is arguable that those epidemiologic studies, while providing very strong
       evidence that the MMR vaccination has not played any significant role in the
       overall causation of autism, do not necessarily completely rule out the possibility
       that the MMR vaccine might play some role in causing the subset of autism
       known as regressive autism.

       But petitioners are wrong in contending that the epidemiologic studies are
       completely irrelevant. First, while those studies cannot completely rule out any
       possibility that the MMR vaccination might play some causative role in a subset
       of the overall autism cases, it seems … that the failure of so many studies to find
       any association between MMR vaccine and autism at least casts some doubt on
       the proposition that the MMR vaccine ever plays a role in causing any type of
       autism, including regressive autism.

Id. at *89 (emphasis in original).

       Moreover, several of the epidemiological studies cited in this case address the MMR
vaccine and regressive and nonregressive autism. The researchers in Taylor questioned whether
there was a potential causal association between MMR vaccination and age of autism onset.
Resp. Ex. J44 at 2028. The study was performed on children with autism born in the United
Kingdom since 1979. Id. at 2026. A total of 498 children with autism were identified, and
Taylor found no evidence of association between MMR vaccination status and age of autism
diagnosis. Id. at 2028. Taylor noted, “Our results do not support the hypothesis that MMR
vaccination is causally related to autism, either its initiation or to the onset of regression…” Id.
at 2029. And while the study did not “rule out the possibility of a rare idiosyncratic response to
MMR …. [I]f such an association occurs, it is so rare that it could not be identified in this large
regional sample.” Id.

       Fombonne also evaluated the relationship between the prevalence of PDD and MMR.
Eric Fombonne et al., Pervasive Developmental Disorders in Montreal, Quebec, Canada:
Prevalence and Links With Immunizations, 118 PEDIATRICS e139 (2006) [Resp. Ex. J9].
Fombonne surveyed 27,749 children born between 1987 and 1998 in Montreal, Canada and
found no association between PDD and one or two doses of MMR. Id. at e139-40. Although

                                                 42
Fombonne’s data did not distinguish regressive versus nonregressive autism, the researchers
noted that “the regressive phenotype of autism has not increased over time,” and stated that as a
result, “our findings of a regular increase in PDD and autistic disorder prevalence while MMR
vaccine uptake was decreasing during the study period are not consistent with any increase in the
risk of PDD, regressive or not, that could be attributed to MMR.” Id. at e148.

         I thus adopt Special Master Hastings’ reasoning in Cedillo, 2009 WL 331968, where he
noted:

         In sum, it is true, as a statistical matter, that the epidemiologic studies detailed …
         above, while showing clearly that the MMR vaccination could not be causing any
         substantial portion of the cases of autism in general, do not completely rule out
         the possibility that the MMR vaccine might be associated with some small subset
         of autism, such as regressive autism. Nonetheless, the balance of evidence from
         those studies weighs against the petitioners’ causation theory. First, it is indeed
         an exceedingly slight point in the petitioners’ favor for them to claim that these
         many studies by different researchers in different countries have not completely
         ruled out the possibility of any merit to their causation claim. The larger point is
         that none of those many competent studies has yielded the slightest bit of
         evidence in the petitioners’ favor – and, of course, it is the petitioners’ burden to
         show that the MMR vaccine does likely cause autism, not the respondent’s burden
         to show that there is absolutely no possibility of a causal link.

         Second, in [ ] view [of] the failure of so many studies to find any association
         between MMR vaccine and autism, while not completely ruling out a possible
         causal role with respect to a subset of autism, at least casts considerable doubt
         upon the proposition that the MMR vaccine ever plays a role in causing any kind
         of autism, including regressive autism. Id. at *89-90 (emphasis in original).

        While no single study is definitive, when different scientifically reliable studies
examining “the same exposure-disease relationship [ ] yield similar results,” particularly when
the studies are performed in “different populations by different investigators,” the combined
results are highly persuasive. REF. MAN. SCI. EV. at 604. The studies cited specifically looked
for evidence that the MMR vaccine caused or contributed to the etiology of autism and failed to
find any evidence. As persuasively explained by respondent’s experts, there is an abundance of
evidence showing no increased incidence of autism in children who have received vaccines as
compared with controls who have not received vaccines. Tr. 432.

            b. Petitioners’ Theories Regarding the Mechanism of Causation

       Petitioners offer two mechanisms by which vaccines containing residual DNA fragments
can cause ASDs. The first is insertional mutagenesis, whereby residual DNA fragments from the
vaccines integrate into and transform host cells in the brain. Tr. 82. The second is based on the
theory of autoimmunity: a child develops antibodies to fetal DNA, which then causes the child’s




                                                  43
body to attack the self.88 Id. at 112-13. Dr. Deisher testified that it is not possible “to clinically
distinguish between AD caused by DNA contamination [and] [AD] caused by something else,”
and that “[t]he clinical symptoms would be similar.” Id. at 248.

                      i. Insertional Mutagenesis 89

       Insertional mutagenesis in a “mutation caused by insertion of new genetic material into a
normal gene.” Farlex, MEDICAL DICTIONARY FOR THE HEALTH PROFESSIONS AND NURSING
(2012). The issue of insertional mutagenesis related to residual DNA in viral vaccines is not
new. See generally, Pet. Ex. 350. Studies have shown, however, that integration of residual
DNA is unlikely. 90 Id. at 16.

        As posited by Dr. Deisher, insertional mutagenesisin the context of this case occurs when
DNA is integrated into a host cell and causes a genetic mutation that is associated with an autism
phenotype. Tr. 82; 100. Dr. Deisher explores four potential ways that insertional mutagenesis
could occur. First, she posits that insertional mutagenesis could occur if fetal DNA fragments
are integrated into hematopoietic stem cells. 91 Second, insertional mutagenesis could result from


88
   In her initial expert report, Dr. Deisher stated that markers of oxidative stress have been found
in the brains of children with ASD. See Pet. Ex. 10 at 4. Presumably, Dr. Deisher posits a
causal theory related to oxidative stress. However, this theory was not further developed and so
it is not entirely clear what Dr. Deisher meant by the statement. The theory of oxidative stress as
it relates to autism has previously been adjudicated and rejected. See King, 2010 WL 892296, at
*24. I find the reasoning of King persuasive on the theory of oxidative stress and adopt its
reasoning and conclusions herein.
89
     Mutagenesis is “the induction of genetic mutation.” DORLAND’S at 1213.
90
  “Ledwith and colleagues demonstrated in a rodent model that integration of a plasmid DNA
vaccine occurred at a very low efficiency,” confirming that DNA integration was unlikely to be a
safety concern. Pet. Ex. 350 at 17 (internal citations omitted). The more germane safety concern
was whether DNA integration could cause infection or “induce oncogenicity,” so as to cause
tumors, not autism. Additional studies were done which showed that even using a “plasmid
containing a strong promoter failed to induce tumors” in mice. Id. As for MRC-5 and WI-38
cell lines, these are not tumor-derived cell lines, nor are they tumorigenic, that is, capable of
forming tumors in animal studies. See Pet. Ex. 350 at 4-5, 17. The vaccines at issue here were
made in “human diploid cell lines (MRC-5 and WI-38), established from cells isolated from
healthy tissues.” Id. at 4. Thus, the risks associated with vaccines made in tumor-derived or
tumorigenic cell lines do not apply to the cell lines at issue here. As for the risk of infection,
petitioners do not provide evidence that MRC-5 and WI-38 cell lines are associated with
infection, or that infection caused by these cell lines is associated with autism. To the extent
that the exhibits filed in this case relate to other types of cell lines or other types of vaccines, they
are not relevant to petitioners’ theories of causation.
91
     Hematopoietic stem cells are “blood cell progenitors that …. have the capacity for replication


                                                   44
particles of human endogenous retrovirus K fragments that become reactivated. Third, fetal
DNA fragments could be transported to the brain by microvesicles, where insertional
mutagenesis would then take place. Finally, Dr. Deisher postulates that fetal DNA fragments
found in vaccines could be transported to the nervous system via retrograde transport. Dr.
Deisher concedes that she does not “know the exact mechanism of action,” but she opines that
“all of these mechanisms are possible ...” Tr. 137. Once transported to the brain, the fetal DNA
could potentially insert in “any cell within the brain … resulting in a mutation.” Tr. 258.

                           1. Human Endogenous Retrovirus Strain K 92

       Retroviruses are a family of viruses whose genomes consist of single-stranded RNA. 93
Human endogenous retroviruses (“HERVs”)94 are “retrovirus like sequences found in the human
genome, thought to constitute the remains of true retroviruses that were absorbed through
evolution.” 95 Retroviruses are “generally inactive,” and are considered “to be innocuous.” Pet.


and differentiation and give rise to precursors of various blood cell lines…” DORLAND’S at 318.
92
   Dr. Deisher cites a number of articles about HERV-K and retroviruses, but they are not all
discussed here, as they do not provide preponderant evidence to support her theory. In addition
to her theory that HERV-K retrovirus fragments may play some role in the insertion of residual
DNA from vaccines, Dr. Deisher seems to suggest that HERV-K fragments themselves,
independent of the residual DNA central to her theory, may cause autism. This aspect of her
theory is not very clear, but for purposes of this decision, I have assumed this idea to be an
additional theory. For example, Dewannieux questions whether in vitro “recombinations among
… HERV-K loci…can generate functional HERV-K elements,” which may have the potential to
produce infectious retroviruses. Marie Dewannieux, Identification of an Infectious Progenitor
for the Multiple-Copy HERV-K Human Endogenous Retroelements, 16 GENOME RESEARCH
1548 (2015) [Pet. Ex. 104]. This seems unlikely because “as a general rule, these [HERV-K]
elements tend to be silenced in the cells…” Id.; see also, Pet. Ex. 105. Additionally,
Dewannieux questions whether “endogenous retroviruses could contaminate the vaccine virus
and be injected together with the vaccine…[which] could result in [ ] infection….” Pet. Ex. 105
at 4. Assuming that this idea that HERV-K fragments may cause infection is one of the
potential theories of causation posited by Dr. Deisher, I do not find this to be a viable theory, as
petitioners have provided no evidence to suggest that infection caused by a HERV-K retrovirus
can cause ASD.
93
     DORLAND’S at 1636.
94
   “Nearly eight percent of the human genome is composed of sequences of retroviral origin.”
Pet. Ex. 104 at 1548. The HERV-K family includes “endogenous retroviruses, most of which []
integrated into the genome [more than] five million years ago.” Pet. Ex. 104 at 1548. These
retroviruses are thought to be the “remnants of ancestral infections of primates.” Id. Despite
numerous studies on HERV-K viruses, researchers failed to produce a “functional provirus
capable of producing infectious particles.” Id.



                                                 45
Ex. 76 at 14. HERV strain K (“HERV-K”) is a type of inactive retrovirus found in most
humans. Pet. Ex. 76 at 14.

        Dr. Deisher testified that fragments of HERV-K have been found in vaccines
manufactured using human fetal cell lines. Tr. 271; Pet. Ex. 76 at 15 (referencing Pet. Ex. 98 96);
see also Pet. Ex. 43 at 10. She hypothesizes that these fragments may “carry” DNA from a
vaccine into the host cell, triggering gene insertion or neuro-inflammation, causing ASD. Tr.
181, 271-272; Pet. Ex. 76 at 14, 15. Dr. Deisher hypothesizes that only a fragment of the
retrovirus is needed to “carry” residual DNA from the vaccine into the host cell. Tr. 272.
Reactivation 97 of the HERV-K retrovirus “may be relevant,” but not necessary. Id.

        More specifically, or perhaps in the alternative, Dr. Deisher opines that HERV-K
fragments in vaccines “code[] for the integrase or the envelope protein,” which “induces gene
insertion or neuro-inflammation.” Pet. Ex. 76 at 15 (internal citations omitted). She posits that
HERV-K fragments act as an “integrase[],” 98 citing a study examining the biology of HERV-K
published by Kitamura et al.99 Pet. Ex. 76 at 15; Pet. Ex. 103 at 3302. However, the findings
stated in Kitamura were quite limited. “Possibly, HERV 100 is one of the agents involved in



95
     DORLAND’S at 1636.
96
  Joseph Victoria et al., Viral Nucleic Acids in Live-Attenuated Vaccines: Detection of Minority
Variants and an Adventitious Virus, 84 J. VIROL. 6033-40 (2010) [Pet. Ex. 98]. The authors
conclude that the vaccines at issue are safe and effective and raise no safety concerns associated
with the finding of HERV-K in vaccines. Id. at 6039.
97
  During the latency phase of a viral life cycle, the virus does not replicate. “Reactivation is the
process by which a latent virus switches to a lytic phase of replication. Reactivation may be
provoked by a combination of external and/or internal cellular stimuli.” C.M. Traylen et al.,
Virus Reactivation: A Panoramic View in Human Infections, 6 FUTURE VIROL. 451 (2011).
98
   An integrase is a retroviral enzyme that binds to the genetic material of a virus and inserts it
into a host cell chromosome. Stephen Hare et al., Retroviral Intasome Assembly and Inhibition
of DNA Strand Transfer, 464 NATURE 232 (2010).
99
  Yoshihoro Kitamura et al., Human Endogenous Retrovirus K10 Encodes a Functional
Integrase, 70 J. VIROL. 3302 (1996) [Pet. Ex 103].
100
   In Kitamura, the authors appear to use the acronyms HERV and HERV-K interchangeably.
The experiment reported in the article, however, dealt with HERVIN, a HERV-K10 integrase
fusion protein. “To examine the biological activity of HERV-K, we have cloned an HERV-K10
DNA fragment encoding putative integrase and expressed it as a fusion protein in E coli. This
report describes the expression and characterization of the HERV-K10 integrase (“HERVIN”)
fusion protein.” Pet. Ex. 103 at 3302.



                                                 46
pathogenesis of seminomas 101 and immunological disorders…” Pet. Ex. 103 at 3306. The
authors in Kitamura do not conclude that HERV-K fragments induce gene insertion. Instead,
they state that “whether HERV can …trigger insertional mutagenesis and whether HERV can be
activated to replicate in human cells remain[s] to be investigated.” Id. The Kitamura study did
not involve residual DNA fragments from vaccines, and the authors did not conclude that
HERV-K could trigger insertional mutagenesis.

       Evidence cited by Dr. Deisher in support of her theory that HERV-K fragments are
involved in the etiology of autism included the report that HERV retroviruses (HERVs E, H, K,
and W) have been found in the peripheral blood mononuclear leukocytes 102 of patients with
autism. Pet. Ex. 76 at 15. Dr. Deisher cites an article by Balestrieri et al. 103 in support of this
alleged evidence. However, this study does not support Dr. Deisher’s claim. While the authors
found that HERVs H and W were elevated in children with autism, HERV-K levels were
approximately equal in both the group of children with ASD and the healthy control group. Pet.
Ex. 110 at 1. Thus, Dr. Deisher’s cite to Balestrieri is erroneous and misleading.

        Respondent’s expert, Dr. Halsey, provided context for the finding of HERV-K fragments
in vaccines. He explained that retroviruses comprise approximately eight percent of the human
genome. Tr. 481; see also Resp. Ex. L17. 104 Retroviruses have been integrated into the human
genome, passed down from one generation to the next. Tr. 480. The HERV-K fragments found
in the vaccines are already present in all of our genomes. Id. at 481. These fragments are not a
new addition to the human genome, and therefore, their introduction into the body by a vaccine
would not constitute a novel environmental factor. Dr. Halsey emphasized that Dr. Deisher
provides no evidence to support her hypothesis that HERV-K plays a role in the etiology of
autism, and she overstated and misinterpreted the literature. Resp. Ex. L at 3. Moreover, studies
have examined the question of whether retroviruses play a role in various diseases, but to date, a
causal relationship has never been established, and they may even play a beneficial role. Resp.
Ex. L at 3; Resp. Ex. L17; see also Pet. Ex. 78.

       Ultimately, Dr. Deisher conceded that current studies regarding HERV-K retroviruses are
“observational” in nature and that the role of these retroviruses in causing disease “is not
known.” Tr. 182. In summary, petitioners provide no evidence to show that HERV-K



101
      Seminomas are malignant tumors of the testes. DORLAND’S at 1690.
102
      Leukocytes are white blood cells. DORLAND’S at 1028.
103
  Emanuela Balestrieri et al., HERVs Expression in Autism Spectrum Disorders, 7 PLOS ONE
1-10 (2012) [Pet. Ex. 110].
104
   Katja Schmitt et al., HERV-K (HML-2) rec and np9 Transcripts not Restricted to Disease but
Present in Many Normal Human Tissues, 6 MOBILE DNA 1-13 (2015) [Resp. Ex. L17; Pet. Ex.
78].



                                                 47
fragments, either through insertional mutagenesis or some other process, play any role in the
etiology of ASD.
                          2. Retrograde Transport

         Another causation scenario proposed by Dr. Deisher involves retrograde transport. Dr.
Deisher used an example of retrograde transport in the giant squid, where the phenomenon was
first studied. Nerve terminals in the giant axon of squid 105 pick up substances that are then
transported into cells in the central nervous system. Tr. 103-04. According to Dr. Deisher, nerve
cells send out axons, 106 “long projections that make[] contact with … the periphery to send
signals from the brain to the periphery….” Tr. 103. Those axons can also carry information
back up into the brain. Id. The advantage of this mechanism, as compared to Dr. Deisher’s other
theories, is that DNA fragments do not have to cross the blood-brain barrier, (“BBB”) 107 because
retrograde transport bypasses the BBB. Id. at 248-49.

       Dr. Deisher hypothesizes that “DNA fragments injected into the muscle [via vaccination]
could be picked up by the terminals of axons and transported …back up to the cell body of the
nerve and the central nervous system (“CNS”).” Tr. 104. Once there, the DNA could insert into
the genome 108 of cells in the CNS. Id. According to Dr. Deisher, insertion of the residual DNA
fragments into the cell “could result in … mutations in the brain cells.” Id.; see also Pet. Ex. 76
at 33-34.



105
  A giant axon is “an axon of certain invertebrates, e.g., the squid, whose size (500 to 700
microns) has facilitated physiological studies of cell membrane excitation.” DORLAND’S at 187.
106
   An axon is “the [prominence] of a neuron by which [nerve] impulses travel away from the
cell body[.]” DORLAND’S at 186.
107
    The BBB is defined as “the barrier system separating the blood from the parenchyma of the
[CNS].” DORLAND’S at 201. Ghadge et al. state that the blood-brain barrier is “a capillary or
barrier that allows relatively little transport of blood-borne molecules.” Pet. Ex. 226 at 132.
Wang et al. note, “The existence of the blood-brain barrier precludes a vascular route of
transgene delivery to the CNS.” Pet. Ex. 217 at 658. Dr. Deisher proposes at least two other
methods whereby DNA fragments could cross the BBB. First, she suggests that a pre-existing
illness could “predispose a child for diminished blood brain barrier competence,” allowing
transport of DNA fragments into the brain. Pet. Ex. 76 at 37-37, 40. Second, Dr. Deisher stated
that an immune response elicited due to vaccinations, along “with its concomitant physiological
changes and cytokine expression, [is] known to increase permeability across the [BBB].” Id. at
49-40. Petitioners provide no evidence that either method could account for how residual DNA
from vaccines cross the BBB to reach the brain and cause ASD.
108
   The genome is “the entirety of the genetic information encoded by the nucleotide sequence of
an organism, cell, organelle, or virus …. In a human being, the genome size is approximately
[three] billion base pairs of DNA and approximately 25,000 genes.” DORLAND’S at 771.



                                                48
        Petitioners cite a number of studies for the proposition that retrograde transport could
deliver DNA fragments to brain cells. Generally, the purpose of these studies is to investigate
the potential for gene therapy, or delivery of genes to the CNS for treatment of disease. None of
these studies address DNA fragments from vaccines or ASD. For example, Wang et al. 109
studied retrograde axon transport in rats and mice. The animals were injected with DNA and
were later found to have gene expression of that DNA in their brain tissue. Pet. Ex. 76 at 39
(referencing Pet. Ex. 217 at 658). Specifically, the tongue was injected with “plasmid DNA
complexed with the cationic polymer polyethylenimine (“PEI”)….” Pet. Ex. 217 at 658. PEI is
a non-viral vector which can be “internalized by nerve endings and retrogradely transported from
the periphery into neuronal cell bodies in the CNS.” Id. The purpose of the study was to
determine whether an intramuscular injection of PEI could be used to “achieve gene transfer in
the CNS.” Id. at 659. Wang concluded that “PEI/DNA complexes can migrate by retrograde
axonal transport to neuronal cell bodies after being internalized by nerve terminals in the
muscle…” Id. at 663. The study “confirmed the feasibility of nonviral gene delivery to the CNS
via peripheral injectional sites.” Id.

        Principally, the goal of the Wang study was to measure the effectiveness of PEI, a
polymer known for its transfection 110 efficiency, for use in gene therapy. Pet. Ex. 217 at 659.
Wang found that “[n]aked DNA, as well as PEI alone, produced no ... activity in the brain
stem....” Id. at 660.

        The findings in Wang do not translate to this case for several reasons. First, in the Wang
experiment, DNA fragments were not used. Instead, DNA was joined with the polymer PEI to
form PEI/DNA complexes to facilitate uptake. Dr. Deisher provided no evidence to suggest that
the residual DNA in vaccines is like the PEI/DNA complexes. Secondly, the PEI/DNA complex
was injected into tongue muscle, which is part of the rat’s hypoglossal nerve system. “Motor
neurons of the hypoglossal nucleus in the brain stem innervate tongue muscles.” Ex. 217 at 660.
Thus, there was a known nerve pathway from the brain stem via the hypoglossal nerve into the
tongue. Petitioners provide no evidence of a similar nerve pathway from a child’s brain to the
muscle where a vaccine is administered. Third, in Wang, “naked” DNA, or DNA that was not
joined with the polymer, did not produce activity in the brain. Id. This finding suggests that
DNA fragments in vaccines are not capable of retrograde transport, absent their combination
with a specifically designed polymer. The Wang study in no way suggests that fetal DNA
fragments found in vaccines could travel to a child’s CNS via retrograde transport, and the study
does not contemplate this possibility.




109
   Shu Wang et al., Transgene Expression in the Brain Stem Effected by Intramuscular Injection
of Polyethylenimine/DNA Complexes, 3 MOLECULAR THERAPY 658 (2001) [Pet. Ex. 217].
110
   Transfection includes “any means of artificial introduction of foreign DNA into cultured
eukaryotic (cells with a true nucleus) cells.” DORLAND’S at 1952, 653.



                                                49
       Dr. Deisher also cited a study by Beier et al, 111 which explores the difficulty of mapping
neuronal connectivity in the CNS. Scientists engineered a recombinant 112 virus, vesicular
stomatitis virus (“VSV”) with a rabies virus glycoprotein (“RABV-G”), and then mapped
connections between neurons. Pet. Ex. 223 at 1. The recombinant virus (“rVSV-RABV-G”)
“spread rapidly from neuron to neuron in only a retrograde manner.” Id. The study shows that
recombinant viruses may be “engineered to transmit across [neuronal] synapses.” Id. However,
Dr. Deisher does not explain how recombinant rVSV with RABV-G, a modified virus with
added glycoprotein, is in any way similar to residual DNA in vaccines.

        Another study cited by petitioners was authored by Ghadge et al. 113 Pet. Ex. 76 at 39.
Ghadge demonstrated “that intramuscular injection of replication-defective recombinant
adenovirus 114 [manufactured with a specialized promoter and cytomegalovirus enhanced used for
its vector 115 qualities] results in high-level recombinant gene expression, specifically in the CNS
motor and sensory neurons that innervate the inoculated muscles.” Pet. Ex. 226 at 132. More
simply put, recombinant replication-defective adenoviruses were used to deliver genes into CNS
neurons via retrograde axonal transport following intramuscular injection. Id.; Tr. 478-79.
Ghadge explained that recombinant replication-defective adenoviruses have “a number of
properties that make them attractive gene transfer vehicles.” Pet. Ex. 226 at 132. Other than
establishing that retrograde transport is a real phenomenon, however, petitioners do not offer any
evidence that the recombinant adenoviruses used as gene transfer vehicles in Ghadge’s study are


111
   Kevin Beier et al., Vesicular Stamatitis Virus with the Rabies Virus Glycoprotein Directs
Retrograde Transsynaptic Transport Among Neurons in Vivo, 7 FRONTIERS IN NEURAL CIRCUITS
1 (2013) [Pet. Ex. 223].
112
  A new entity, such as a “gene, protein, cell…that results from genetic recombination.”
DORLAND’S at 1607.
113
   G.D. Ghadge et al., CNS Gene Delivery by Retrograde Transport of Recombinant
Replication-Defective Adenoviruses, 2 GENE THERAPY 132 (1996) [Pet. Ex. 226]; see also Anne
Hennig et al., Intravitreal Gene Therapy Reduces Lysosomal Storage in Specific Areas of the
CNS in Mucopolysaccharidosis VII Mice, 23 J. NEUROSCIENCE 3302 (2003) [Pet. Ex. 498],
discussed at Tr. 174. The findings of the study indicated that “[a]xonal transport from the retina
can be used to deliver therapeutic agents into the brain,” in lieu of intracranial injections. Id. at
3307.
114
   Adenoviruses belong to the family of DNA viruses with a genome consisting of a “single
linear molecule of double-stranded DNA.” DORLAND’S at 30. “Conditionally replicative
adenoviruses,” are “mutant adenoviruses that can replicate only inside certain types of tumor
cells, infecting host cells with lethal abnormalities and thus being potentially useful in gene
therapy for cancer.” Id. In Ghadge, “replication-defective” adenoviruses were used.
115
   A vector is, generally, “a carrier.” DORLAND’S at 2028. A recombinant vector carries “both
the vector and foreign inert sequences.” Id.



                                                 50
similar to residual DNA in vaccines, or that residual DNA can travel via retrograde transport so
as to cause ASD.

        Dr. Halsey agreed that retrograde transport is a known phenomenon and that live viruses
have been shown to be transported in retrograde fashion via neurons, as was demonstrated by
Ghadge. Tr. 478-79. But Dr. Halsey testified that he has never seen evidence that injection of
DNA in a peripheral part of the body can lead to transport across multiple synapses in the human
neural system, up to the CNS, to different areas of the brain. Id. at 503. Dr. Halsey also testified
that Dr. Deisher misrepresented the findings in Ghadge and Hennig.116 The authors did not
inject DNA or DNA fragments in the mice; instead, they injected a live virus in an attempt to
devise a method of gene therapy. Tr. 479-80. While viruses may be delivered by retrograde
transport, the same is not true of DNA. Id. at 500.

                             3. Microvesicle Transport

        Microvesicle transport is the third mechanism proposed by Dr. Deisher whereby DNA
fragments found in vaccines could be transported in the blood circulation and taken up by a CNS
cell. Tr. 106. Dr. Deisher testified as follows:

          [Another] possible way that the contaminants [residual DNA fragments] injected
          into a peripheral muscle, like an arm or a leg, could reach the central nervous
          system and potentially be taken up by a central nervous system cell and cause
          insertional mutagenesis is by transporting the blood in what are called
          microvesicles. 117 Tr. 105-06.


116
    In Hennig, a “recombinant adeno-associated virus” was used as a vector for gene therapy via
injection into the vitreous humor of the eye of mice for delivery within the CNS. Hennig et al.,
23 J. NEUROSCIENCE at 3302. “The findings suggest that…trans-synaptic transfer contribute[d]
to [] dissemination…within the CNS.” Id. Dr. Deisher cited a number of articles about
retrograde transport, but none relate to the facts and circumstances here, and none of the articles
provide preponderant evidence that retrograde transport is a plausible method of delivering
residual DNA fragments in vaccines to the CNS, so as to cause autism. For examples, see Ping
Yang et al., Lentiviral Vector Mediates Exogenous Gene Expression in Adult Rat DRG
Following Peripheral Nerve Remote Delivery, 47 J. MOL. NEUROSCI. 173 (2012) [Pet. Ex. 218]
(sciatic nerve retrograde transport experiment); Zarife Sahenk et al., Gene Delivery to Spinal
Motor Neurons, 606 BRAIN RESEARCH 126 (1993) [Pet. Ex. 219]; Beier et al., 7 FRONTIERS IN
NEURAL CIRCUITS 1 (2013) [Pet. Ex. 223]; and Kevin Beier et al., Anterograde or Retrograde
Transsynaptic Labeling of CNS Neurons with Vesicular Stomatitis Virus Vectors, 108 PNAS
15414 (2011) [Pet. Ex. 224] (VSV serve as vectors for retrograde transport). Dr. Deisher also
cited studies dealing with gene therapy and retrograde transport, for example, see Devang
Thakor et al., Subcutaneous Peripheral Injection of Cationized Gelatin/DNA Polyplexes As a
Platform for Non-Viral Gene Transfer to Sensory Neurons, 15 MOLECULAR THERAPY 2124
(2007) [Pet. Ex. 496].
117
      Dr. Deisher defined a microvesicle as a lipid vesicle “known to carry nucleic acids.” Tr. 106.


                                                  51
        Microvesicles are a known method of transporting “nucleic acids through the
circulation.” Tr. 106. Dr. Deisher cites an article by Bess et al. 118 to support this theory. In
Bess, the authors describe the finding of nonviral membrane protein particles, or microvesicles,
in “purified preparations of immunodeficiency viruses (HIV-1).” Pet. Ex. 207 at 143. The
microvesicles contained RNA and DNA. Other than showing that microvesicles contain DNA
and that they are a method of transport within the circulatory system, Bess does not provide any
evidence that microvesicles transport residual DNA from vaccines as suggested by Dr.
Deisher.119

         Additionally, Dr. Deisher seems to conflate or otherwise combine the theories of
microvesicle transport (circulatory system) and retrograde transport (nervous system). She states
that “DNA-containing microvesicles can be transported retrograde to the brain by motor nerve
proteins such as kinesin120 or its homologs, which are known to transport vesicles in axons.”
Pet. Ex. 76 at 37. To support this assertion, Dr. Deisher cited an article by Coy and Howard 121
related to organelle transport. 122 Id. The authors discuss the transport of materials from the
nerve cell body to the axon. Pet. Ex. 208 at 662. The authors do not reference “microvesicles”
or the theory posited by Dr. Deisher, but they do mention the transport of “multivesicular
bodies” from synaptic terminals toward the cell bodies. Id. The article does not discuss the
potential for DNA fragments to be transported to neurons by microvesicles, and Dr. Deisher does
not explain how organelle transport is comparable, if at all, to the transport of fetal DNA
fragments. Regardless of how this component of Dr. Deisher’s theory is described, the
articles 123 cited in support of it do not appear relevant to the facts presented by this case or the
theories being advanced by petitioners.


118
   Julian Bess et al., Microvesicles Are a Source of Contaminating Cellular Proteins Found in
Purified HIV-1 Preparations, 230 VIROLOGY 134 (1997) [Pet. Ex. 207].
119
   Dr. Deisher also cites the Dinu paper, a discussion of the cellular function of kinesins,
including the role of kinesins in “the movement of organelles and vesicles,” but the article does
not provide support of petitioners’ microvesicle transport theory. C.Z. Dinu et al., Cellular
Motors for Molecular Manufacturing, 290 ANATOMICAL RECORD 1203 (2007) [Pet. Ex. 209].
120
   Kinesin is a “family of large cytoplasmic proteins with ATPase activity that bind to vesicles
and particles and transport them along microtubules, usually toward the plus end, using energy
from ATP hydrolysis …. [C]ytosolic kinesins are responsible for the transport of vesicles and
organelles.” DORLAND’S at 987.
121
  David Coy and Jonathon Howard, Organelle Transport and Sorting in Axons, 4 CURRENT
OPINION IN NEUROBIOLOGY 662 (1994) [Pet. Ex. 208].
122
   An organelle is defined as “any of the membrane-bound organized cytoplasmic structures of
distinctive morphology … including such structures as the nucleus, mitochondria, [etc].”
DORLAND’S at 1334.
123
      These articles include Merck, Summary For Basis of Approval: Varicella Virus Vaccine Live,


                                                 52
                           4. Hematopoietic Stem Cells

         According to Dr. Deisher, the most likely mechanism for insertional mutagenesis of DNA
fragments is via hematopoietic stem cells. Tr. 107. She opines that a hematopoietic stem cell in
the peripheral circulation may take up a DNA fragment from a vaccine and insert it in the
genome, causing a mutation in that cell. Id. Dr. Deisher testified that hematopoietic stem cells
produce all blood-forming cells, including immune cells, such as lymphocytes, in the blood. She
further testified that immune cells give rise to glial cells. 124 Id. Dr. Deisher stated that
hematopoietic stem cells circulate in the periphery (blood vessels and lymph system) but are
concentrated in the bone marrow and spleen. She also stated that hematopoietic stem cells give
rise to immune modulating cells, and that the cells can replace other cells in the brain and
provide new microglial cells.125 Id. at 251. She posits that a mutated hematopoietic stem cell
could lead to, or produce, a “mature glial cell, that could get into the brain.” Tr. at 107. Once in
the brain, Dr. Deisher believes the cells could impact “nerve signaling and nerve cell survival,”
which, she theorizes, may cause ASD. Id.

        In support of this theory, Dr. Deisher cites a study by McNeer et al.126 to support her
opinion that DNA fragments can be inserted into the genome of hematopoietic stem cells. See
Tr. 98. In McNeer, the authors developed a novel technique to modify a defective gene in mice.
The goal was to devise an in vivo, 127 “site-specific gene editing” tool using hematopoietic stem


Reference No. 90-0395 [Pet. Ex. 91]; Li Sheng et al., Oncogenicity of DNA in vivo: Tumor
Induction with Expression Plasmids for Activated H-ras and c-myc, 36 BIOLOGICALS 184 (2008)
[Pet. Ex. 86]; U.S. Dept. of Health and Human Servs., World Health Organization, Evolving
Scientific and Regulatory Perspectives on Cell Substrates for Vaccine Development, Rockville,
MD (Sept. 7, 1999) [Pet. Ex. 87]; World Health Organization, WHO Expert Committee on
Biological Standardization, Forty Seventh Report, 878 (1998) [Pet. Ex. 88]; Coy et al., 4
CURRENT OPINION IN NEUROBIOLOGY 662 [Pet. Ex. 208]; Dinu et al., 290 ANATOMICAL RECORD
1203 [Pet. Ex. 209]; and Bess et al., 230 VIROLOGY 134 [Pet. Ex. 207].
124
   Glial cells, also referred to as “neuroglia,” are “the cells of the supportive tissue of the central
nervous system.” There are three types of glial cells: astrocytes, oligodendrocytes, and
microglia. DORLAND’S at 321.
125
    The microglia are “the small, nonneural, interstitial cells of mesodermal origin that form part
of the supporting structure of the central nervous system …. They are migratory and act as
phagocytes to waste products of nerve tissue.” DORLAND’S at 1159.
126
   N.A. McNeer et al., Systemic Delivery of Triplex-Forming DNA and Donor DNA by
Nanoparticles Mediates Site-Specific Genome Editing of Human Hematopoietic Cells in Vivo,
20 NATURE GENE THERAPY 658 (2013) [Pet. Ex. 184].
127
   The phrase “in vivo” describes a process, procedure, or test within an intact organism.
DICTIONARY OF BIOMEDICINE, Oxford University Press (2010). In contrast, “in vitro,” is an


                                                  53
cells for the treatment of diseases. Pet. Ex. 184 at 658. The authors note that historically, gene
therapy was unsuccessful or had limited use due in part to problems with delivery, such that
genes were integrated into random sites. Id. To address this problem, McNeer’s group designed
a tool that would be capable of specific editing of genes at their “endogenous loci.” 128 Id. None
of the previous techniques for “site-specific gene editing [had] been used directly to edit human
genes in human cells in vivo.” Id. The researchers combined two technologies, 129 “synthetic
triplex-forming oligonucleotides and polymer nanoparticles – to modify human cells after [ ]
delivery into [ ] mice.” Id. at 659. Using this technology, the researchers modified the human
CCR5 gene in hematolymphoid cells in the mice. Id. at 658. McNeer, however, does not
support Dr. Deisher’s theory as it relates to hematopoietic stem cells. Instead, McNeer
establishes that the delivery and insertion of donor DNA requires “the use of molecular tools” for
delivery as well as technical manipulation at every stage of the process. Id.

       In addition to McNeer, Dr. Deisher cites several articles 130 about gene therapy trials in
children with severe combined immunodeficiency (“SCID”), also known as “Bubble boys.” Tr.


experiment “observable in a test tube.” DORLAND’S at 956.
128
   Loci is the plural form of “locus,” a genetic term for “the position of a gene on a
chromosome, different forms of genes (alleles) being found at the same position on homologous
chromosomes.” DORLAND’S at 1072.
129
   The technology used in McNeer is complex and far beyond the scope of this Decision.
Specially engineered polylactic co-glycolic acid (“PLGA”) nanoparticles were used to deliver
peptide nucleic acids (“PNA”) for the purpose of gene modification. Pet. Ex. 184 at 659.

Moreover, the McNeer researchers note that their results suggest that “PLGA nanoparticles
become widely distributed throughout the mouse, where they are taken up in human cells,
allowing for reliable gene modification, which was not achievable with equivalent dosages of
naked oligonucleotide.” Pet. Ex. 184 at 661 (emphasis added). [PLGA is “a previously
engineered poly(lactic-co-glycolic acid), an FDA-approved biocompatible material, to produce
nanoparticles that deliver nucleic acid cargo.” Pet. Ex. 184 at 2.] In fact, there was only “low to
negligible gene modification detected when naked oligonucleotides were used.” Id. at 661-62
(referencing Figure 4a). Thus, McNeer shows that DNA fragments that are not specifically
engineered to combine with a specialized delivery vehicle, like those in vaccines, would not be
taken up by hematopoietic cells.
130
   Salima Hacein-Bey-Abina et al., A Serious Adverse Event After Successful Gene Therapy for
X-Linked Severe Combined Immunodeficiency, 348 N. ENGL. J. MED. 255 (2003) [Pet. Ex. 81];
Salima Hacien-Bey-Abina et al., Insertional Oncogenesis in 4 Patients After Retrovirus-
Mediated Gene Therapy of SCID-X1, 118 J. CLINICAL INVESTIGATION 3132 (2008) [Pet. Ex.
82]; Steven Howe et al., Insertional Mutagenesis Combined with Acquired Somatic Mutations
Causes Leukemogenesis Following Gene Therapy of SCID-X1 Patients, 118 J. CLINICAL
INVESTIGATION 3143 (2008) [Pet. Ex. 83]; David Williams and Christopher Baum, Gene
Therapy: New Challenges Ahead, 302 SCIENCE 400 (2003) [Pet. Ex. 134].


                                                54
206. In one of these clinical trials, 10 boys had hematopoietic stem cells extracted from their
bone marrow. The researchers then combined a retroviral vector with corrected and defective
gene fragments creating a transgene 131 that encoded the protein that was defective in the boys
and which compromised their immune systems. Pet. Ex. 134 at 400. The treated stem cells were
then transfused back into the patients. Id. Nine of the 10 boys had “clinically significant, long
term improvements.” Id. Subsequently, however, several of the boys developed T-cell
leukemia. Further research revealed that the retroviral vector that carried the transgene inserted
“near the promoter of the proto-oncogene 132 LM02.” 133 Id. This unexpected downstream
insertion caused leukemia.

       As it relates to her theory, the SCID trials illustrate that retroviral vectors carrying a
transgene can be inserted into stem cells, which may then insert into a child’s genome to cause a
mutation. Gene therapy, however, is not comparable to vaccination. 134 Petitioners offer no
evidence to show that DNA fragments in vaccines insert into the human genome via the
techniques used in gene therapy procedures. The process of removing hematopoietic stem cells
and then transfusing them back into a child 135 after highly engineered gene therapy is not
analogous to giving a child a vaccine.




                  ii. Insertion, Mutation and Proliferation


131
   A transgene is a “segment of recombinant DNA that has been transferred from one genome to
another; the term is sometimes used specifically to denote one that has been integrated into the
germline of the recipient…” DORLAND’S at 1953.
132
   An oncogene is “a gene capable under certain conditions of causing the initial and continuing
conversion of normal cells into cancer cells.” DORLAND’S at 1321.
133
   The LMO2 gene encodes for a protein that is required for normal hematopoiesis (the
formation and development of blood cells). “Aberrant expression of this [protein] has been
implicated in…T cell acute lymphoblastic leukemia.” Pet. Ex. 134 at 400; DORLAND’S at 833.
134
   For a complete explanation of the multi-step processes utilized in gene therapy techniques,
see Pet. Exs. 81-83.
135
    Hematopoietic stem cells were harvested from the bone marrow of 10 patients with SCID.
Pet. Ex. 134 at 400. There are two main components of the SCID gene therapy process:
transduction and transplantation. Transduction involves introducing foreign DNA to a
hematopoietic stem cell ex vivo through the use of a gamma retroviral vector carrying a
transgene. Pet. Ex. 82 at 3132; Pet. Ex. 134 at 400. After the foreign DNA was introduced, the
hematopoietic stem cells containing the foreign DNA were then transplanted back to the patients.
Id.



                                               55
        Throughout her expert reports as well as during the hearing, Dr. Deisher emphasized that
she did not know the exact manner in which insertional mutagenesis occurs so as to cause ASD.
See Tr. 108; Pet. Ex. 76 at 31. She also testified that one or more of the mechanisms described
above may combine so as to result in a mutation that causes ASD. Regardless of the exact
underlying mechanism, in order to establish insertional mutagenesis as a plausible theory,
petitioners must provide evidence that residual DNA from the vaccines could insert into the
genome of the vaccine recipient, resulting in a mutation along with proliferation of that
mutation(s), and that the mutation(s) is associated with an ASD phenotype. 136

                           1. Insertion

        Dr. Deisher posits that a vaccine recipient’s cells take up “extracellular DNA fragments
by receptor mediated endocytosis.” 137 Pet. Ex. 76 at 16. Dr. Deisher stated that uptake is “most
efficient at low concentrations of extracellular DNA,” and peaks at two hours. Pet. Ex. 76 at 16
(citing Pet. Exs. 117 138 and 118 139). Based on experiments cited by Dr. Deisher, fragments of
nucleic acids, or DNA, “readily enter cultured cells through receptor mediated uptake 140 within
[two] to [four] hours.” Id. She hypothesizes that these DNA fragments then insert into a cell’s
genome and cause a mutation.

        Dr. Deisher opines that insertion of short DNA fragments is more efficient than large
DNA fragments and cites a number of studies to support this proposition. See Pet. Ex. 76 at 27-
31. However, none of these studies support her novel idea that DNA fragments from vaccines
are inserted into a child’s genome, as opposed to being destroyed through the usual process of


136
   Phenotype is defined as “the observable…characteristics of an individual…as determined by
a combination of the genotype and the environment.” DORLAND’S at 1431.
137
    Endocytosis is defined as “the uptake by a cell of material from the environment by
invagination of its plasma membrane; it includes both phagocytosis and pinocytosis.”
DORLAND’S at 617. Phagocytosis is the uptake of cell fragments. “The material is taken into the
cell in membrane-bound vesicles (phagosomes) … Phagosomes fuse with lysosomes, forming
phagolysosomes in which the engulfed material is killed and digested.” Id. at 1423. Pinocytosis
is “the cellular uptake of extracellular fluid and its contents by enclosing them in vesicles derived
from the plasma membrane.” Id. at 1449.
138
  Leonid Yakubov, et al., Mechanism of Oligonucleotide Uptake by Cells: Involvement of
Specific Receptors? 86 PROC. NATL. ACAD. SCI. USA 6454 (1989) [Pet. Ex. 117].
139
   Valentin Vlassov et al., Transport of Oligonucleotides Across Natural and Model Membranes,
1197 BIOCHEMICA ET BIOPHYSICA ACTA 95-108 (1994) [Pet. Ex. 118].
140
   “Receptor mediated uptake” is a synonymous term for “receptor mediated endocytosis.” See
infra note 137.



                                                 56
phagocytosis. 141 She posits that the ability of the DNA fragments to insert may turn on the size
of the fragments, because insertion of short fragments is more efficient and more likely. Id. at
26. Insertion is “maximal when fragments are between 100 and 1000 base pairs 142 in length.” 143
Id.

        Dr. Deisher measured the size of the residual DNA fragments in the MMR, hepatitis A,
and varicella vaccinations. She opines that the DNA fragments in MMR II and Varivax are
shorter and thus more likely to insert, and that the fragments in HAVRIX are “relatively intact”
and large, and thus, unlikely to insert. Tr. 96. Thus, she concedes that her theory of insertional
mutagenesis is not a good fit for the hepatitis A vaccine. 144

        According to Dr. Deisher, the MMR vaccine contains approximately “150 nanograms
[of] cell substrate [double-stranded] DNA and [single-stranded] DNA per dose, fragmented to
approximately 215 base pairs in length.” Pet. Ex. 76 at 12; Pet. Ex. 322 at 8; Tr. 94. Dr. Deisher
performed an experiment using “Human Cot1 DNA (Invitrogen),” to measure its ability to insert.
Pet. Ex. 322 at 6. She used Human Cot1 DNA because it is 315 base pairs in size, and it “has
reverted epigenetically towards undifferentiated primitive fetal type cells,” making it similar to
the DNA fragments in MMR. Id. The results of the experiment showed “[s]pontaneous cellular
and nuclear DNA uptake,” within “24 to 48 hours after addition of … the Cot1 DNA to the
culture media of U937 or NCCIT cells.” Id. at 58. While this experiment appears to support Dr.
Deisher’s hypothesis of DNA fragment insertion, it did not involve the residual DNA in
vaccines, and it was an in vitro experiment, where the DNA fragments were added directly to
prepared cell cultures. Thus, Dr. Deisher’s experiment does not simulate vaccination.




141
    As for children who receive the vaccines at issue and who do not develop ASD, Dr. Deisher
testified that DNA fragments would be engulfed and destroyed by the child’s innate immune
system. Tr. 324-25.
142
   Base pairs are defined as “a pair of hydrogen-bonded bases, a pyrimidine with a purine base
that bind together two strands, or two parts of a strand, of nucleic acid. In DNA, the pairs are
guanine-cytosine and adenine-thymine.” DORLAND’S at 1363.
143
   Dr. Deisher also testified that insertion of residual DNA fragments is more likely when the
vaccine contains a higher concentration of DNA fragments. See Pet. Ex. 76 at 12-13. Petitioners
provide no evidence that DNA fragments insert into human cells, regardless of fragment size or
concentration.
144
   Even assuming that Dr. Deisher’s theory regarding insertional mutagenesis is correct, her
concession that the hepatitis A vaccine is not a good fit for the insertional mutagenesis theory in
turn calls into question the validity of her change point study as it relates to the hepatitis A
vaccine and its association with the increasing prevalence of autism.



                                                57
         The paper by Petricciani and Horaud 145 further demonstrates that Dr. Deisher’s
hypothesis regarding insertion of residual DNA is not viable. By way of background, residual
DNA is known to be circulating in our blood and is thought to be the result of the breakdown of
leukocytes, bacteria, and cell necrosis. See Pet. Ex. 495 at 2-3. “Extracellular DNA is [also]
present in [our] blood plasma and other interstitial fluids.” Pet. Ex. 94 at 191. “Fetal DNA has
[even] been detected in the blood of mothers during pregnancy.” Id. DNA can also be
introduced by blood transfusions of whole blood, which contain large amounts of cellular DNA.
See Pet. Ex. 72 at 235. Dr. Deisher agreed that patients who receive whole blood transfusion are
exposed to human DNA fragments from other persons. Tr. 269-271. However, she did not
opine that insertional mutagenesis is a risk due to residual DNA from blood transfusions. Id. at
271. 146

         In Petricciani, the authors generally discuss DNA as a risk factor in a number of
biological products, and they specifically address the issue of whether the high levels of DNA in
blood plasma pose a risk of mutagenesis for patients receiving blood transfusions. Pet. Ex. 72 at
233. To address this question, Petricciani reviewed studies done in the 1970s in which no
statistical difference was found in the incidence of leukemia in patients who received blood
transfusions and those who did not. The research indicates that although foreign DNA is given
to a patient receiving a blood transfusion, “substantial amounts of cellular DNA, as well as the
cells themselves, do not carry a measurable risk,” of insertional mutagenesis causing leukemia.
Id. at 235.

        Dr. Deisher cites numerous studies 147 related to uptake of oligonucleotides, presumably
in support of her theory of DNA insertion. Generally, these are older reports on in vitro studies
related to the delivery and uptake of nucleic acids for research and development related to gene
therapy. Findings or conclusions set forth in these in vitro experiments cannot be extrapolated
beyond the cell lines, culture conditions, and/or methodologies used in any particular study. As


145
   John Petricciani & Horaud Florian, DNA, Dragons and Sanity, 23 BIOLOGICALS 233-38
(1995) [Pet. Ex. 72].
146
   Dr. Deisher testified that DNA in blood used for transfusions “is not fetal DNA,” and that it
does not readily insert because it is not “primitive.” Tr. 271.
147
    See Vlassov et al., 1197 BIOCHIMICA ET BIOPHYSICA ACTA 95 [Pet. Ex. 118]; Frank Orson et
al., Oligonucleotide Inhibition of IL2Rα mRNA Transcription by Promoter Region Collinear
Triplex Formation in Lymphocytes, 19 NUCLEIC ACIDS RESEARCH 3435 (1991) [Pet. Ex. 119];
Paul Zamecnik et al., Inhibition of Replication and Expression of Human T-cell Lymphotropic
Virus Type III in Cultured Cells by Exogenous Synthetic Oligonucleotides Complementary to
Viral RNA, 83 PROC. NATL. ACAD. SCI. USA 4143 (1986) [Pet. Ex. 120]; S.L. Loke et al.,
Characterization of Oligonucleotide Transport into Living Cells, 86 PROC. NATL. ACAD. SCI.
USA 3474 (1989) [Pet. Ex. 121]; and E.H. Postel et al., Evidence that a Triplex-Forming
Oligodeoxyribonucleotide Binds to the c-myc Promoter in HeLa Cells, Thereby reducing c-myc
mRNA Levels, 88 PROC. NATL. ACAD. SCI. USA 8227 (1991) [Pet. Ex.123].



                                                58
the researchers in Loke concluded, “whether there is a physiological role for oligo transport is
unknown. We may, nevertheless, utilize our understanding of the properties of the uptake
process to design oligos that are transported more efficiently and are more resistant to
degradation.” Pet. Ex. 121 at 3478. This sentiment is echoed by Vlassov, as follows: “Although
the existing methods of delivery of nucleic acids into cells allow easy transfection of any kind of
cells in vitro, the in vivo incorporation of oligo and polynucleotides in heterogeneous
populations of different cells in organism[s] remains a problem.” Pet. Ex. 118 at 95-96.

        Another idea advanced by Dr. Deisher is that DNA, once inserted into a host cell, may
contribute to chromosomal “breaks or rearrangements.” Pet. Ex. 76 at 7. In variations on this
theme, she also posits that DNA fragments could more easily insert during ongoing cellular
processes “such as DNA repair, recombination, and replication.” Id. at 22. Cells can “repair by
homologous recombination 148 and by illegitimate recombination of DNA fragments.” Id. She
suggests that this cellular repair process “provides the opportunity for insertion of DNA
fragments.” Id. Petitioners, however, provide no evidence that DNA fragments from vaccines
are involved in chromosomal breaks or rearrangements, or that they insert in the cell’s genome
during the cellular repair process described here.149

        Dr. Deisher opines that DNA “integration is opportunistic and most likely occurs during
gene repair which is maximized during periods of disruption, such as…when a child’s neurons
are being pruned, i.e. from [one] to [three] years of age.” Pet. Ex. 76 at 5. However, petitioners
provided no evidence that residual DNA fragments from vaccines integrate into the genome
during “pruning.” Further, Dr. Deisher proposes that “[m]eiotic recombination involves highly
regulated pathways of double strand break formation and repair. [It] occurs at clustered sites
within the human genome, termed recombination hotspots….Sites of [meiotic recombination]
have been demonstrated to be [] susceptible to double strand breaks and mutations.” Pet. Ex. 76
at 24. Dr. Deisher suggests that hotspots are areas where DNA fragments from vaccines could
insert into the genome and cause a mutation. Id. at 23-26; 34-35. Petitioners offered no
evidence to show that DNA fragments from vaccines could insert in this manner.


148
   Recombination is “the process that creates new combinations of genes by shuffling the linear
order of the DNA, such as occurs naturally by crossing over of homologous chromosomes during
meiosis or of homologous DNA sequences in somatic cells during mitosis, or occurs in vitro
when DNA or RNA is manipulated for genetic engineering.” DORLAND’S at 1607. Homologous
recombination “comprises a series of interrelated pathways that function in the repair of DNA
double-stranded breaks…. [it] plays a prominent role in faithfully duplicating the genome by
providing critical support for DNA replication…” Xuan Li & Wolf-Dietrich Heyer, Homologous
Recombination in DNA Repair and DNA Damage Tolerance, 18 CELL RES. 99 (2008).
149
   Dr. Deisher also opines that “[a]ltered double strand break formation and repair pathways
may be a commonality among the extremely diverse genetic mutations observed in ASD.” Pet.
Ex. 76 at 26. She suggests that residual DNA from vaccines may insert during the repair
process, and that this would account for the many diverse genetic mutations reported in ASD, but
petitioners offer no evidence to support this idea.



                                                59
        One of the reasons that Dr. Deisher favors hematopoietic stem cells as the most likely
mechanism is due to their use in gene therapy studies.150 In these experiments, researchers use
specifically designed DNA fragments as “agents for gene replacement therapy.” Pet. Ex. 127 at
2293. “Gene targeting modifies a gene in its chromosomal location, preserving existing
mechanisms to regulate its function in cells, and thereby holds great promise as a medical
treatment strategy.” Id. These experiments may result in uptake or insertion of small fragments
of DNA but with specifically produced “DNA constructs.” Id. Yakubov provides a brief
summary of the different types of DNA constructs used in those experiments. See also Pet. Exs.
131, 132. Dr. Deisher does not provide evidence that these experiments simulate the conditions
of vaccination.

        Another variation on the theme of insertion relates to insertions and deletions. Dr.
Deisher states that “[w]hole exome sequencing of DNA [] from the peripheral blood of 20
children with [ASD] has identified non-inherited insertions and deletions….Insertions/deletions
are known to cause subsequent additional mutations and therefore, this observation requires
further studies to determine the DNA source for the[se] de novo insertions.” Pet. Ex. 76 at 42.
This idea adds an additional step to the process. Dr. Deisher suggests that DNA fragments from
vaccines cause insertions/deletions, and that these insertions/deletions cause additional mutations
which cause ASD.

       Ultimately, however, Dr. Deisher concedes that even if insertion could be proven, the
question then becomes how “such an insertion would impact neural development or would occur
within a cell in the [CNS], [given that] autism spectrum is a neurodevelopmental disorder.” Pet.
Ex. 76 at 31.

                           2. Mutation

        Assuming that DNA fragments from vaccines could insert into a host genome, the next
question is whether there is evidence that insertion could cause a mutation. 151 Fundamental to
Dr. Deisher’s theory is that “small DNA fragments efficiently insert into the recipients’ genome
… [and are] involved in de novo mutations.” 152 Pet. Ex. 76 at 41. She states that approximately
nine to 10 percent of children with ASD have de novo mutations. Pet. Ex. 76 at 42 (referencing


150
   Dr. Deisher states that the Chin and Liu studies both demonstrate “the efficiency of DNA
integration into stem cells.” Pet. Ex. 76 at 30 (referencing Pet. Exs. 184 and 185).
151
   Dr. Deisher also stated that, “DNA can insert into a genome, cause mutations upstream or
downstream of that insertion and then be excised from the genome, a phenomenon termed [h]it-
and-run.” Pet. Ex. 76 at 41. She suggests that this idea may make it difficult to measure
genomic insertions, presumably caused by vaccines. Id. at 42. Petitioners offer no evidence to
show how this idea is relevant to their theories.
152
   Dr. Deisher also posits that “DNA fragments could cause “de novo mosaic mutations among
nerve cells.” Pet. Ex. 76 at 34. Petitioners offered no evidence to support this idea as it relates to
her theory here.


                                                 60
Pet. Ex. 238 153). She believes these de novo mutations are caused by vaccines (postnatally). Tr.
132, 185. Additionally, Dr. Deisher posits that the genes associated with ASD “have a more
concentrated susceptibility for insults to genomic stability” as compared to other genes, and that
“regions of the genome where meiotic recombination 154 occurs,” (i.e. hotspots) may be “highly
predisposed … to disease causing mutations.” Pet. Ex. 322 at 4.

       Dr. Deisher readily conceded that there is a problem of evidence. She stated, “this
observation [of de novo mutations] requires further studies to determine the DNA source for the
de novo insertions and whether the DNA fragments contained in childhood vaccines may
provide the DNA documented in de novo insertions.” Pet. Ex. 76 at 42. Thus, by her own
admission, current studies do not provide evidence that DNA fragments in vaccines cause the
mutations at the heart of her theory.

       While Dr. Deisher did not provide an evidence-based explanation as to how these de
novo mutations occur, she testified that many studies demonstrate that children with ASD have
diverse mutations in lymphoblastoid cell lines.155 Tr. 125-26; see also Pet. Ex. 283. The



153
  Brian O’Roak et al., Sporadic Autism Exomes Reveal a Highly Interconnected Protein
Network of De Novo Mutations, 485 NATURE 246 (2012) [Pet. Ex. 238].
154
   Meiotic recombination (“MR”) is defined by Dr. Deisher as the process during meiosis in
which “genomic material is exchanged between the maternal and paternal chromosomes.” Pet.
Ex. 322 at 50. “Hotspots are sites in the genome … where MR occurs most frequently.” Id.
“[R]egions of the genome where [MR] has occurred (hotspots) have been shown to be highly
predisposed to … disease causing mutations.” Id. She further hypothesizes that autism
associated genes (“AAGs”) have a “concentrated susceptibility for insults to genomic
stability…” Id. at 48. Specifically, she suggests that X-chromosome genes may be susceptible
to DNA fragment insertion, which could “lead to de novo mutations.” Id. at 55-59. Dr. Deisher
urges “additional study and investigation of this potential relationship.” Id. at 59.
155
    Dr. Deisher opined that de novo mutations account for approximately 10 percent of ASD
cases. Pet. Ex. 10 at 6. She proposes that residual DNA fragments from vaccines could insert
into lymphocytes, which are derived from hematopoietic stem cells. Tr. 130. A lymphocyte is
“any of the mononuclear, nonphagocytic leukocytes, found in the blood, lymph, and lymphoid
tissues, that are the body’s immunologically competent cells and their precursors.” DORLAND’S
at 1084. A lymphoblast is “an activated lymphocyte that has that has been transformed in
response to antigenic stimulation.” Id. After a lymphoblast is activated, it divides and makes
clones of the original cell, and the copies of the original all carry the same mutation. In this way,
lymphoblastoid cell lines are useful tools for researching genetic diseases.
When a lymphocyte becomes activated by an antigen, it creates a lymphoblast, which then
divides and creates more lymphocytes. This process creates lymphoblastoid cell lines, and all of
the cells in the lineage are identical. Dr. Deisher points to several genetic studies which have
found that “rare diverse mutations” are present in the lymphoblastoid cell lines of children with
ASD. Tr. 125. She cites to the 2012 O’Roak paper to support her theory that de novo mutations


                                                 61
mutations cause “deletions in exomes” 156 that result in the lack of a protein, or a “truncated
protein that may not work.” Tr. 127-28.

        Dr. Arking strongly disagreed with Dr. Deisher’s theory of insertional mutagenesis. A de
novo mutation is a mutation seen in the child that is not found in the parent. Tr. 572-73. When a
de novo mutation occurs postnatally, 157 it will only be observed in the cell that mutates and the
cells that divide from that mutated cell. It will not be observed in other sets of cells in the body.
Id. at 574. Thus, a single mutated cell, even one that divides exponentially, may lead to a
disease, such as a localized tumor, but would not cause a diffuse brain disease like ASD.

       Further, there is a question about how a mutation in a single cell could cause ASD. An
individual neuron with a mutation does not cause disease. Tr. 575. 158 For neurons to cause
disease, Dr. Arking testified that the mutation must occur in a significant percentage of cells.159


found in lymphoblastoid cell lines could cause ASD. Tr. 130 (referencing Pet. Ex. 238; Resp.
Ex. H7).

O’Roak compared the lymphoblastoid cell lines of children with autism with their non-autistic
siblings and found that both affected and unaffected children had de novo mutations that their
parents did not have. Pet. Ex. 238 at 585. The results also showed that affected children had
insertions and deletions (“indels”) that their unaffected siblings did not have. Id. at 586. Dr.
Deisher testified that because the de novo mutations were found in lymphoblastoid cell lines, the
O’Roak results demonstrate that ASD can be caused by de novo mutations. Tr. 126. She further
postulates that the de novo insertion mutations are caused by residual DNA fragments found in
vaccines. Id. at 130, 132. However, the O’Roak paper does not contemplate the mechanism for
the creation of indels, nor do the authors hypothesize that residual DNA fragments from vaccines
could cause insertion mutations.
156
  An exome is part of the genome formed by exons, or “coding sequences in a gene.”
DORLAND’S at 660.
157
   Postnatal mutations occur after the child’s birth (as the result of vaccinations, as posited by
Dr. Deisher).
158
   The brain is tolerant to mutations in individual neurons; people with normal development may
have abnormal neurons. To affect function, one must have the “same mutation in lots of
neurons.” See Resp. Ex. H10; Tr. 589. Even assuming that DNA from a vaccine can get into the
brain and cause a mutation, “the brain is robust to those mutations.” Id. at 589-90.
159
   Under Dr. Deisher’s theory of insertional mutagenesis, once DNA reaches the brain, it then
must integrate into the genome of neurons. Tr. 255. Dr. Deisher testified that the quantity of
DNA that reaches the brain is irrelevant. Even “a very small percent[age]” may be sufficient.
Id. Using her method of hematopoietic stem cells as a vehicle for DNA insertion as an example,
Dr. Deisher testified that six percent of hematopoietic stem cells with the mutation would be
sufficient to cause disease. Id. at 257. “[T]heoretically, uptake from a very small percent[age] of


                                                 62
The only way that a mutation can be found in a substantial number of neurons is for it to occur
early in the prenatal period, not postnatally, when children receive vaccines. See id. at 575.
Respondent filed six articles to support his position that genetic mutations which cause ASD
most likely occur prenatally. 160

        One paper cited by respondent, O’Roak, suggests that the majority of mutations found in
ASD occur pre-conception, in the sperm of the father. Tr. 585, 574; see also Resp. Ex. H7 (Pet.
Ex. 238). A mutation in the sperm cell of the father could be in all of the cells of the child. Tr.
574. The earlier a mutation occurs post-conception, but before birth, the more cells will be
affected. Id. If, for example, the mutation occurs when the embryo is 64 cells, then the vast
majority of the cells will have the mutation. If the mutation occurs later, it may be tissue
specific, depending on what stage the mutation occurs during development. Id. at 574.

       Dr. Arking also cites the Iossifov et al. 161 paper to support his opinion that de novo
mutations associated with ASD occur prenatally. Tr. 599; Resp. Ex. H4; Pet. Ex. 641. Iossifov


the hematopoietic stem cells could lead to a mutated cell that takes over and outgrows the other
cells.” Id. at 258. However, Dr. Deisher concedes that the mutation of one neuron does not
trigger autism. Id. at 261. And she does not know the percentage of mutated cells that would be
required to cause autism. Id. at 259-60.

In addition to the issue of what percentage of mutated cells are required to cause disease, there is
also the issue of whether insertional mutagenesis would give rise to one type of mutation, or
many mutations. Dr. Deisher gave contradictory answers when asked whether neurons would
have to share the same mutation as a result of insertional mutagenesis to result in ASD. Initially,
she testified that “I would not necessarily expect [] other neurons to share the same mutation.”
Tr. 262. Later, she testified that if the mutated cell gives rise to a monoclonal cell line, then all
of the cells would carry the same mutation. Id. at 265. However, she then testified that based on
published studies, children with ASD “all have different mutations …. [and] each child has a
different mutation.” Id. at 266. She posits that her theory of insertional mutagenesis
contemplates that “insertion is a random event,” leading to “diverse mutations.” Id.
160
   O’Roak et al., 485 NATURE 246 [Resp. Ex. H7; Pet. Ex. 238]; Annapurna Poduri et al.,
Somatic Mutation, Genomic Variation, and Neurological Disease, 341 SCIENCE 43 (2013) [Resp.
Ex. H9]; Xuyu Cai et al., Single-Cell, Genome-Wide Sequencing Identifies Clonal Somatic
Copy-Number Variation in the Human Brain, 8 CELL REP. 1280 (2014) [Resp. Ex. H10];
Michael McConnell et al., Mosaic Copy Number Variation in Human Neurons, 342 SCIENCE
632-37 (2013) [Resp. Ex. H11]; Frederico Azevedo et al., Equal Numbers of Neuronal and
Nonneuronal Cells Make the Human Brain an Isometrically Scaled-Up Primate Brain, 513 J.
COMP. NEUROL. 532-41 (2009) [Resp. Ex. H12]; Rich Stoner et al., Patches of Disorganization in
the Neocortex of Children with Autism, 370 N. ENG. J. MED. 1209 (2014) [Resp. Ex. H24].
161
   Ivan Iossifov et al., The Contribution of De Novo Coding Mutations in Autism Spectrum
Disorder, 515 NATURE 216 (2014) [Resp. Ex. H4].



                                                 63
focused on ultra-rare mutations passed from parent to child, as well as genes expressed in the
embryonic brain, and concluded that evidence suggests that de novo mutations causing ASD
occur prenatally. Tr. 599-601.

        Dr. Arking also cited a paper by Poduri et al.,162 regarding de novo mutations that arise in
the germline cells,163 as well as “after fertilization during embryonic development”, which cause
somatic mutations associated with neurodevelopmental disease. Resp. Ex. H9 at 43. While
Poduri suggests that somatic mutations can cause disease, these mutations are thought to “occur
during [ ] cell divisions that generate the embryo after fertilization and zygote formation.” Id. at
44. That is, these mutations “occur early enough in development to be present in many tissues.”
Id. at 46. Moreover, “patients can show dysfunction … when only [eight] to 35 percent of the
brain cells carry the mutation.” Id. at 43. Dr. Arking testified that the eight percent of neurons
referenced in Poduri would be impossible to achieve with Dr. Deisher’s insertional mutagenesis
hypothesis. Tr. 588. Even if one accepts Dr. Deisher’s idea that DNA can get into the brain and
cause a mutation, it would not affect a sufficient number of neurons to cause autism. Id. at 590.
And a mutation of one neuron would not lead to an observable phenotype such as ASD. Id. at
592.

                             3. Proliferation

        A fundamental problem with Dr. Deisher’s theory, as explained by Dr. Arking, is that she
posits that autism is caused by a postnatal mutation, which by its very nature would only affect a
small number of cells, as opposed to a mutation found throughout all the cells of the brain. Tr.
643. Autism is a diffuse syndrome of the brain, and thus it is not conceivable that a single cell
mutation occurring postnatally could affect a sufficient number of cells so as to cause such a
diffuse process. Tr. 639-40. This is why cell proliferation, the idea that the mutated cells
multiply so as to cause ASD, is a basic tenet of Dr. Deisher’s theory.

        One of the reasons Dr. Deisher favors hematopoietic stem cells as a mechanism is that
they have a “survival advantage,” and proliferate much more than other cells. 164 Tr. at 260.
Presumably, if a stem cell has a mutation, it would multiply and take over so as to outgrow other
cells. To illustrate her hypothesis that hematopoietic stem cells proliferate and can lead to the


162
      Poduri et al., 341 Science 43 [Resp. Ex. H9].
163
   A mutation in the sperm or egg is called a germline mutation. “Mutations in germline cells
are transmitted to progeny; those in somatic cells (all other body cells) are not.” DORLAND’S at
773.
164
   Dr. Deisher testified that she could not comment on what quantity of fetal DNA in the brain
required to cause autism, because “experiments have not been done to determine that.” Tr. 254.
Although she testified that “one mutated nerve cell,” could cause “significant disease,” she does
not believe that the mutation of a single neuron is a trigger for autism, and that is not one of her
theories. Id. at 259, 261.



                                                  64
development of autism, Dr. Deisher cited articles by Lu et al., 165 Naik et al., 166 Cheung et al., 167
Busque et al., 168 Smith et al., 169 Garrits et al., 170 and Verovskaya et al.171 Generally, these
articles discuss experiments in mice using cellular barcoding analysis of hematopoietic stem
cells. Barcoding allows tracking of individual stem cells with the goal of better understanding
clonal 172 dynamics and characteristics, including size, age, lineage, and proliferation tendencies.
After reviewing the articles, the most that can be said is that “the number of hematopoietic stem
cells that contribute[] to blood formation and the dynamics of their clonal contribution is a matter
of ongoing [research and] discussion.” Pet. Ex. 691 at 523.

        For example, in the Lu article, individual hematopoietic stem cells were tracked using
“barcodes” that allowed the researchers to follow and measure the proliferation of an individual
cell. Pet. Ex. 685 at 928. The researchers then transplanted 9,000 stem cells into irradiated
mice. Id. at 932. Twenty-two weeks after transplantation, the mice were sacrificed and


165
   Rong Lu et al., Tracking Single Hematopoietic Stem Cells In Vivo Using High-Throughput
Sequencing in Conjunction with Viral Genetic Barcoding, 29 NAT. BIOTECHNOL. 928 (2002)
[Pet. Ex. 685]. According to Dr. Deisher, the researchers in this study used a process known as
bar coding in order to track blood cell cloning. Tr. 858.
166
   Shalin Naik et al., Diverse and Heritable Lineage Imprinting of Early Hematopoietic
Progenitors, 496 NATURE 229 (2013) [Pet. Ex. 686] (discussing the clonality of the blood
system); see Tr. 680.
167
   Alice Cheung et al., Analysis of the Clonal Growth and Differentiation Dynamics of Primitive
Barcoded Human Cord Blood Cells in NSG Mice, The American Society of Hematology, (2013)
[Pet. Ex. 687] (cited by Dr. Deisher to show the clonality of the blood system); see Tr. 861.
168
   Lambert Busque et al., Recurrent Somatic TET2 Mutations in Normal Elderly Individuals
with Clonal Hematopoiesis, 44 NAT. GENET. 1179 (2012) [Pet. Ex. 688] (cited by Dr. Deisher to
show the clonality of the blood system); see Tr. 680.
169
    Laurie Smith, Clonal Analysis of Hematopoietic Stem-Cell Differentiation In Vivo, 88 PROC.
NATL. ACAD. SCI., USA 2788 (1991) [Pet. Ex. 689] (cited by Dr. Deisher to show the clonality
of the blood system); see Tr. 860.
170
   Alice Gerrits et al., Cellular Barcoding Tool for Clonal Analysis in the Hematopoietic
System, 115 BLOOD 2610 (2010) [Pet. Ex. 690].
171
   Evgenia Verovskaya et al., Heterogeneity of Young and Aged Murine Hematopoietic Stem
Cells Revealed by Quantitative Clonal Analysis Using Cellular Barcoding, 122 BLOOD 523
(2013) [Pet. Ex. 691].
172
   Clonal is defined as “one of a group of genetically identical cells or organisms derived …
from a single common ancestor.” DORLAND’S at 373.



                                                  65
analyzed, and approximately 50 to 80 of the 9,000 originally transplanted cells had begun to
proliferate in the mice. Id. This finding “suggests that [hematopoietic stem cells] do not equally
contribute to blood cells after irradiation-mediated transplantation.” Id. at 928. Dr. Deisher used
the Lu experiment to opine that only “seven or eight hematopoietic stem cells at any one time are
making all the cells in the body, and one or two of them are actually making the most of the cells
….” Tr. 858. Thus, Dr. Deisher infers that a mutation in a single stem cell could proliferate
sufficiently to cause ASD. 173 Id.

         Dr. Arking explained why these barcoding studies do not support Dr. Deisher’s
hypothesis. Resp. Ex. P at 2. All of the studies were performed in mice, whose native
hematopoietic stem cells had been lethally irradiated, which is very different from the normal
human blood cell production process. Id. The researchers “recovered barcodes after the infected
[hematopoietic stem cells] had undergone proliferation and differentiation in vivo.” Pet. Ex. 685
at 935. This means that “50 [to] 100 cells … originally engrafted … expanded to replace the
radiation destroyed native [stem cells], over time expanding out to the [approximately] 15,000
[stem cells] that a typical mouse requires to maintain its blood cells.” Resp. Ex. P at 2. It does
not mean that under normal circumstances, the body only uses 50 to 100 hematopoietic stem
cells to make all of the blood in the body. The most one can say based on the Lu experiment is
that hematopoietic stem cells may not equally contribute to the formation of blood cells in mice




173
    Dr. Deisher also cited the SCID gene therapy trials to support her idea that “a mutation in [a]
single cell could … contribute significantly to a disease other than cancer.” Tr. 856. She also
cited to a paper by Josef Prchal et al. for the proposition that “just a handful of stem cells
contribute to all of the blood cells of our body, and that [their] contribution is stable over time.”
Id. at 857 (referencing Pet. Ex. 864). She further testified that Prchal’s research shows that the
majority of blood cells come from a single clone.173 Id. (referencing Pet. Ex. 864, Table 1, at
563).

Dr. Arking disagreed that the SCID trials support Dr. Deisher’s notion of cell proliferation. He
explained that in the SCID trials, 20 million cells per kilogram of body weight were removed
from each child. After gene therapy procedures were performed, the cells were infused back into
the children. Tr. 594. Thirty-five percent of the cells given back to the children had the
abnormal gene, which propagated in the child’s bone marrow, ultimately causing leukemia.

Dr. Arking further testified that Dr. Deisher incorrectly cited the Prchal study, stating that the
paper does not address “the number of active [hematopoietic stem cells] for normal blood
production.” Resp. Ex. P at 2 (referencing Pet. Ex. 684).



                                                 66
after “irradiation-mediated transplantation.” Pet. Ex. 685 at 928; see also Resp. Exs. P1 174 and
P2.175

        In summary, Dr. Arking explained that a mutation arising from a vaccination, occurring
after birth, cannot result in autism for several reasons. First, the timing is wrong. The current
state of scientific knowledge suggests that autism is a neurodevelopmental disorder that occurs
prenatally during brain development. Tr. 575. Second, effects on individual neurons, through
the process of insertional mutagenesis as contemplated by Dr. Deisher, will not have an effect on
the number of cells that would be necessary to cause disease. Id. For the effect to be observed,
the mutation would need to be present in a substantial portion of cells. And for that to occur the
mutation would need to occur prenatally, during the first or second trimester. Id. If the mutation
occurs postnatally, as suggested by Dr. Deisher, it will be found in far fewer cells. If the
mutation occurs in a single cell, as contemplated by Dr. Deisher, then mutations would only be
observed in that cell and immediately around that cell as it divides. Id. at 574. Third, the brain is
robust to postnatal somatic mutations. Tr. 201 (citing Resp. Ex. H10; Resp. Ex. H11).

                     iii. Autoimmunity

        Dr. Deisher’s second proposed mechanism is that human DNA fragments in vaccines
cause an autoimmune reaction that causes ASD. Tr. 82; Pet. Ex. 10 at 3. She opined that
“autoimmunity is demonstrated to be a likely mechanism by publications that have come out
since 2012, in approximately 40 percent of children with autistic disorder.” 176 Tr. at 256. Dr.
Deisher testified that an autoimmune response can occur due to homology between the DNA
fragments in the vaccine and the DNA of the vaccine recipient. Id. at 116. Although she opined
that autoimmunity may be a “possible mechanism,” she did not focus on it in her written papers,
in part because, in its Summary Basis of Approval for the varicella vaccine, Merck reported that
“they had not seen any potential antibody responses that could trigger an autoimmune response.”
Tr. 97-98 (citing Pet. Ex. 28 at 3).


174
   Katrin Busch et al., Fundamental Properties of Unperturbed Haematopoiesis [sic] From Stem
Cells in Vivo, 518 NATURE 542 (2015) [Resp. Ex. P1] (“[B]arcoding of transplanted
[hematopoietic stem cells] suggest that very low numbers of [hematopoietic stem cells]
perpetuate a continuous stream of differentiating cells. However, the numbers of productive
[hematopoietic stem cells] during normal hematopoiesis, and the flux of differentiating progeny
remain unknown.”)
175
    Katrin Busch and Hans-Reimer Rodewald, Unperturbed vs. Post-Transplantation
Hematopoiesis: Both in Vivo but Different, 23 CURRENT OPINION HEMATOLOGY 295 (2016)
[Resp. Ex. P2] (“Noninvasive genetic experiments in mice have identified a major role of stem
and progenitor cells downstream from [hematopoietic stem cells] as drivers of adult
hematopoiesis, and revealed that post-transplantation differs quantitatively from normal steady-
state hematopoiesis.”).
176
      It is not clear which studies Dr. Deisher is referencing.
.


                                                    67
        Dr. Deisher testified that “autism is probably a multi-hit disease, similar to [] other
autoimmune diseases, where [] children may have underlying genetic susceptibility, exposure to
something that[] … trigger[s] antibodies against their own DNA, and then perhaps a viral insult
… [or] infection breaks down the blood-brain barrier,” with the result being that “circulating
antibodies are … present to the brain.” Tr. 123. She referred to this as “exposure and
opportunity.” Id. at 124. She posits that an “autoimmune attack” could cause permanent damage
to the child’s brain. Id.

         Dr. Deisher stated that HERV-K fragments may also cause an autoimmune response and
have been “associated with several autoimmune diseases.” Pet. Ex. 76 at 15. She cites articles
by Tai, Freimanis, and Dickerson 177 in support of these assertions but does not further explain
how they apply to her theory. Id. (referencing Pet. Ex. 111-113). The article by Tai et al.
discussed the expression of a HERV-K envelope protein and its potential role in the development
of multiple sclerosis. Pet. Ex. 111 at 1176. Freimanis et al. studied the potential role of HERV-
K in causing rheumatoid arthritis, noting that a significant percentage of patients with
rheumatoid arthritis showed serological increases of HERV-K. Pet. Ex. 112 at 340. Dickerson
et al. studied HERV-K in the context of individuals with schizophrenia who are also at risk of
developing type 2 diabetes. Pet. Ex. 113 at 121. However, none of these articles discuss HERV-
K in the context of ASD, nor are they based on residual HERV-K fragments found in vaccines.
The authors of these studies do not contemplate that HERV-K fragments in any way create an
autoimmune reaction that leads to the development of ASD.

        Dr. Deisher also posits that from birth to approximately three years of age, “nerve cell
death occur[s] on a massive scale. During periods of intense brain cell death such as this, DNA
not otherwise found extracellularly would be present and serve as the target for autoimmune
attacks, originally triggered by exposure of a young child to the fetal DNA fragments found in
vaccines.” Pet. Ex. 76 at 21-22. This idea appears to add another step in the theoretical process.
Dr. Deisher seems to suggest that once residual DNA from vaccines triggers an autoimmune
process, the extracellular DNA from the breakdown of the child’s own neurons during a period
of intense cell death causes ASD. Petitioners provided no evidence to support this idea.




177
   A.K. Tai et al., Human Endogenous Retrovirus-K18 Env as a Risk Factor in Multiple
Sclerosis, 14 MULTIPLE SCLEROSIS 1175 (2008) [Pet. Ex. 111]; G. Freimanis et al., A Role for
Human Endogenous Retrovirus-K (HML-2) in Rheumatoid Arthritis: Investigating Mechanisms
of Pathogenesis, 160 Clinical and Experimental Immunology 340 (2010) [Pet. Ex. 112]; Faith
Dickerson et al., Polymorphisms in Human Endogenous Retrovirus K-18 and Risk of Type 2
Diabetes in Individuals with Schizophrenia, 104 SCHIZOPHRENIA RESEARCH 121 (2008) [Pet. Ex.
113].



                                                68
                             1. Auto-Antibodies and Autoimmunity 178
        Petitioners cite several papers published by Mostafa and his colleagues that report an
increase in autoantibodies, antibodies directed against the self, in children with autism as
compared to controls. 179 For example, in a study published in 2014,180 Mostafa demonstrated the
presence of anti-double-stranded-DNA antibodies 181 and anti-nuclear antibodies (“ANA”) 182 in a
group of autistic children. Pet. Ex. 551 at 94. These antibodies were assessed in 80 children
with autism and 80 controls. Significantly higher levels of the antibodies were found in children
with autism as compared to the control group. 183 Id. at 97. In a 2010 study by Mostafa 184
analyzing a subgroup of children with severe autism, the finding was more pronounced. Pet. Ex.
620 at 464. The authors postulate that these antibodies may cause diffuse brain abnormalities,
however, “it is far from clear whether autoimmunity to neuronal antigens is a consequence of the

178
   I also note prior cases in which the theory of autoimmunity as a mechanism for ASD has been
rejected. See R.K., 2015 WL 10911950; Cunningham v. Sec’y of Health & Human Servs., 2016
WL 4529530 (Fed. Cl. Spec. Mstr. Aug. 1, 2016); mot. for rev. denied 2017 WL 1174448 (Fed.
Cl. 2017); R.V., 2016 WL 3882519.
179
   See Gehan Mostafa et al., Systemic Auto-Antibodies in Children with Autism, 272 J. IMMUN.
94 (2014) [Pet. Exs. 481, 551]; Gehan Mostafa et al., The Relationship Between the Increased
Frequency of Serum Antineuronal Antibodies and the Severity of Autism in Children, 16
EUROPEAN J. PAEDIATRIC NEUROL. 464 (2012) [Pet. Exs. 489, 620].
180
      Mostafa et al., 272 J. IMMUN. 94 [Pet. Ex. 551].
181
    Anti-DNA antibodies are a subtype of anti-nuclear antibodies. “The anti-DNA antibody test
is useful for the diagnosis and follow-up of systemic lupus erythematosus.” MOSBY’S MANUAL
OF DIAGNOSTIC AND LABORATORY TESTS, (“MOSBY’S”) (5th ed.) at 78. (2014). There are two
types. “The first and most commonly found is the antibody against double-stranded DNA (“anti-
ds-DNA”). The second type is the antibody against single-stranded DNA (“anti-ss-DNA”).” Id.
182
    ANAs are “autoantibodies to intracellular antigens.” Pet. Ex. 481 at 94. They are “used to
diagnose systemic lupus erythematosus (“SLE”) and other autoimmune diseases.” MOSBY’S at
88.
183
   The words “anti-human anti-double stranded DNA antibodies,” “antineuronal antibodies,”
and “anti-double stranded DNA antibodies” are generally synonymous for purposes of this
decision. See Tr. 119; see also Tr. 469.
184
   Mostafa et al., 16 EUROPEAN J. PAEDIATRIC NEUROL. 464 [Pet. Ex. 620]; see also, Pet. Ex.
481 at 97 (“[I]ncreased frequency of autoimmune disease among families of patients with autism
may … point to [ ] auto-immune background.”). However, replication studies of larger samples
are warranted to validate whether autoantibodies are “a mere association or have some
pathogenic role.”); Pet. Ex. 489 at 466 (“However, it is far from clear whether autoimmunity to
neuronal antigens is a consequence of the autoimmune diseases or actually initiates the
process.”).


                                                  69
autoimmune diseases or actually initiates the process.” Id. at 466. 185 Dr. Deisher concedes that
while anti-DNA antibodies have been found in autistic patients, it is not known whether they
represent a pathological finding or a compensatory response. Tr. 278.

        Dr. Halsey testified that while the Mostafa studies provide an interesting observation,
they do not provide evidence of causality. Tr. 469. Dr. Halsey provides context for
understanding the findings reported in the Mostafa studies. He cites to a paper by Aggarwal, 186
which explains that autoantibodies are found in the general population as well as in those with
autoimmune disorders. Tr. 470-71. Thus, “the presence of autoantibod[ies] alone do[] not make
a diagnosis.” Resp. Ex. L24 at 907. “The pathological significance of autoantibodies in the
causation of disease is limited.” Id. at 909. For many autoimmune disorders, the presence of
antibodies is believed to be a secondary effect, caused by the breakdown of human cells. Tr.
543. DNA left from the destruction of cells may trigger the formation of antibodies. Id. Thus,
the presence of antibodies is not evidence that the antibody caused the illness. Id.

       Dr. Deisher testified that with regard to children who receive a vaccine with DNA
fragments who do not develop any adverse autoimmune reaction, the body’s innate immune
system would recognize the DNA as foreign, and it would engulf and destroy the residual DNA
fragments through the process of phagocytosis. Tr. 324-25.

        A varicella vaccine safety study187 was performed by the manufacturer to assess whether
residual DNA in the vaccine could induce a harmful anti-DNA response. The study was
performed on 293 people who received the vaccine. Pet. Ex. 28 at 14. Anti-DNA titers were
tested before vaccination, at six weeks, and one year after vaccination. There was no significant
change in titers before or after the vaccination. 188 Id. Dr. Halsey testified that the study showing
“no increase in autoantibod[ies] after two doses of [the] vaccine … is evidence against the
hypothesis that the residual DNA might induce an immune response to the DNA.” Tr. 475.




185
   In Mostafa, the authors speculate that an autoimmune reaction to neurons might be triggered
by infectious agents (chronic bacterial infections), food allergies, heavy metals, and latex.
Further studies are recommended. Pet. Ex. 620 at 467.
186
  Amita Aggarwal et al., Role of Autoantibody Testing, 28 BEST PRACT. & RESEARCH CLIN.
RHEUMATOLOGY 907 (2014) [Resp. Ex. L24].
187
  Merck and Company, Summary For Basis of Approval: Varicella Virus Vaccine Live,
Reference No. 93-0395 [Pet. Ex. 28].
188
   Dr. Deisher was critical of the study’s use of the phrase “mammalian DNA.” “They do not
specify what species of DNA (human vs. another mammal) they are using to look for antibody
responses in the children. That’s very odd.” Tr. 86.



                                                 70
        Ultimately, Dr. Deisher agrees with Dr. Halsey that “autoimmunity can [at] times, be a
reaction and not a cause.” Tr. 828. With regard to whether DNA from the vaccines may cause
an autoimmune response, Dr. Deisher concedes that “causality has not been examined.” Tr. 828.

                          2. Analogy to PANDAS
        Petitioners’ expert, Dr. Burkhard, 189 hypothesized that the varicella vaccine causes an
autoimmune response that attacks a child’s brain, interfering with development and causing
autism. Tr. 369-70. Her hypothesis is derived from pediatric autoimmune neuropsychiatric
disorders after strep infection (“PANDAS”). She explained that PANDAS is associated with
certain neuropsychiatric disorders, including obsessive compulsive disorders, Tourette’s
syndrome, 190 and abnormal movement disorders. Id. at 369. She posits that if strep infection can
cause neuropsychiatric disorders, then the varicella vaccine could cause autism. Id. at 369-70.

        In 2015, Dr. Burkhard reviewed data 191 related to the incidence of autism and noted an
“abrupt increase in the rate of autism,” within a year in countries that mandated that children
receive the varicella vaccine. Tr. 371. She cited the Walker 192 article to support her hypothesis
that vaccine-related autism is an autoimmune illness like PANDAS. Tr. 378. Walker provides a
summary of studies that used diffusion tensor imaging 193 (“DTI”) to study the brains of children

189
   Dr. Burkhard has no training in the field of immunology or infectious disease. Tr. 407. She
did not review the expert reports of Dr. Halsey, Dr. Fallin, or Dr. Arking. Id. Her understanding
of genetics appeared to be limited, and with regard to questions in medical articles by Iossifov
(Pet. Ex. 641), she deferred to a scientist with knowledge in the field. Tr. 409-10.
190
    Tourette’s syndrome is “a syndrome comprising both multiple motor and one or more vocal
tics, occurring over a period of at least one year, at least intermittently but sometimes as
frequently as many times daily. Obsessions, compulsions, hyperactivity, distractibility, and
impulsivity are often associated. Onset is in childhood and tics often lessen in severity and
frequency and may even remit during adolescence and adulthood.” DORLAND’S at 1831.
191
   Dr. Burkhard testified that an intern completed this research. She did not produce the data or
research referenced. Tr. 371.
192
   Lindsay Walker et al., Diffusion Tensor Imaging in Young Children with Autism: Biological
Effects and Potential Confounds, 72 BIOL. PSYCHIATRY 1043 (2012) [Pet. Ex. 644].
193
    DTI is defined as “a magnetic resonance imaging (“MRI”) technique that allows in vivo
investigation of compositional, microstructural, and architectural characteristics of tissues … and
is currently the most common method for examining the architecture of white matter in the
human brain.” Pet. Ex. 644 at 1043. Fractional anisotropy and mean diffusivity are calculations
used in the evaluation of DTIs. Fractional anisotropy is “a measure indicating the overall
directionality of water diffusion that is greater in organized white matter tracts and lower in
[cerebrospinal fluid] disorganized fibers.” Kristi Clark et al., Mean Diffusivity and Fractional
Anisotropy as Indicators of Disease and Genetic Liability to Schizophrenia, 45 J. PSYCHIATR.
RES. 980 (2011). Mean diffusivity “describes the rotationally invariant magnitude of water


                                                71
with autism. Pet. Ex. 644 at 1043; Tr. 378. Dr. Burkhard testified that 80 to 90 percent of the
studies showed dysfunctional myelitis in the brain, including areas of the brain responsible for
executive functions. 194 Tr. 379. Dr. Burkhard suggested that the studies show “widespread and
diffuse dysfunction of myelin [or white matter] in brains of … children with autism.” Id. Dr.
Burkhard testified that the abnormal areas seen on the imaging correspond to the functional
abnormality in the brains of autistic children. Id. at 388-90. She further testified that certain
childhood diseases thought to be autoimmune in nature are thought to be caused by an attack on
the myelin by autoantibodies. Tr. 379.

        In Walker, DTI was used to make images of the brains of 39 children with autism and 39
controls. The authors found “reduced fractional anisotropy (“FA”) and increased mean
diffusivity (“MD”) in [the] children with autism.” Pet. Ex. 644 at 1043. The authors also
reviewed similar studies done by other researchers summarizing the brain regions of statistically
significant differences. Id. at 1044. The goal of the study was to “characterize the regional
distribution of differences in the brains of children with autism,” as compared to children with
“typical development.” Id. at 1045. The DTI images of autistic children “revealed widespread
differences of FA and MD in brain parenchyma,” as compared to the control group, with a
“predominant pattern of reduced FA and increased MD.” Id. at 1047-488. 195 While most of the
studies showed the same changes of reduced FA and increased MD, the regions of the brain
affected were inconsistent. Pet. Ex. 644 at 1048.

        Walker strongly cautioned against drawing false conclusions from the data and using the
study to suggest that reduced FA is a measure of “white matter integrity” or evidence of
demyelination. Pet. Ex. 644 at 1049.196 In spite of the caveat issued by Walker, Dr. Burkhard


diffusion within brain tissue.” Id.
194
   “Executive function refers to a domain of cognitive abilities (e.g., self-regulation, set
maintenance, cognitive flexibility, planning, prioritizing, organizing time and space) that
provides support for organization, anticipation, inhibition, working memory, and control and
autoregulation of behavior.” Kenneth F. Swaiman, Pediatric Neurology: Principles & Practice
892 (4th ed. 2006).
195
   I note the caveat that some of the studies looked at the entire brain, while other only imaged
certain regions. See Pet. Ex. 644 at 1044.
196
    The authors go on to state, “For example, in healthy white matter the underlying organization
of fibers heavily influences the value of anisotropy (i.e., the more coherent the fiber organization,
the higher the measured value of FA. In regions with complex white matter architecture, FA
might even paradoxically increase after white matter degeneration. More recently, it was shown
that FA values increased in perilesioned cortex after traumatic brain injury in a rat model,
because of organized gliosis, not axonal regeneration. In healthy white matter, diffusion
anisotropy is known to increase during postnatal maturation, although the relative importance of
each specific maturational process (i.e. change in the size of the extracellular space, composition
of the extracellular matrix, and degree of myelination) in driving the FA increase is not clear.”


                                                 72
testified that Walker shows “widespread and diffuse dysfunction of myelin in the brains of [ ]
children with autism.” Tr. 379. Walker also cautioned that “DTI studies of autism should be
interpreted with caution, because their small magnitude 197 make these measurements particularly
vulnerable to the effects of artifacts and confounds, which might lead to false positive and/or
false negative biological inferences.” Pet. Ex. 644 at 1043. Moreover, Walker did not discuss
any of the theories proposed by petitioners as to the cause of autism, especially Dr. Burkhard’s
theory of autoimmunity.

        Moreover, postmortem studies cited by respondent do not support Dr. Burkhard’s
testimony that autistic brains show “widespread and diffuse dysfunction of myelin.” Resp. Ex.
J3 at 183. Bauman and Kemper 198 have extensively studied the autistic brain, and they report
few gross abnormalities. Id. at 184. Specifically, they state that “patterns of myelination have
appeared to be comparable to that of controls….” Id. Bauman and Kemper have found
abnormalities in the cerebellum, brainstem, and cerebral cortical area, suggesting a prenatal
origin, and a “pattern consistent with developmental curtailment.” Id. “Available data provides
evidence for a prenatal onset of at least some of the neuroanatomic abnormalities reported in the
autistic brain.” Id. at 184.

        In a more recent article, Stoner et al. 199 described abnormal “prefrontal and temporal
cortical tissue,” which suggests a problem with “neuronal differentiation at prenatal development
stages.” Resp. Ex. H24 at 1209. Further, while a number of neurobiological mechanisms have
been proposed, “there is no firm pathological evidence to support any of these suggested
hypotheses.” Resp. Ex. J3 at 186. Suggested mechanisms identified by Bauman and Kemper
include “brain over growth,” and neurogenesis, “decreased neuronal cell death, increased
production of non-neuronal brain tissues (i.e. glial cells), decreased synaptic pruning and
abnormalities of myelin.” Id.

      IX.        Petitioners have failed the Althen Test For Determining Causation-In-Fact

   In Althen, the United States Court of Appeals for the Federal Circuit discussed the issue of
“causation-in-fact” in Vaccine Act cases. The court stated:

            [Petitioner’s] burden is to show by preponderant evidence that the vaccination
            brought about [the child’s] injury by providing: (1) a medical theory causally


Pet. Ex. 644 at 1049.
197
   In fact, Walker states, “[E]quating FA to a specific measure of integrity of white matter is
misleading.” Pet. Ex. 644 at 1049. The finding of reduced “FA in widespread regions,” and MD
“only in posterior regions” of the brain is indicative of a pattern that “could be consistent with
global differences in the level of tissue maturity between groups, abnormal maturation, or
degenerative processes.” Id.
198
      Bauman & Kemper, 23 INT. J. DEVL. NEUROSCIENCE 183 [Resp. Ex. J3].
199
      Stoner et al., 370 N. ENG. J. MED. 1209 [Resp. Ex. H24].
                                                   73
       connecting the vaccination and the injury; (2) a logical sequence of cause and
       effect showing that the vaccination was the reason for the injury; and (3) a
       showing of a proximate temporal relationship between the vaccination and injury.
       If [petitioner] satisfies this burden, she is entitled to recover unless the
       [government] shows, also by a preponderance of the evidence, that the injury was
       in fact caused by factors unrelated to the vaccine.

Althen, 418 F.3d at 1278 (internal citations and quotations omitted). In the pages above, I have
provided a detailed explanation of how petitioners have failed to demonstrate preponderant
evidence of “causation-in-fact.” The next section shows how that analysis fits within the Althen
test. For the reasons set forth below, I find that petitioners have failed to satisfy the Althen test
and are therefore not entitled to compensation.

   a. Althen Prong One: Lack of a Reliable Medical Theory

        As noted at the outset, the sole issue to be decided is whether Dr. Deisher’s theory of
vaccine-caused autism meets petitioners’ burden in this case under Althen Prong One.
Petitioners must set forth a medical theory explaining how the vaccines could have caused
V.J.M.’s autism. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1375 (Fed. Cir.
2009); Pafford v. Sec’y of Health & Human Servs., 451 F.3d 1352, 1355-56 (Fed Cir. 2006).

         Although petitioners need not identify the exact mechanism involved, their theory of
causation must be informed by a “sound and reliable medical or scientific explanation.”
Knudsen v. Sec’y of Health & Human Servs., 35 F.3d 543, 548-49 (Fed. Cir. 1994); see also
Veryzer v. Sec’y of Health & Human Servs., 98 Fed. Cl. 214, 223 (2011) (noting that special
masters are bound by both § 300aa- 13(b)(1) and Vaccine Rule 8(b)(1) to consider only evidence
that is both “relevant” and “reliable”). If petitioners rely upon medical opinions to support their
theory, the basis for the opinion and the reliability of that basis must be considered in the
determination of how much weight to afford the offered opinion. See Broekelschen v. Sec’y of
Health & Human Servs., 618 F.3d at 1347 (Fed. Cir. 2010) (“The special master’s decision often
times is based on the credibility of the experts and the relative persuasiveness of their competing
theories.”); Perreira v. Sec’y of Health & Human Servs., 33 F.3d 1375, 1377 n.6 (Fed. Cir. 1994)
(stating that an “expert opinion is no better than the soundness of the reasons supporting it.”)
(citing Fehrs v. United States, 620 F.2d 255, 265 (Ct. Cl. 1980)). However, petitioners are not
required to file medical literature proving their theory. As the Federal Circuit noted in Althen,
“the purpose of the Vaccine Act’s preponderance standard is to allow the finding of causation in
a field bereft of complete and direct proof of how vaccines affect the human body.” Althen, 418
F.3d at 1280.

        Petitioners argue that the evidence they have presented “satisfies the criteria for
establishing a plausible theory of causation, as that criteria is recognized by the scientific
community.” Pet. Prehrg Br. dated January 15, 2016 (ECF No. 202) at 6. They concede that
“the precise way the DNA fragments from the human cell lines cause the injury in issue is
subject to debate.” Id. They state that “where expert opinions extrapolate from existing data, the
weight to be given to an expert’s opinion is based, in part, on the size of the gap between the
science and the opinion proffered.” Id. at 7 (citing Cedillo v. Sec’y of Health & Human Servs.,

                                                 74
617 F.3d 1328 at 1339 (Fed. Cir. 2010) (quoting Gen. Elec. Co., 522 U.S. 136, 146 (1997))).
They also agree that evidence of causation must be “more than a mere scintilla,” and that to
establish relevant and reliable evidence there much be “such relevant evidence as a reasonable
mind might accept as adequate to support a conclusion.” Id. at 7. (citing Huvis Corp v. United
States, 570 F.3d 1347, 1351 (Fed. Cir. 2009) (quoting Consol. Edison Co. v. NLRB, 305 U.S.
197, 229 (1938))). Cases in which there are close calls “must be resolved in favor of the
petitioner.” Id. Evidence “should be viewed under the preponderance standard, as it is
understood in civil courts, and ‘not through the lens of the laboratorian.’” Id. at 9 (citing
Andreu, 569 F.3d at 1380.

        Respondent disagrees that petitioners have established Prong One. Respondent argues
that Dr. Deisher “has not set forth a cogent theory of vaccine causation that makes sense to
unbiased, knowledgeable scientists.” Resp. Prehrg Br. dated February 8, 2016 (ECF No. 222) at
2. Respondent further argues that Dr. Deisher’s “methodology is unscientific,” and that her
expert reports contain “scientifically inaccurate or dubious propositions.” Id. at 3.




                                              75
                                i. Hill Criteria 200

       Both parties cited the Hill criteria, developed by Arthur Bradford Hill in 1965, as a
method to evaluate Dr. Deisher’s theories of causation in this case. See Pet. Prehrg Br. at 5;
Resp. Ex. J at 3. The criteria are:

           (1) strength of association (e.g. correlation coefficient); (2) consistency across
           data sets and populations; (3) specificity of finding to a particular cause and
           particular outcome; (4) evidence that the causal factor occurred prior to
           disease onset; (5) evidence for dose-response; (6) biological plausibility; (7)
           coherence with other types of evidence (e.g., animal models); (8)
           experimental evidence that removing the causal factor prevents the outcome;
           and (9) analogy to other known causes of the outcome.

Resp. Ex. J at 3.

        It is important to note that these criteria or guidelines are generally considered “only after
a study finds an association to determine whether that association reflects a true causal
relationship.” REF. MAN. SCI. EV. at 598-599. Dr. Deisher’s change point study, however, uses


200
    I include Bradford Hill criteria in my analysis, because petitioners urge that Dr. Deisher’s
study and opinion should be found persuasive when viewed in the context of the Hill criteria.
Pet. Prehrg Memo at 5. Several courts have cited the Hill criteria as a helpful tool for
determining whether an epidemiological study establishes causation. See, e.g. Amorgianos v.
Nat. R.R. Passenger Corp., 137 F. Supp. 2d 147, 168 (E.D. N.Y. 2001) (stating that
“epidemiologists generally look to several additional criteria to determine whether a statistical
association is indeed causal.”); In re Breast Implant Litig., 11 F. Supp. 2d 1217, 1243 (D. Co.
1998) (“Plaintiffs have not demonstrated that Dr. Blais’ methodology or opinions are generally
accepted in the scientific community. To the contrary, the accepted method for determining the
cause of disease is epidemiology and, if necessary, the Bradford Hill criteria.”). Other courts,
however, have held that the Hill criteria are not “necessary or helpful” when considering
reliability under Daubert. In re Phenylpropanolamine Prod. Liab. Litig., 289 F. Supp. 2d 1230
(W.D. Wa. 2003). In any event, the Hill criteria are not necessarily dispositive even when
viewed as helpful. In re Viagra Prod. Liabl. Litig., 572 F. Supp. 2d. 1071, 1081 (D. Mn. 2008)
(“The court agrees that the Bradford Hill criteria are helpful for determining reliability, but
rejects Pfizer’s suggestion that any failure to satisfy those criteria provides independent grounds
for granting its Daubert motion.”). In that regard, prior vaccine cases have included
consideration of the Hill criteria in conjunction with other factors in deciding whether petitioners
have provided preponderant evidence of a theory of causation. See Koehn v. Sec’y of Health &
Human Servs., 11-355V, 2013 WL 3214877 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for rev.
denied 113 Fed. Cl. 757 (2013), aff’d 773 F.3d 1239 (Fed. Cir. 2014); Baker v. Sec’y of Health
& Human Servs., 99-653-V, 2003 WL 22416622 (Sept. 26, 2003). In this case, I need not reach
the question of how much weight to place on the Hill criteria, because I have found, for the
reasons detailed below, that Dr. Deisher’s opinion in this case is not in accord with the Hill
criteria. Further, my decision in this case does not turn on my analysis of the Hill criteria, and
even without it, I find petitioners have not proven Althen Prong One by preponderant evidence.
                                                 76
an ecological design, which, as discussed above, is not well suited to establishing causation. See
REF. MAN. SCI. EV. at 561. As such, Dr. Deisher’s study cannot answer the question of whether
an association exists between exposure to vaccines which contain residual DNA fragments and
autism. Moreover, Dr. Deisher’s change point study, and her causal conclusions, are “built on
[an] unproven link.” See Pet. Ex. 62 at 7. Nevertheless, the Hill criteria provide a framework to
analyze the evidence. The criteria are useful to evaluate the question of whether there is a “true
cause-effect relationship.” REF. MAN. SCI. EV. at 597.

                                       1. Strength of Association

        The first Hill criterion assesses the strength of the association between the exposure
(vaccines) and the disease (autism). See REF. MAN. SCI. EV. at 602. Strength of association is
often measured by relative risk, the “ratio of the incidence rate … of disease in exposed
individuals to the incidence rate in unexposed individuals.” REF. MAN. SCI. EV. at 566. “The
higher the relative risk, the greater the likelihood that the relationship is causal.” Id. at 602. For
example, for cigarette smoking, the “estimated relative risk for lung cancer is very high, about
10. That is, the risk of lung cancer in smokers is approximately 10 times the risk in
nonsmokers.” Id.

        Petitioners argue that this criterion has been met because the change point study showed
an increase in autism following the introduction of or increased doses of the vaccines at issue in
the geographical areas studied. Pet. Prehrg Memo at 5. Respondent disagrees, and counters that
the study only shows a correlation between the change points and the dates of vaccine licensure,
“although this is at the ecological level and based on unverified assumptions.” Resp. Ex. J at 5.

        Dr. Fallin explained that in ecological studies, the strength of association is often
measured by a correlation coefficient, which is a measurement of the strength of the correlation
of the amount of exposure at the group or aggregated level, and the amount of outcome at the
group or aggregated level. Tr. 719. Dr. Deisher’s change point study does not contain any such
“numeric metric” by which to measure the correlation. Id. at 720. Because her study does not
contain measurable correlation parameters, Dr. Deisher’s claim that the association between fetal
manufactured vaccines and AD prevalence change points are consistent across each different
geographic location cannot be verified. Id. at 721. The only way to compare prevalence data
sets from Denmark and prevalence data sets from California is by looking at the year in which
the prevalence was measured and comparing it with the year that fetal manufactured vaccines
were licensed. This comparison, however, does not meet the first Hill criterion for measuring the
strength of association, using relative risk, correlation coefficient, or other verifiable parameters.




                                                  77
                                     2. Consistency 201

        The second Hill criterion, the consistency factor, assesses whether “the findings are
consistent with other relevant knowledge.” REF. MAN. SCI. EV. at 606. Relevant to this criterion
is whether other epidemiological studies have shown an association between vaccines and
autism. Tr. 721; Resp. Ex J at 5. Petitioners argue this criterion was satisfied because there was
“an increase in autism follow[ing] every introduction or increased dose of [the] vaccines in every
jurisdiction studied.” Pet. Prehrg Br. at 5. Respondent disagreed, noting that no other studies
verified Dr. Deisher’s results, and numerous studies have shown that there is no association
between vaccines and autism. Resp. Ex. J at 5.

       Dr. Fallin cited a number of epidemiological studies, all of which found no association
between vaccines and autism. 202 Moreover, there are no studies or literature, other than Dr.
Deisher’s study, which show any association between fetal manufactured vaccines and autism.
See Tr. 219.

        Dr. Deisher’s 1988 change point was reported by McDonald. In effect, Dr. Deisher
verified McDonald’s 1988-1989 change point. However, McDonald cited the numerous studies
on the MMR vaccine and the 2004 IOM report and rejected a causal relationship between the
MMR vaccine and autism. Pet. Ex. 27 at 2. McDonald did not identify the other two change
points reported by Dr. Deisher, and Dr. Deisher conceded that no one else has confirmed her
change points in published literature.203 Tr. 236-237.




201
   Petitioners refer to this criterion as “the consistency of the association in varied
circumstances.” Pet. Prehrg Br. at 5. However, the REF. MAN. SCI. EV, quoted by petitioners,
uses the phrase, “consistency with other knowledge.” REF. MAN. SCI. EV. at 600, 606. Dr.
Fallin’s explanation of this criterion appears more accurate than petitioners’.
202
   These studies include Jain et al., 313 JAMA 1534 [Resp. Ex. J18]; Madsen et al. 347 N. ENG.
J. MED. 1477 [Resp. Ex. J26]; Taylor et al., 333 Lancet 2026 [Resp. Ex. J44]; Demicheli et al.,
Cochrane Database of Systematic Reviews [Resp. Ex. J8]; Fombonne et al., 118 PEDIATRICS
e139 [Resp. Ex. J9]. These articles are discussed earlier in the epidemiology section. See also
Robert Schechter and Judith Grether, Continuing Increases in Autism Reported to California’s
Developmental Services System, 65 ARCH. GEN. PSYCHIATRY 19 (2008) [Resp. Ex. J41]; Anne
Hurley et al., Thimerosal-Containing Vaccines and Autism: A Review of Recent Epidemiologic
Studies, 15 J. PEDIATR. PHARMACOL. THER. 173 (2010) [Resp. Ex. J16]; and Yota Uno et al.,
Early Exposure to the Combined Measles-Mumps-Rubella Vaccine and Thimerosol-Containing
Vaccines and Risk of Autism Spectrum Disorder, 33 VACCINE 2511 (2015) [Resp. Ex. J45].
203
   Dr. Deisher testified that “several independent scientists have corroborated” her change
points, but this information is not published. Tr. 294.



                                               78
        Dr. Deisher’s study and her theories of causation are not consistent with other relevant
and reliable knowledge, and her findings have not been reported by others or verified by
epidemiological studies.204

                                       3. Specificity

        The third Hill criterion, specificity of the association, requires a showing that the effect of
exposure on a particular outcome is specific to that outcome. Tr. 722. “An association exhibits
specificity if the exposure is associated only with a single disease or type of disease.” REF. MAN.
SCI. EV. at 605. The rationale behind this criterion is that the “vast majority of agents do not
cause a wide variety of effects.” Id. at 605-6.

        When asked whether this criterion had been met, Dr. Deisher testified that she is not
claiming vaccines are “responsible for all childhood diseases.” Tr. 220. Instead, she is studying
the “relationship and the biology that would tell us how [children with autism] could be harmed
by the vaccine.” Tr. 220. Petitioners’ theory is only designed to explain the cause of autism, not
other diseases.

       Dr. Fallin explained that specificity could not be assessed by Dr. Deisher’s change point
research. Resp. Ex. J at 5. In order to meet this criterion, Dr. Deisher would need to compare
children with autism to children with other developmental disabilities and demonstrate “evidence
of specificity to autism specifically as opposed to other kinds of disorders.” Tr. 722. Thus, Dr.
Deisher’s study does not address specificity.

                                       4. Temporal Relationship 205

        “A temporal, or chronological, relationship must exist for causation to exist. If exposure
causes disease, the exposure must occur before the disease develops.” REF. MAN. SCI. EV. at
601. Dr. Fallin testified that this factor is met when exposure to the cause of the disease predates
the actual disease. Tr. 722-23.

        Dr. Deisher testified that she did not address this criteria in her study. Tr. 220. In order
to fully investigate whether vaccine exposure occurred prior to disease onset, Dr. Deisher



204
   I stress that I am not requiring petitioners to provide epidemiological evidence of their
mechanisms of causation. However, petitioners cited epidemiological evidence, so I may
evaluate it. See W.C. v. Sec’y of Health & Human Servs., 704 F.3d 1352 (Fed. Cir. 2013); Grant
v. Sec’y of Health & Human Servs., 956 F.2d 1144 (Fed. Cir. 1992).
205
   For purposes of this decision, I am applying the temporal relationship factor as part of my
analysis of Althen Prong One, as it is a factor in the Hill criteria. This section is not meant to
constitute a discussion of Prong Three of Althen, which measures the temporal relationship
between the receipt of a vaccination and the onset of the injury.



                                                  79
testified that she would need access to the VSD 206 so that she could study children on an
individual basis. Tr. 221. Dr. Fallin agreed that this criterion was not satisfied. The change
point research contains imprecise dates and ecological data. Resp. Ex. J at 5.

       Moreover, Dr. Fallin testified that “the field [of epidemiology] overwhelmingly now
believes that the … most likely environmental susceptibility window [for ASD] is in utero,”
which is prior to the time that children receive vaccinations. Tr. 723. Dr. Deisher’s change point
study and theories of causation contemplate exposure after birth, during vaccine administration.
Thus, the theory is inconsistent with current scientific knowledge with regard to exposure.

       There is also an issue with regard to disease onset relevant to the criterion of temporal
association. Dr. Deisher opined that autism disease onset due to her theory “could be as short as
a few days … up to a few years from a first exposure.” Pet. Ex. 10 at 23. “If the phenomenon is
genomic insertion into a stem cell, onset … could be … even years.” Id. It is not clear whether
Dr. Deisher’s change point study takes into account this wide range of exposure to disease onset
from a few days to years.

                                      5. Dose-Response

       A “dose-response relationship means that the greater the exposure, the greater risk of
disease. Generally, higher exposures should increase the incidence (or severity) of disease.”
REF. MAN. SCI. EV. at 603. In this case, the greater the coverage of a vaccine, the higher the
prevalence of the disorder should be, if there is evidence of dose-response. Tr. 725. Dose-
response is often confirmed by correlation, and the higher the correlation, the greater the
evidence of dose response. Id. at 724.

        Dr. Deisher testified that petitioners “clearly demonstrated evidence for a dose-response,”
by evaluating “autistic disorder prevalence compared to uptake” with the varicella and hepatitis
vaccines. She attempts to demonstrate dose-response by displaying the graphs below, which
depict autism prevalence and varicella vaccine coverage over time, respectively. Pet. Ex. 265 at
10. Recall that Dr. Deisher attributes the third change point in approximately 1995, in part, to
the varicella vaccine.




206
   Dr. Deisher explains in her affidavit that “[t]he [VSD] contains data regarding immunizations
and autism disorder for hundreds of thousands of children.” Pet. Ex. 10 at 25. She testified that
she was denied access to the VSD partly due to lack of funding. Tr. 327.


                                                80
                                                                       The graphs show the
                                                                       increase in autism
                                                                       prevalence over time, and
                                                                       the coverage and uptake of
                                                                       the varicella vaccine over
                                                                       time. Pet. Ex. 265 at 10;
                                                                       Tr. 725. Dr. Deisher
                                                                       opines that increased
                                                                       coverage of the varicella
                                                                       vaccine results in higher
                                                                       prevalence of autism. Id.
                                                                       However, the graphs raise
                                                                       a significant question. In
                                                                       the bottom graph, varicella
                                                                       coverage plateaus at
                                                                       approximately 2002, but
                                                                       the top graph shows that
                                                                       the prevalence of autism
                                                                       continues to increase. If
                                                                       the two were causally
                                                                       associated, one would
                                                                       expect that autism
                                                                       prevalence would level off
                                                                       as varicella coverage
                                                                       plateaus. The charts do not
                                                                       explain why autism
                                                                       continues to increase when
                                                                       the coverage of the
                                                                       varicella vaccine coverage
                                                                       levels out. Tr. 725.
Moreover, Dr. Deisher concedes that her study “does not rule out the possibility of sociologic
effects artificially elevating AD prevalence after 1996.” Pet. Ex. 419 at 19. As such, I find there
is insufficient evidence of a dose-response relationship.

                                      6. Coherence

        The sixth Hill criterion measures coherence with other types of evidence, including
animal models. Tr. 222; Resp. Ex J at 6; Tr. 726. Dr. Deisher testified that anti-double-strand-
DNA antibodies and published evidence of mutations in lymphoblastoid cell lines are evidence
of “actual clinical observation in autistic children.” Tr. 222. There is, however, no evidence
which establishes that anti-double-strand-DNA antibodies found in autistic children are caused
by vaccines. Likewise, there is no evidence that mutations in lymphoblastoid cell lines are
associated with vaccines. Therefore, Dr. Deisher’s testimony on this point is erroneous.

       Dr. Fallin opines that coherence with other types of evidence such as animal models has
not been shown. Dr. Deisher’s hypothesis is not consistent with current autism research,

                                                81
especially with regard to the time of exposure (prenatal vs. after birth). Resp. Ex. J at 6. I agree
with Dr. Fallin that Dr. Deisher’s research and theories do not meet this criterion.

                                      7. Effect of Ceasing Exposure

       The seventh Hill criterion explores whether the outcome (autism) could be prevented by
removing the causal factor (vaccines). Tr. 727. “If an agent is a cause of disease, then one
would expect that cessation of exposure to that agent ordinarily would reduce the risk of the
disease.” REF. MAN. SCI. EV. at 605.

         Dr. Fallin testified that ecological studies can never meet this criterion. Tr. 727. This
criterion requires an experimental study design with randomized control trials to assess exposure
and outcome. Tr. 727. Even at an individual level, experimental evidence can be difficult to
demonstrate, because the exposure of interest has to occur in subjects that are reasonably alike.
Dr. Deisher’s research reaches conclusions at an aggregate level and thus cannot meet this
criteria. Id.

        Dr. Deisher testified that this criterion was satisfied by her paper published in 2015, an
ecological study about autism incidence following the “Wakefield scare.” 207 Tr. 223. For this
study, Dr. Deisher obtained autism prevalence data from five sources: two from Norway, two
from the UK, and one from Sweden. She reported that the “average MMR coverage” for
Norway, Sweden, and the UK fell below 90percent after Dr. Wakefield’s 1998 paper. Pet. Ex.
675 at 2. During the same time frame, she reported that the prevalence of average ASDs in these
same three countries decreased “substantially after birth year 1998 and gradually increased again
after birth year 2000.” Id. She concluded that the “Wakefield scare” resulted in decreased
vaccine coverage, which “created a natural experiment that may demonstrate a causal
relationship between fetal cell-line manufactured vaccines and ASD prevalence.” Id. Dr.
Deisher testified that when the vaccines were removed, autism decreased, and when the vaccines
were reintroduced, autism increased. Tr. 218.

       Dr. Arking testified that Dr. Deisher’s presentation of the data could be misleading
because it came from “multiple sources within a country and multiple sources across countries.”
Tr. 735-38. Using the same data used by Dr. Deisher, Dr. Arking hand-plotted it separately for
each country, yielding different results. There was a decrease in autism for the UK, but for
Norway, there was an increase, and for Sweden, there was no change and then an increase. Id. at
738. Dr. Arking then plotted data from just one of the UK studies (Wales), and that data was


207
    In 1998, Dr. Andrew Wakefield published a paper in The Lancet, “suggesting a link between
MMR and autism.” Tr. 217. Dr. Deisher testified that there was widespread coverage by the
media in the three countries referenced above, and “compliance with the MMR…decline[d]
abruptly.” Id. Subsequently, Wakefield was discredited by Kaye’s paper published in the
British Medical Journal, and others. James A. Kaye et al., Mumps, measles, and rubella vaccine
and the incidence of autism recorded by general practitioners: a time trend analysis, BRIT. MED.
J. 322 (2001). Dr. Deisher testified that once Wakefield was discredited, “compliance rose again
in those countries.” Tr. 217. For a full discussion of the Wakefield paper and the subsequent
course of events, see Cedillo, 2009 WL 331968.
                                                 82
“almost flat.” Tr. 739. While Dr. Arking emphasized that his illustrations and examples were
cursory, they served to illustrate that using data at an aggregate level can be misleading. Id. at
740. “Every time you aggregate, you lose something.” Id. Dr. Arking concluded that Dr.
Deisher’s paper regarding the “Wakefield scare” did not provide evidence of a decrease in
vaccine coverage associated with decreased autism prevalence. Id. He also made another
important point: rigorous epidemiological studies using individual level data have shown no
association between vaccines and autism. If Dr. Deisher’s theories were correct, studies about
the MMR vaccine would have shown an association. See id. at 741-42. On these points, Dr.
Arking was more persuasive.

                                      8. Analogy to Other Known Causes

       The eighth Hill criterion measures whether the hypothesized cause of the outcome is
analogous to any other known causes of the outcome. Resp. Ex. J at 6; Tr. 728. According to
Dr. Deisher, petitioners have presented:

       [A] large body of scientific evidence in multiple disciplines … immunology,
       virology, gene therapy, genetic engineering, manufacturing, process development,
       clinical interventions in autoimmune diseases, and actual empirical evidence from
       the SCID gene therapy trials, that the potential damages of the contaminants
       found in the vaccines are real and present; that the mechanisms of action are not
       only plausible, but possible.

         Tr. 223. Respondent disagrees. Dr. Fallin explained that Dr. Deisher’s research does not
meet this criterion because “other known causes [of autism] are rare genetic anomalies that occur
at the time of conception, or very close [there]after.” Tr. 728. Recent research overwhelmingly
shows that the greatest potential for autism risk factors points to the prenatal period. Id.

        An example of an autistic disorder known to be caused by a “germline mutation,” is Rett
syndrome. Tr. 133, 185, 246. Dr. Deisher agrees that Rett syndrome is caused by a de novo
germ cell mutation that leads to autism. Id. at 133, 185. A germline mutation is a mutation
occurring in the parent’s egg or sperm cells. Therefore, it is an example of a mutation occurring
in the prenatal period that is known to cause autism.

        I find respondent’s position more persuasive. Dr. Deisher’s research and theories
suggesting that fetal manufactured vaccines are a cause of autism is not analogous to the current
understanding of the timing or mechanisms of the potential causes of autism, or to the example
of Rett syndrome and thus do not show evidence of any other analogous causes.

                                      9. Biological Plausibility

        “Biological plausibility is not an easy criterion to use and depends upon existing
knowledge about the mechanisms by which the disease develops.” REF. MAN. SCI. EV. at 604.
“The saliency of this factor varies depending on the extent of scientific knowledge about the
cellular and subcellular mechanisms through which the disease process works.” Id. at 605.



                                                 83
        With regard to environmental causes of autism, “[t]he majority of autism research to date
implicates the gestational period as the window of risk.” 208 Resp. Ex. J at 5. Based on existing
knowledge about the mechanisms by which autism develops, respondent’s experts unanimously
agree that “the idea that there can be an adequate amount of human DNA transferred to the
children and that then within each child enough of that can insert itself into the genome of cells
in ways that would manifest disease [postnatally] is unlikely.” Tr. 726.

                                      10.    Replication of the Findings

       Another Hill criterion not specifically enumerated by petitioners, but generally
recognized as a Hill criterion, as well as important factor to “assess whether a causal inference is
appropriate,” is whether the results of a study have been replicated. REF. MAN. SCI. EV. at 600.
“Rarely, if ever, does a single study persuasively demonstrate a cause-effect relationship. It is
important that a study be replicated in different populations and by different investigators before
a causal relationship is accepted by epidemiologists and other scientists.” Id. at 604.

        Dr. Deisher concedes that her theories, as well as her change point study findings, have
not been published by anyone else. “The need to replicate research findings permeates most
fields of science.” REF. MAN. SCI. EV. at 604. Without replication, it is very difficult to draw
any reasonable inferences from Dr. Deisher’s study or her theories.

       In summary, Dr. Deisher’s change point study does not offer persuasive evidence of
causation based on the Hill criteria. The study does not contain any parameters by which to
measure the strength of association between the vaccines at issue and the prevalence of autism.
Dr. Deisher’s epidemiological study has not been verified and her findings have not been


208
   In support of this assertion, Dr. Fallin referenced studies by Patricia Rodier et al.,
Embryological Origin for Autism: Developmental Anomalies of the Cranial Nerve Motor Nuclei
370 J. COMP. NEUROLOGY 247 (1996) [Resp. Ex. J38]; A. Bailey et al., A Clinicopathological
Study of Autism 121 Brain 889 (1998) [Resp. Ex. J2]; Bauman and Kemper, 23 INT. J. DEVL.
NEUROSCIENCE 183 [Resp. Ex. J3]; Joachim Hallmayer et al., Genetic Heritability and Shared
Enviornmental Factors Among Twin Pairs with Autism, 68 ARCH. GEN. PSYCHIATRY 1095
(2011) [Resp. Ex. J11]; Sally Ozonoff et al., Recurrence Risk for Autism Spectrum Disorders: A
Baby Siblings Research Consortium Study, 128 PEDIATRICS e488 (2011) [Resp. Ex. J34];
Matthew Johnson et al., Functional and Evolutionary Insights Into Human Brain Development
Through Global Transcriptome Analysis, 62 NEURON 494 (2009) [Resp. Ex. J19]; Irina
Voineagu et al., Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular
Pathology, 474 NATURE 380 (2013) [Resp. Ex. J46]; Willsey et al., 155 CELL 997 [Resp. Ex.
J47]; Marilyn T. Miller, Thalidomide Embryopathy: A Model for the Study of Congenital
Incomitant Horizontal Strabismus, LXXXIX TR. AM. OPTH. SOC. 623 (1991) [Resp. Ex. J29]; K.
Stromland et al., Autism in Thalidomide Embryopathy: A Population Study, 36 DEVL. MED. AND
CHILD NEUROL. 351 (1994) [Resp. Ex J43]; Lonnie Zwaigenbaum et al., Behavioral
Manifestations of Autism in the First Year of Life, 23 INT. J. DEVL. NEUROSCIENCE 143 (2005)
[Resp. Ex. J48]; and A.N. Bhat et al., Relationship Between Early Motor Delay and Later
Communication Delay in Infants At Risk for Autism, 35 INFANT BEHAV. DEVL. 838 (2012)
[Resp. Ex. J4].
                                                 84
replicated by others. Moreover, her results are directly contrary to many other epidemiological
studies which do not demonstrate a correlation between vaccines and autism. The change point
study does not demonstrate that exposure to vaccines containing human DNA fragments is
specific to the outcome of autism. Due to the ecological design of the study, it cannot provide
evidence that the vaccines were given prior to the onset of autism. Dr. Deisher’s study does not
show evidence of dose-response, and her hypothesis is not consistent with current autism
research. She has not demonstrated that autism could be prevented by discontinuing the use of
vaccines manufactured with residual DNA fragments, and her causal theories are not analogous
with existing and current knowledge and understanding that the timing of the cause of autism is
likely during prenatal development. To the extent that there may be environmental triggers
involved in the etiology of autism, these are thought to occur during the prenatal period. Dr.
Deisher has not offered a biologically-plausible mechanism by which vaccines containing
residual DNA could cause autism.

                               ii. Epidemiological Evidence

       In addition to arguing that they have satisfied the Hill criteria, petitioners assert that Dr.
Deisher’s change point study satisfies the following three questions, set forth in the REF. MAN.
SCI. EV.:

       1) Do the results of an epidemiology study reveal an association between an agent and
          disease?
       2) Could this association have resulted from limitations of the study (bias, confounding
          or sampling error), and, if so, from which?
       3) Based on the above analysis, and on other evidence, how plausible is a causal
          interpretation of the association?

Pet. Prehrg Br. at 10.

       These three issues arise when an epidemiology study is used in a legal dispute. To assess
“the methodological soundness of a study and its implications for resolution of the question of
causation,” these three questions must be addressed. REF. MAN. SCI. EV. at 554.

       Respondent’s counsel generally argues that Dr. Deisher’s change point study is flawed,
and that “no reliable scientific conclusions” can be drawn from it due to its “substandard
methodology.” Resp. Prehrg Br. at 7.

                                       1. The results of Dr. Deisher’s Study Do Not Reveal an
                                          Association Between Vaccines and Autism

        Dr. Deisher employed an ecological study design which, by definition, is one in which
data is collected about a group or groups. Generally, the goal of ecological studies is to identify
a difference between different groups, so as to study disease trends in a population. While
ecological studies are useful for identifying associations, “they rarely provide definitive causal
answers.” REF. MAN. SCI. EV. at 561. Ecological studies provide “nearly no evidence on
causality.” Tr. 451. That is because what appears to be a cause-and-effect relationship at the

                                                  85
group level may not be true at the individual level. This can lead to an ecological fallacy, such
as the example given by Dr. Fallin with computer use and asthma. Therefore, Dr. Deisher’s
change point study, even if perfectly executed, cannot reveal an association between residual
DNA in vaccines and autism.

                                       2. Dr. Deisher’s Study Has Numerous Limitations
                                          Which Render Its Conclusions Invalid

       There are a number of limitations to Dr. Deisher’s change point study which call into
question her conclusions. There are many sources of potential error in the data used to calculate
incidence and prevalence data which may have produced erroneous results. As carefully and
thoughtfully explained by Dr. Fallin, the changes in diagnostic criteria changed over the time
frame relevant to the study. Four different DSM editions and revisions were published, with
changes to the number of symptoms needed to establish a diagnosis of autism. For example,
from 1968 to 1980, symptoms that described what is now called autism were described under the
diagnostic rubric for schizophrenia, childhood type. In 1980, the diagnosis “infantile autism”
was published in the DSM-III. McDonald and others have suggested that the changes in
diagnostic criteria accounted for a 2.2-fold higher incidence of the autism diagnosis in the
California data used.

        How physicians and other health care providers apply the criteria presents another issue.
Because autism is a clinical diagnosis, the criteria for diagnosis are subject to the interpretation
of the person applying them. There is no easy way to quantify how this problem affects
prevalence data.

        Once autism is diagnosed, it must be reported to be counted in incidence and prevalence
data. Reporting practices changed over the time frame relevant to Dr. Deisher’s study. For
example, in Denmark, the prevalence of autism increased, perhaps as much as 60 percent once
outpatient data and changes in diagnostic criteria were accounted for. Similarly, access to
services presents an issue, which may account for why children who have not started school may
be underreported. Funding for programs to treat children with autism may affect whether
children are diagnosed or reported. Data may change due to “diagnostic substitution,” where a
certain diagnosis is required in order for a child to receive services. Physician and parental
awareness, stigma, geographical location – all may affect whether accurate data is reported. The
average age at the time of diagnosis continues to decrease, which has been noted by McDonald
and others as a cause of the increase in autism incidence in the California data. For all of these
reasons, the prevalence data in Dr. Deisher’s study may not be accurate.

        Another source of error which may have contributed to a false result in Dr.
Deisher’s change point study is the inappropriate use of R software. If an exponential or
curved model had been used, as suggested by Dr. Fallin, the study may have shown
different change points, or no discrete change points at all. And Dr. Deisher’s analysis of
the vaccine uptake data and her use of vaccine licensure dates are also problematic.

       The change point study may also lack reliability due to Dr. Deisher’s failure to
adequately account for confounding factors. Confounding factors create interference so

                                                 86
as to “distort the association being studied between two variables.” DORLAND’S at 403.
Confounding can occur “when a confounder is both a risk factor for the disease and a
factor associated with the exposure of interest.” REF. MAN. SCI. EV. at 591. An example
of a potential confounding factor here is paternal age. As shown by Dr. Fallin, Dr.
Deisher’s analysis as to the effect of paternal age on her study was inadequate.

        The most glaring source of error in Dr. Deisher’s study is her underlying presumption
that residual DNA in vaccines cause autism. This may be viewed as “information bias” as “a
result of inaccurate information about either the disease or the exposure status of the study
participants or a result of confounding.” REF. MAN. SCI. EV. at 585. This may also be viewed as
a conceptual problem with the study. See REF. MAN. SCI. EV. at 590. This bias by Dr. Deisher to
attribute the disease of autism to a vaccine-related cause affects the overall reliability and
validity of the study.

         Dr. Deisher’s conceptual bias against the use of human fetal cells for vaccines has
been identified before in other contexts. 209 In 2011, Dr. Deisher, as principal investigator
for Sound Choice, applied to the NIH for funding for a study entitled, “Safety Study of
Human Fetal DNA and HERVK Contaminants in Childhood Vaccines.” 210 See Pet. Ex.
62. Members of the Scientific Review Group (“SRG”), noted professors from prestigious
universities and medical schools, were asked to review and comment on the application.
Id. at 1. Dr. Deisher proposed three studies:

          1) A trend analysis of Varicella vaccination and autism using the Vaccine Data
          Safety Link database, 2) an ecological analysis of the association between MMR
          vaccine and autism using data collected through web searches and contact with
          Southeast Asian and African health officials, and 3) a lab based study to measure
          DNA incorporation into human cell lines.

Pet. Ex. 62 at 2.

        The application was reviewed and three written critiques were issued by the SRG.
The first reviewer acknowledged the importance of ongoing safety evaluations for
vaccines, but expressed concern that Dr. Deisher’s approach was “heavily biased,
including an assessment of the current literature that fails to adequately consider the
recent data that has rebuked the association between vaccination and autism.” Pet. Ex. 62
at 2. The reviewer also noted additional weaknesses, including that “the concept of birth
year change points is a weak approach to defining causal links between vaccine exposure
and adverse outcomes.” Id. The reviewer criticized the study design, stating that, “the
ecological analysis proposed…is unlikely to generate significant, valid results given
multiple threats to internal validity.” Id.

209
    Dr. Deisher’s company, Sound Choice, is “opposed to the use of exploitation of [human
embryos] for biomedical research.” Tr. 239. Further, Dr. Deisher was a plaintiff in a lawsuit
filed to halt federal funding for embryo-destroying stem cell research. Tr. 244. Sherley v.
Sebelius, 644 F.3d 388 (D.C. Cir. 2011).
210
      The application discussed was filed as Pet. Ex. 62.
                                                  87
       The second reviewer agreed that the ecological study design was problematic. Dr.
Deisher’s proposed research “relies heavily on ecological associations that would not
advance this line of research.” Pet. Ex. 62 at 4. The third reviewer stated that “all the
epidemiological and scientific evidence suggest that there is no link between autism and
vaccines. Yet, the entire application is built on this unproven link.” Id. at 7.

        Dr. Deisher formed Sound Choice for the purpose of informing the public about
human exploitation in biomedical research and to conduct research into the link between
human fetal manufactured vaccines and autism. Tr. 45. She spent 18 months working
with Japanese manufacturers to develop animal cell lines and to work on licensing these
vaccines in the U.S. Tr. 163-164. She also had discussions with a Japanese vaccine
manufacturer, Takeda, about bringing back their animal-based MMR vaccine. Tr. 164.
She had similar discussions with Merck and the Kitasato Institute. Tr. 229. Ultimately,
these discussions were not successful, and Dr. Deisher did not pursue developing, or
aiding in the development of vaccines to replace the current MMR vaccine used in the
U.S. 211 However, her moral opposition to the use of human cell lines and her business
plan to develop alternative animal manufactured vaccines are issues that raise grave
concerns about her ability to present objective data and conclusions, especially when she
ignores the weight of the evidence presented by countless epidemiology studies which
have been performed using much more rigorous methodology.

                                      3. Dr. Deisher’s Causal Interpretation Is Not Plausible

        Possible theories or mechanisms are insufficient to establish causation by a
preponderance of evidence. “Expert medical testimony which merely expresses the possibility –
not the probability – of the occurrence of a compensable injury is insufficient, by itself, to
substantiate the claim that such an injury occurred.” LaCour v. Sec’y of Health & Human
Servs., 90-316V, 1991 WL 66579, at *5 (Fed. Cl. Spec. Mstr. April 15, 1991); accord Burns v.
Sec’y of Health & Human Servs., No 90-953V, 1992 WL 365410 (Fed Cl. Spec. Mstr. Nov. 6,
1992), aff’d 3 F.3d 415 (Fed. Cir. 1993).

        The Federal Circuit has made clear that the mere possibility of a link between a
vaccination and a petitioner’s injury is not sufficient to satisfy the preponderance standard.
Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1322 (Fed. Cir. 2010) (“proof of a
‘plausible’ or ‘possible’ causal link between the vaccine and the injury” does not equate to proof
of causation by a preponderance of the evidence.); Waterman v. Sec’y of Health & Human
Servs., 123 Fed. Cl. 564 (2015) (denying petitioner’s motion for review and noting that a
possible causal link was not sufficient to meet the preponderance standard). While certainty is
by no means required, a plausible or possible mechanism does not rise to the level of
preponderance. Id.; see also de Bazan v. Sec’y of Health & Human Servs., 539 F.3d 1347, 1351
(Fed Cir. 2008); Capizzano, 440 F.3d at 1323.



211
   In 2011, Dr. Deisher ceased her efforts to develop a vaccine that did not use fetal cell lines.
Tr. 312.


                                                 88
        In her expert reports and during the hearing, Dr. Deisher candidly and not infrequently
acknowledged the speculative nature of her theories by using the words “possible,” “possibly,”
and “possibility.” For example, in her initial report, Dr. Deisher stated that “[w]hile not yet
proven medically,” in reference to her assertion that the “manufacturing process is the cause of
the increase in autism.” Pet. Ex. 10, ¶ 21, at 18. Throughout her reports, Dr. Deisher stated,
“[w]e don’t, at this point, know what the mechanism is.” Id., ¶ 27, at 23. She goes on to state
that, “[w]e do not yet know how the debris from the manufacturing process is causing [autism].”
Id. 212

        In her second expert report, Dr. Deisher stated that “we cannot show exactly what effect
these insertions are having by experimentation.” Pet. Ex. 76 at 2. Again, referencing her theory
of insertional mutagenesis, she says, “We do not know the exact mechanism for how DNA
insertion reaches the brain to elicit autism.” Id. at 31-3. Repeatedly, Dr. Deisher testified that
she does not know how DNA reaches the CNS. She testified that her different theories were
“possibilities” of how DNA might get into the CNS. Tr. 249. She also testified about the
“possibilities” of her mechanisms. Tr. 829.

        Referencing her proposed mechanism using hematopoietic stem cells and the survival
advantage of certain cells, she stated “that advantage could increase the possibility.” Tr. 847. As
for the proposed theory related to microvesicle transport, Dr. Deisher testified that it was “a
second possible way that contaminants injected into a peripheral muscle … could reach the
CNS.” Tr. 105-06.

        Dr. Deisher’s use of words suggesting her theories are speculative constitute expert
scientific testimony which “merely expresses the possibility – not the probability” of her
proposed theories, and thus, her opinions are insufficient to substantiate petitioners claim.
LaCour, 1991 WL 66579, at *5




212
    Although petitioners are not required to provide a specific biological mechanism, the theory
they propose must be plausible. Knudsen, 35 F.3d at 548-49 (“The determination of causation
in fact under the Vaccine Act involves ascertaining whether a sequence of cause and effect is
‘logical’ and legally probable, not medically or scientifically certain.”); see also Colon v. Sec’y
of Health & Human Servs., No. 04-44V, 2007 WL 268781, at *19 (Fed. Cl. Spec. Mstr. Jan. 10,
2007) (“While the [p]etitioner is not required to propose or prove that a specific biological
mechanism can and did cause [the child’s] death, she must still proffer a plausible medical theory
that causally connects the vaccine with the injury.”); Betancourt v. Sec’y of Health & Human
Servs., No. 04-458V, 2007 WL 4820969, at *22 (Fed. Cl. Spec. Mstr. Dec. 10, 2007)
(“[p]etitioner is not required to propose or prove definitively that a specific biological
mechanism can and did cause the injury leading to his condition, he must still proffer a plausible
medical theory that causally connects the vaccine with the injury alleged.”).



                                                89
                              iii. Adverse Inference Rule

        In their prehearing memorandum, petitioners’ counsel argue that respondent’s failure to
provide Dr. Deisher with access to the VSD 213 warrants application of the adverse inference
rule, giving rise to “an inference that the evidence is unfavorable” to respondent. Pet. Prehrg Br.
at 13-15. Petitioners’ counsel further argue that Dr. Deisher’s change point study should
therefore be “deemed conclusive.” Id. at 16.

        In support of this argument, petitioners cite Federal Rule of Evidence 301 214 and
Langford v. Norris, 614 F.3d 445, 462 (8th Cir. 2010). In Langford, however, the court of
Appeals did not apply the adverse inference rule because there was no evidence to show
that the documents at issue “were destroyed or misplaced.” Further, the court stated that
where a party fails to produce evidence in their control, the adverse inference “is open
always to explanation by circumstances which make some other hypothesis a more
natural one than the party’s fear of exposure.” Id. at note 8 (internal citations omitted).

       Similarly, there is no evidence in this case that the VSD has been destroyed or
misplaced. A formal application process is in place for researchers to access VSD data.
See Resp. Ex. C at 35-37. In fact, Dr. Deisher sought access to the VSD and was denied
such access prior to her involvement as an expert in this case. As previously discussed,
in 2011, she applied for an NIH grant for a study that would provide access to the VSD.
Tr. 245. In her application, Dr. Deisher proposed a “trend analysis of varicella
vaccination and autism using the [VSD] database.” See Pet. Ex. 62. The application was


213
    Petitioners filed several motions requesting that the Court give them access to the VSD. The
first motion for access to the VSD was filed on February 3, 2012, while former Chief Special
Master Patricia Campbell-Smith was assigned to the case. Chief Special Master Campbell-Smith
denied petitioners’ motion in a detailed order filed on June 12, 2013. [redacted], 2013 WL
3368236. Shortly after the order was issued, the case was transferred to Special Master George
Hastings. On July 12, 2013, petitioners filed a motion for reconsideration of Chief Special
Master Campbell-Smith’s Order. Respondent requested additional time to respond to the
motion, which was granted, and several managed care organizations whose data are held in the
VSD also filed responses. On October 24, 2013, Special Master Hastings denied petitioners’
motion for reconsideration. [redacted], 2013 WL 6038670.

After I was assigned to the case, petitioners made a third attempt to gain access to the VSD on
October 1, 2015. (ECF No. 164). On August 30, 2016, I denied petitioners’ motion. [redacted],
2016 WL 5362878. On May 11, 2017, petitioners made a fourth attempt to renew their motion
for access to the VSD during the rebuttal testimony of Dr. Deisher, which I denied from the
bench. Dr. Deisher’s requests for access to data from Norway and the United Kingdom were
also denied. Tr. 318-19.
214
   Petitioners incorrectly cite FRE 301, which states, “In a civil case, unless a federal statute or
these rules provide otherwise, the party against whom a presumption is directed has the burden
of producing evidence to rebut the presumption. But this rule does not shift the burden of
persuasion, which remains on the party who had it originally.”
                                                 90
reviewed by prestigious scientists and physicians from preeminent medical schools and
universities across the country. Three reviewers read and critiqued Dr. Deisher’s
application, providing specific reasons for denying it. See Id. One reviewer concluded
that the “proposed methods are weak” and that there were “major methodological
concerns throughout.” Id. at 2. Another said there was inadequate “evidence of prior
experience working with [the VSD] or similar large scale epidemiological databases.” Id.
at 3. Another reviewer stated “[t]he investigator is not trained as a statistician or
epidemiologist and does not acknowledge the assumptions and complexities of
interpreting data analyzed in the way it is proposed.” Id. at 5. With regard to Dr.
Deisher’s 2011 application for use of VSD data, the reviewers gave reasonable
explanations as to why Dr. Deisher was not granted access to VSD data.

        Once Dr. Deisher became an expert in this case, petitioners filed several motions seeking
access to the VSD. Each time, there was a detailed and reasoned order issued explaining the
basis for denial of the motion. There is no evidence of bad faith or negligence by respondent.
As such, the adverse inference rule is not applicable. Likewise, there is no support for
petitioners’ assertion that Dr. Deisher’s study “should be deemed conclusive.” Pet. Prehrg Br. at
16.

       Previously, I stated:

       [A] party seeking an adverse instruction on the basis that evidence was not
       produced in time for trial must show: (1) that the party having control over the
       evidence had an obligation to timely produce it; (2) that the party that failed to
       timely produce the evidence had a “culpable state of mind”; and (3) that the
       missing evidence is “relevant” to the party's claim or defense such that a
       reasonable trier of fact could find that it would support that claim or defense.

[redacted], 2016 WL 5362878, at *8 (citing Residential Funding Corp. v. DeGeorge Financial
Corp., 306 F.3d 99, 107 (2d Cir. 2002)). Now, as then, it is reasonable to conclude that the
adverse inference rule is not appropriate in this situation.

                               iv. Summary of Analysis of Petitioners’ Theories of
                                   Causation

        At the outset of the hearing, petitioners identified their focus – to show that DNA
fragments in vaccines “can cause damage to brain cells by disrupting their function, manifesting
clinically as symptoms, now diagnosed as autism.” 215 Pet. Prehrg Br. at 3. Respondent
countered by identifying “a fatal shortcoming” – the failure to present a “plausible scientific


215
   Petitioners also state in their prehearing memo that DNA fragments in vaccines “can cause an
encephalopathy manifesting clinically as autism.” There is no evidence in this case that V.J.M.
had encephalopathy. To the extent that they argue that DNA fragments or HERV-K fragments
cause encephalopathy, that argument is also rejected, for all the reasons cited herein.



                                                91
explanation” as to how DNA fragments or HERV-K fragments in the vaccines “reach the brain.”
Resp. Prehrg Br. at 9. I agree with respondent that petitioners have failed by preponderant
evidence to provide a plausible scientific explanation as to how fragments of DNA or HERV-K
reach the brain of a child so as to cause ASD. There are, however, many other problems with
petitioners’ theories that are just as fatal to their claim as the problems with petitioners’
epidemiologic evidence discussed above. As for HERV-K retroviruses, Dr. Deisher concedes
that current studies as to these retroviruses are “observational” and that their role in causing
disease is not known. As for DNA fragments, Dr. Deisher did not proffer preponderant evidence
showing that retrograde transport was a viable hypothesis. While viruses have been shown to
travel from neuron to neuron in a retrograde manner, the petitioners provided no study or
experiment to show that peripheral intermuscular injection of DNA fragments from vaccines
travel in the same way, neuron to neuron, in a retrograde fashion.

        Dr. Deisher’s hypothesis about microvesicle transport is similarly undeveloped.
Assuming that microvesicles are transported in the circulatory system, Dr. Deisher did not
provide a plausible hypothesis as to how they could cross the BBB. As for Dr. Deisher’s most
likely hypothesis, that DNA fragments are taken up by hematopoietic stem cells, she failed to
adequately explain and provide evidence of how stem cells cross the blood brain barrier, reach
the brain and cause disease. While she suggested that vaccination might set up an immune
response, or an ill child might have an infection at the time of vaccination, either of which might
allow a breakdown of the BBB so that DNA fragments could reach the brain, the evidence was
woefully lacking.

       Another fundamental flaw is that there is no evidence that residual DNA in vaccines
cause genetic mutations. Petitioners provided preponderant evidence that ASD is associated
with many different mutations, including de novo mutations. But there was no evidence
presented that any mutation associated with any disease, let alone ASD, is caused or could be
associated with residual DNA in the vaccines at issue. Dr. Deisher readily conceded that there is
a problem of evidence. She advocates for more studies to determine whether residual DNA in
vaccines presents a safety issue. But a lack of evidence is not evidence.

        In contrast, Dr. Arking carefully and persuasively testified about the current state of
knowledge regarding genetics. Dr. Arking’s report, testimony, and medical literature provide a
more credible and plausible explanation as to how mutations, particularly de novo mutations,
play a causal role in the development of autism.

        Similarly, petitioners failed to provide preponderant evidence that residual DNA or
HERV-K retrovirus fragments in vaccines trigger an autoimmune process that causes ASD. The
studies cited by petitioners about auto-antibodies did not support their hypothesis. All that can
be said is that auto-antibodies have been found in autistic individuals. What this means is simply
not yet known.

        The testimony by Dr. Burkhard drawing an analogy to PANDAS was not persuasive.
Neither was her testimony as to the findings on DTI studies and how they support petitioners’
theories. She provided no evidence to tie together the findings on the imaging studies with an
autoimmune response secondary to residual DNA or HERV-K fragments from vaccines. Her

                                                92
testimony on this point also ignored the caveat issued by the author of the study cited, that DTI
studies of autism should be interpreted with caution.

       Dr. Deisher specifically opines that her causal theories apply to autism caused by de novo
mutations, which account for approximately 10 percent of ASD cases, and/or autoimmunity,
which accounts for 40 percent of ASD cases. See Pet. Ex. 10 at 6; Pet. Ex. 76 at 25. However,
her change point study appears to address all cases of autism, regardless of etiology.
Additionally, Dr. Deisher opined that her causal mechanisms applied to “regressive” autism.
Again, her change point study does not appear to address only the regressive form of autism,
which accounts for approximately one-third of all autism cases. Thus, there appear to be
disconnects between her change point study and her causal mechanisms, which also call into
question their validity.

        My decision in this case does not turn solely on the deficiencies in Dr. Deisher’s change
point study. Even if the study provided credible and reliable evidence of the three change points
presented, petitioners failed to provide preponderant evidence of causation because their
proposed theories lack an evidentiary foundation. Many of Dr. Deisher’s hypotheses are pulled
from medical articles and are taken out of context. Petitioners’ counsel argues that it is
acceptable for experts to “extrapolate from existing data,” and that the “weight to be given to an
expert’s opinion is based, in part, on the size of the gap between the science and the opinion
offered.” Pet. Prehrg Br. at 7 (citing Cedillo, 2009 WL 331968). However, the gaps between the
science and the opinion offered in this case are too large and too many.

        Moreover, petitioners often make conclusory statements not supported by the evidence.
For example, petitioners state that DNA fragments can “enter the brain via any gap in the
[BBB],” but this was not shown by preponderant evidence. See Pet. Prehrg Br. at 1-2. They
state that DNA fragments “disrupt[] cell function,” but offer no evidence that this could occur.
See id. They state that the DNA fragments from the vaccines at issue are “homologous with the
protein in the tissues of the vaccine recipient.” Id. But this was not shown. They also state that
“the injury (from residual DNA from vaccines) can be detected in relevant areas of the brain.”
Id. Again, this was not shown. Ultimately, petitioners concede that, “as is the case with many
human diseases, we know what happens but we do not know how it happens.” Id. But here,
they have provided no evidence of “what happens” or “how it happens.”

        Petitioners ask me to consider the following concept of biological plausibility: “The
concept of biological plausibility…asks whether the hypothesized causal link is credible in light
of what is known from science and medicine about the human body and the potential offending
agent.” Pet. Prehrg Br. at 3 (citation omitted). I agree with petitioners that “substantial evidence
means ‘more than a mere scintilla’ and ‘such relevant evidence as a reasonable mind might
accept as adequate to support a conclusion.’” Pet. Prehrg Br. at 7. I find, however, that
petitioners have failed to show by preponderant evidence that residual DNA fragments and/or
HERV-K fragments from the vaccines at issue in this case cause autism. Petitioners have failed
to prove by preponderant evidence Dr. Deisher’s theory of vaccine-caused autism, and therefore
have failed to meet their burden under Prong One of Althen.




                                                93
      X.     Conclusion

       I extend my deepest sympathy to the petitioners and V.J.M. for the difficulties and
challenges they have faced. However, I cannot decide this case based upon my sympathy for the
family but by my analysis of the evidence.

       For the reasons discussed above, I find that petitioners have not established entitlement to
compensation and thus that their petition must be dismissed. Therefore, this case is dismissed
for insufficient proof. 216 The Clerk of Court SHALL ENTER JUDGMENT in accordance
herewith.

           IT IS SO ORDERED.

                                                     s/ Nora Beth Dorsey
                                                     Nora Beth Dorsey
                                                     Chief Special Master




216
   The 23 cases in the mini-omnibus include: J.M. et al. (02-010V), J.K.R. et al. (09-143V),
Fuesel (02-095V), E.H. et al. (09-206V), Arranga (02-1616V), B.W. (14-375V), J.H.R. et al.
(03-1156V), M.P. et al. (07-750V), Coiro-Lorusso (04-258V), S.O. et al. (08-125V), Young (05-
207V), Graddy (08-416V), C.B. et al. (05-1168V), Eworonsky (04-992V), C.B. et al. (08-131V),
King (05-717V), F.J.D. et al. (08-254V), P.R. et al. (10-096V), F.J.D. et al. (08-253V), Torres
(15-561V), N.P. et al. (08-388V), M.J. et al. (16-434V), and A.E.R. (17-470V). This Decision
applies to all of these cases.
                                                94
