M. v. Secretary of Health and Human Services

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 cel

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