# M. v. Secretary of Health and Human Services > United States Court of Federal Claims · February 7, 2018 URL: https://www.frixlaw.com/law-library/cases/4243116 ## Case - **Court:** United States Court of Federal Claims - **Decided:** February 7, 2018 - **Precedential status:** Published - **Opinion:** Opinion - **Judges:** Nora Beth Dorsey - **Cited by:** 0 later opinions in the Frix Law Library ## Citator (automated) - No negative treatment found by the automated citator. That is not the same as a confirmation that the case is good law; read the citing cases. - Full citator and citing cases: https://www.frixlaw.com/law-library/cases/4243116 ## How later opinions describe it (automated extraction) - stating that “epidemiologists generally look to several additional criteria to determine whether a statistical association is indeed causal.” - noting that special masters are bound by both § 300aa- 13(b)(1) and Vaccine Rule 8(b)(1) to consider only evidence that is both “relevant” and “reliable” ## Opinion text 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-cont [Text truncated at 120,000 characters. The full text is on the page linked above.] --- Source: Frix Law Library, https://www.frixlaw.com/law-library/cases/4243116. Public record. Not legal advice.