Mark F' Blaxill

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WHY ARE SO MANY CHILDREN SICK? A Review of the
Strategic Direction of Autism Research and
Recent Activities at the NIH And with the IOM

• Mark F. Blaxill
• SafeMinds
• Autism One Conference
• May, 2007

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EMERGING EVIDENCE REQUIRES A NEW DISEASE
MODELAND DEFINES THE AGENDA FOR POLITICAL ACTION
From
To

• An alarmingly frequent disease
• rising incidence
• An environmental disease, with possible genetic
  vulnerability factors
• Outcomes result from preventable events in
  otherwise normal children
• A multi-disciplinary problem, spanning
  toxicology, epidemiology, neurology, immunology,
  gastroenterology, etc.
• Many opportunities for prevention, treatment and
  recovery
• Our children are sick

• A rare tragic disorder
• constant prevalence
• Clear, if complex, genetic causes
• Outcomes are inevitably determined in utero
• A neuro-genetics problem
• The best (and only) treatment is behavioral
  therapy
• Your children are defective

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WHY ARE SO MANY CHILDREN SICK?

• The autism epidemic
• Epidemic denial
• The heritability hypothesis
• Environmental factors research
• Accountability

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DISCOVERING AUTISM LEO KANNER IN 1943An
Extremely Rare Disorder

• Since 1938, there have come to our attention a
  number of children whose condition differs so
  markedly and uniquely from anything reported so
  far that each case meritsand, I hope will
  eventually receivea detailed consideration of
  its fascinating peculiarities....
• These characteristics form a unique syndrome,
  not heretofore reported, which seems to be rare
  enough, yet is probably more frequent than is
  indicated by the paucity of observed cases.
• -Leo Kanner, Autistic disturbances of
  affective contact, Nervous Child, 1943
• The fact that an average of not more than eight
  patients per year over twenty years could be
  diagnosed with reasonable assurance as autistic
  in a center serving as a sort of diagnostic
  clearinghouse, speaks for the infrequency of the
  disease, especially if one considers that they
  recruit themselves from all over the North
  American continent...
• -Leo Kanner, The specificity of early
  infantile autism Acta Paedopsychiatrie, 1958

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WHATS GOING ON? THE QUESTION OF TIME TRENDS
RATE INCREASES IN U.S. AND U.K. AUTISM SURVEYS
Cases per 10,000
U.S.
U.K.
ASD Autistic disorder
Midpoint year of birth
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WHY DOES THE EPIDEMIC MATTER?
Statement
Implication
Autism rates are 1 in 166, and We dont know
how much of the increases have come from
increased awareness It doesnt matter whether
autism rates have increased Lets rule out
inconvenient hypotheses such as vaccines and
their preservatives, e.g., thimerosal We have a
crisis and the explosion in rates is a national
emergency
No need for changes of any kind in funding or
science strategy Only need is to increase
overall funding, not its direction Impose
blinders on investigation by mandating selective
ignorance in research scope Urgent need to
increase environmental/treatment research and
respect plausible theories of causation
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WHY ARE SO MANY CHILDREN SICK?

• The autism epidemic
• Epidemic denial
• The heritability hypothesis
• Environmental factors research
• Accountability

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THE E.D. HYPOTHESIS

• To date, the epidemiologic data for a secular
  increase in the incidence of PDDs is both meager
  and negative. We simply lack good data to test
  hypotheses on secular changes in the incidence of
  autism. Because of specific methodologic
  limitations, the high prevalence rates reported
  in recent autism surveys cannot be used to derive
  conclusions on this issue. Prevalence data
  nevertheless point to the magnitude of the
  problem, which had clearly been underestimated in
  the past. But there is no need to raise false
  alarms on putative epidemics nor to practice poor
  science to draw attention to the unmet needs of
  large numbers of seriously impaired children and
  adults.
• -Eric Fombonne, Is There an Epidemic of
  Autism?, letter to Pediatrics, February, 2001.

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THREE (AND ONLY THREE) POSSIBLE SOURCES OF
DIAGNOSTIC ERROR
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DIAGNOSTIC SUBSTITUTION A DISCREDITED THEORY,
BUT IT KEEPS COMING BACK

• Tests of the diagnostic substitution hypothesis
• California, claim retracted by authors
• Croen et al, J Autism Dev Disord.
  200232(3)207-15.
• Blaxill et al, J Autism Dev Disord.
  200333(2)223-6
• 2. UK, argument disavowed by authors
• Jick H, Kaye JA. Pharmacotherapy.
  200323(12)1524-30. Erratum later
• Blaxill, Pharmacotherapy. 200424(6)812-3
• Minnesota, investigated, not found
• Gurney et al, Arch Pediatr Adolesc Med.
  2003157(7)622-7
• Barbaresi et al, Arch Pediatr Adolesc Med.
  2005159(1)37-44
• U.S. IDEA statistics, findings disputed
• Newschaffer et al, Pediatrics. 2005115(3)e277-82
  
• Shattuck, Pediatrics. 2006117(4)1028-37
• Blaxill et al, submitted

Diagnostic substitution
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CROEN ET AL (2002), ON DIAGNOSTIC SUBSTITUTION

• To evaluate the role of diagnostic substitution,
  trends in prevalence of mental retardation
  without autism and autism...were investigated
• During the study period, autism prevalence
  increased from 5.8 in 1987 to 14.9 per 10,000
  in 1994, for an absolute change of 9.1 per
  10,000 during the same period, the prevalence
  of mental retardation without autism decreased
  from 28.8 to 19.5 per 10,000, for an absolute
  change of 9.3 per 10,000.
• These data suggest that improvements in
  detection and changes in diagnosis account for
  the observed increase in autism.

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IS AUTISM DIAGNOSIS SUBSTITUTING FOR MENTAL
RETARDATION IN CALIFORNIA?
Prevalence rate by age cohort (cases per
10,000)
Mental retardation of unknown cause
Autism
Birth year
Source California Department of Developmental
Services, state census department on live births
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CRITIQUE OF CROEN ET AL

• We disagree...Closer examination of the data and
  methods shows that Croen et al made analytic
  errors in several areas.
• They did not consider the trend information
  within their own dataset
• They did not consider obvious ascertainment
  biases within their youngest autism cohorts
• They did not consider similar ascertainment
  biases in the MR category
• They did not analyze the implications of their
  own records review
• They did not define a key element of their
  principal disease frequency measure prevalence.
• -Blaxill MF, Baskin DS and Spitzer WO, JADD,
  April 2003

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DIAGNOSTIC EXPANSION NO EVIDENCE HAS EVER
SUPPORTED THIS THEORY

• Tests of the diagnostic expansion hypothesis
• Intent of the designers The change from DSM-III
  to DSM-III-R is an example of the broadening of
  the concept of autism from DSM-III-R to DSM IV,
  a corrective narrowing occurred.
• -Volkmar et al, 1997
• Analysis of diagnostic criteria adding
  Aspergers Syndrome is only change to the PDDs
  -Blaxill, 2004
• Cohort comparisons no difference in false
  positive rate in California autistic population
  between 1983-85 and 1993-95 -Byrd et al,
  2002
• Broader criteria for research identified autism
  fail to locate older children with looser
  criteria
• -Barbaresi et al, 2005

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MIND INSTITUTE STUDY REVIEWED CALIFORNIA AUTISM
CASES DIAGNOSED IN TWO TIME PERIODS TO TEST
DIAGNOSTIC EXPANSION HYPOTHESIS
Birth year 1983-85
Birth year 1993-95
p-value
Interviewed Met ADI-R criteria for
autism Percent positive for autism Percent
positive for autism (adjusted for study design)
135 120 88.9 88.2
216 193 89.4 88.7
0.97 0.90
SourceMIND Institute, Report to the Legislature
on the Principal Findings from the Epidemiology
of Autism in California, October 17, 2002
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DIAGNOSTIC OVERSIGHT THE HIDDEN HORDE THEORY
HAS BEEN TESTED AND PROVEN FALSE

• Tests of the diagnostic oversight hypothesis
• 1. Burd et al, 2000, International Journal of
  Circumpolar Health, 59(1)74-86
• the original...methodology identified 98 of the
  cases...in the population
• 2. Gillberg et al, 1991, Br J Psychiatry
  1991158403-9
• no new cases found after 4 years, adjusting for
  immigration, in 11-13 vs. 7-9 year olds
• 3. Nylander and Gillberg, 2001, Acta Psychiatra
  Scandinavia, 103428-434
• lt1 of outpatient population screened received
  diagnosis, only 2.7 per 10,000
• 4. Chang et al, 2003, Gen Hosp Psychiatry,
  2003(4)284-8
• lt1 of outpatient population screened received
  diagnosis, lt1 per 10K

Diagnostic oversight (1.5 million in
U.S., millions more globally)
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CALIFORNIA REGISTRY HAS BEEN IN PLACE FOR MANY
YEARS, UNLIKE THE IDEA REGISTRY

• 1969 Lanterman Developmental Disabilities
  Services Act passed
• Autism (full syndrome), mental retardation,
  cerebral palsy, epilepsy services guaranteed
• 1976 21 Regional Centers established to
  administer and coordinate services
• Case registry now centralized
• Medicaid reimbursement introduced in the 1980s
• 1994 DSM IV adds Aspergers Syndrome to PDDs
• Unlikely to affect DDS services criteria and
  registered case count
• 1995 Early Start program implemented statewide
• Likely impact on age at diagnosis
• 2003 Eligibility requirements for all DDS
  services became more strict
• Likely to support restrictive intent of service
  eligibility

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TIME TO SHIFT THE BURDEN OF PROOF

• Epidemic denial theory is a testable hypothesis
  and fails all tests
• Comprehensive tests of ED have been run in
  California with not a shred of support for the
  theory
• E.D. theory is treated seriously by mainstream
  scientists, press and medical establishment
• Unscientific speech
• No facts or evidence to support it
• Delays shift in resources and attention to
  environmental factors research and thereby harms
  children

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WHY ARE SO MANY CHILDREN SICK?

• The autism epidemic
• Epidemic denial
• The heritability hypothesis
• Environmental factors research
• Accountability

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AUTISM IS INHERITED
Autism is one of the most heritable complex
disorders, with compelling evidence for genetic
factors and little or no support for
environmental influence. The estimated prevalence
of autism has increased since molecular genetic
studies began, owing to loosening of diagnostic
criteria and, more importantly, to more complete
ascertainment strategies - Jeremy
Veenstra-VanderWeele, Susan Christian and Edwin
Cook, 2004
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TWIN STUDIES THE CORNERSTONE OF THE GENETIC CASE
Identical (monozygotic) twins
Fraternal (dizygotic) twins
Concordance rate ()
Concordant
Concordance rate ()


Concordant
Discordant
Discordant
0 0 0 4 2 6

• Folstein and Rutter, 1977
• Steffenburg et al, 1989
• Bailey et al, 1995
• Ritvo et al, 1985
• Cited in Ritvo et al, 1954-79

4 10 11 22 3 50
7 1 5 1 1 15
36 91 69 96 75 77
10 10 11 17 6 54
0 10 11 13 4 48
0 0 0 24 33 11
11 11 16 23 4 65
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TEN MAJOR GENOME SCANS FROM EIGHT SEPARATE GROUPS
FUNDED BEFORE THE AGPC
Size, Countries, HQ
Team
Scans published
Selected members
Multiplex families
63, 6, London 31, 1 (US), Stanford 22, 7,
Paris 30, 1 (US), Boston 11, 1 (US),
NY/LA 10, 1 (US), NY 17, 1 (US South),
Duke 9, 1 (Finland), Helsinki
Bailey, Fombonne, Cook, Rutter, Lord, Volkmar,
Leventhal Risch, Cafalli-Sforza Gillberg,
Coleman Folstein, Piven Geschwind, Lord,
Iverson, CAN Buxbaum, CAN Pericak-Vance,
Ashley-Koch, NAAR Auranen, Peltonen
1. International Molecular Genetic Study of
Autism Consortium (IMGSAC) 2. Stanford group 3.
Paris Autism Research Intl Sibpair (PARIS)
Study 4. Collaborative Linkage Study of Autism
(CLSA) 5. Autism Genetic Resource Exchange
(AGRE) Consortium 6. Seaver Autism Center
Group 7. Collaborative Autism Team (CAT) 8.
Helsinki group
IMGSAC, 1998 IMGSAC, 2001 Risch et al,
1999 Philippe et al, 1999 Barret et al,
1999 Liu et al, 2001 Yonan et al,
2003 Buxbaum et al, 2001 Shao et al,
2002 Auranen et al, 2002
99 152 90 51 75 110 95 99 38
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LANDER AND KRUGLYAK GUIDELINES FOR STATISTICAL
SIGNIFICANCE IN GENOME SCANS

• LOD/MLS Score
• Highly significant gt5.40 expected 1 in 10,000
  scans at random
• Significant gt3.60 expected 1 in 20 scans at
  random
• Suggestive gt2.20 expected once at random in any
  scan
• Added by autism authors
• Critical level gt1.0 standard set in some
  recent autism scans
• Non-negative gt0 used as evidence of replication
  in some recent autism scans

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LANDER AND KRUGLYAK RAN A SIMULATION TO PROVIDE
GUIDANCE ON SETTING STANDARDS OF PROOF IN A FULL
GENOME SCAN

• To illustrate the random fluctuations expected
  in a whole genome scan, we generated simulated
  genotypes assuming independent assortment
  throughout the genomethat is that there are no
  trait causing loci. All positive scores in such
  data necessarily represent random fluctuations,
  not true linkageIn the simulation, a single
  region on chromosome 14 reached the status of
  suggestive linkage, as expected, while no region
  showed significant linkage. If these results had
  occurred in a real dataset, an investigator would
  likely call attention to the possibility of
  linked genes on chromosome 14The example thus
  illustrates that false positives can cluster in
  candidate regions and otherwise mimic true loci.

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WEAK RESULTS FROM TEN GENOME SCANSNO
REPRODUCIBLE AND SIGNIFICANT FINDINGS
MLS score
Highly significant
Significant
IMGSAC B
IMGSAC B
Suggestive
Critical level
X
X

Chromosome
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THE MEDIA SPIN

• "We have known for years that autism is a
  strongly genetic disorder--this study helps us to
  significantly advance research on genetic
  mechanisms," said Dr. Fred Volkmar, study
  co-author, Yale Child Study Center Director and
  the Irving B. Harris Professor of Child
  Psychiatry, Pediatrics and Psychology.
• "Not only have we found which haystack the needle
  is in, we now know where in the haystack that
  needle is located," said Dr. Peter Szatmari
  head of child psychiatry at McMaster University.
  "This is a major breakthrough in our efforts to
  better understand the disorder and improve
  diagnosis and treatment for patients and their
  families."
• The evidence suggests that autism is over 90
  percent caused by genes, said Dr. Joseph
  Buxbaum.

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ITS TIME TO SET ASIDE THE HERITABILITY
HYPOTHESIS OF AUTISM AND MOVE ON TO ENVIRONMENTAL
FACTORS

• Consistently negative results from numerous
  genome scans
• Massive large scale collaborationthe AGPCfinds
  nothing
• Nearly 1500 families, 135 authors and 24 lead
  investigators
• Findings are little different from the results
  one would expect from a random number generator
• Findings falsified all suggestive study results
  from previous regions of interest (chromosomes
  2q, 7q and 17q)
• Heritability assumptions a based on a false
  foundation
• Overstatement of MZ/DZ twin evidence
• Ignores recent twin evidence that is far more
  equivocal

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WHY ARE SO MANY CHILDREN SICK?

• The autism epidemic
• Epidemic denial
• The heritability hypothesis
• Environmental factors research
• Accountability

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CHALLENGING THE ALLOCATION OF SCIENTIFIC RESOURCES
Genetics
Environment
Treatment
Cause
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ADVANCING THE PRIORITY OF ENVIRONMENTAL FACTORS
RESEARCH (1)

• National Institutes for Environmental Health
  Sciences
• Sponsored by outgoing NIEHS Director, Dr. Ken
  Olden
• Environmental Factors in Autism Research
• August 25-26, 2005
• Participants included
• Neurotoxicology Conference
• Sponsored by Dr. Joan Cranmer
• Neurotoxicity in Development and Aging
  Advancing the Science of Autism Spectrum Disorder
• September 18, 2006
• Participants included

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ADVANCING THE PRIORITY OF ENVIRONMENTAL FACTORS
RESEARCH (2)

• Institute of Medicine
• Sponsored by DHHS Science Advisor, Dr. William
  Raub
• Workshop on Autism and the Environment
• April 18-19, 2007
• Participants included

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AT ONE MONTH OF AGE, HIGH MERCURY EXPOSURES
RESULTED IN ELEVATED RELATIVE RISKS FOR SEVERAL
NEUROLOGICAL DISORDERS, INCLUDING AUTISM
ADHD (8.29)
Relative risk of disorder
Autism (7.62)
ADD w/o hyper (6.38)
Tics (5.65)
Sleep disorders (4.98)
Speech/language (2.08)
Unspecd devel. delays (0.49-gt2.08)
Coordination disorders
Other specific devel. delays
Cerebral palsy (0.25)
Statistically significant increased risk from
vaccine mercury exposure
Vaccine mercury exposure level at one month (mcg)
Statistically significant reduced risk from
vaccine mercury exposure
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ONE MONTH EXPOSURE SUMMARY ANALYSIS OF FIVE
NDDsCompared to Control Diagnoses Epilepsy and
Febrile Seizures
Relative risk of disorder
Autism (11.35)
Sleep disorders (4.64)
ADD (3.96)
Mix of 5 NDDs (2.38)
Speech/language (1.95)
Febrile seizures
Epilepsy
Vaccine mercury exposure level at one month (mcg)
Statistically significant increased risk from
vaccine mercury exposure
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IT JUST WONT GO AWAY

• From Verstraeten, Thomas
• Sent Friday, December 17, 1999 440 PM
• To Robert Davis
• Cc Destefano, Frank
• Subject It just wont go away
• Hi,
• Attached please find four tables with RRs
  relative risks and three SAS programs...
• As youll see, some of the RRs increase over the
  categories and I havent yet found an alternative
  explanation...Please let me know if you can think
  of one. Frank proposes we discuss this on a call
  after the New Year...
• Happy Holidays!
• Thomas Verstraeten, M.D.

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HAIR MERCURY LEVELS IN AUTISTIC VS. CONTROL
GROUPS
Hair Hg level (ppm)
Autistic Mean0.47 n94
Non-autistic Mean3.79 n34
Source Holmes AS, Blaxill MF, Haley BE, Reduced
mercury hair levels in autistic children
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HAIR MERCURY LEVELS BY SEVERITY OF AUTISM
Hair Hg level (ppm)
Mild Mean0.71 n27
Moderate Mean0.46 n43
Severe Mean0.21 n24
Source Holmes AS, Blaxill MF, Haley BE, Reduced
mercury hair levels in autistic children
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ACTUAL VERSUS PREDICTED HAIR MERCURY LEVELS
Actual hair Hg level (ppm)
Predicted hair Hg level (ppm)
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AUTISM RATES IN CALIFORNIA OVER TEN YEARS BY AGE
AT TIME OF DATA COLLECTION 12/97-12/06
Prevalence rate by age cohort (cases per
10,000)
6 year olds
5 year olds
7 year olds
8 year olds
4 year olds
10 year olds
12 year olds
3 year olds
14 year olds
21 year olds
27 year olds
Birth year
Source State of California Department of
Developmental Services, 1997-2006
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WHY ARE SO MANY CHILDREN SICK?

• The autism epidemic
• Epidemic denial
• The heritability hypothesis
• Environmental factors research
• Accountability

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SUPPORT ANDY WAKEFIELD

• Sign the Nigel Thomas petition
• AUTISM STOP THE DECEIT START THE TREATMENT
• http//www.ipetitions.com/petition/GMC/