medical findings from the autism treatment network

Funded by cooperative agreement UA3 MC 11054 through the U.S. Department of Health & Human Services, Health Resources & Services Administration, Maternal & Child Health Research Program

Funded by cooperative agreement UA3 MC 11054 through the U.S. Department of Health & Human Services, Health Resources & Services Administration, Maternal & Child Health Research Program

Medical Findings from the

Autism Treatment NetworkNisonger Center Brown Bag Series

March 10, 2011

Daniel L. Coury MDMedical Director, Autism Speaks Autism Treatment Network

Professor of Pediatrics and PsychiatryThe Ohio State University

Daniel L. Coury MDHas documented that he/she has no

relevant financial relationships to disclose or COIs to resolve.

Objectives

• Describe the Autism Treatment Network (ATN) Registry and the data it collects

• Review recent findings from analysis of the ATN Registry

• Discuss research studies currently undertaken by the ATN

The Autism Treatment Network

• The Autism Treatment Network (ATN) is a collaboration that arose in 2003 from a partnership between the Northwest Autism Foundation and the MassGeneral Hospital for Children’s Learning and Developmental Disabilities Evaluation and Rehabilitation Service program (MGHfC/LADDERS).

• The group identified 5 medical centers that were committed to working together to address medical issues relevant to children with ASD and design an extensive common database for the developing network.

• The database did not reflect specific research questions or hypotheses but rather the desire to gather consistent data on the evaluation and treatment of children with ASD.

• Inclusion of items or domains came from consensus among the participating clinicians

ATN Growth and Development• 2005: Initial private funding, with five founding sites

– Baylor, Columbia, MGH/Harvard, Oregon, Washington

• 2006-7: Merger with Cure Autism Now and then with Autism Speaks

• Substantial new resources allowed expansion to 15 sites, with the following new sites:– Arkansas, Cincinnati, Colorado, Kaiser, Kennedy-

Krieger, Missouri, Pittsburgh, Rochester, Toronto, Vanderbilt

• 2008: Successful application to HRSA, Maternal and Child Health Bureau, for Autism Intervention Research Network for Physical Conditions (AIR-P)

ATN and Autism Intervention Research Network Physical Health (AIR-P)

• Funded by a grant from the Maternal and Child Health Bureau, Health Resources and Services Administration

• The AIR-P has a goal of – Conducting research in physical health aspects of

autism spectrum disorders (ASD) – Developing evidence-based guidelines for care in

ASD – Providing community education regarding ASD

• The AIR-P project utilizes the infrastructure of the ATN to carry out its projects

ATN Patient Registry

• Includes children 2-17• De-identified data collected on clinical

assessments required in the ATN battery• Data collected on subsequent clinical

visits including required annual follow up• Track subspecialty referrals

ATN Assessment BatteryBased on expert consensus

• Assessment includes review of Diagnostic and Statistical Manual (DSM) criteria and Autism Diagnostic Observation Schedule (ADOS)

• Cognitive testing, either developmental (Mullen or Bayley) or intelligence (Stanford-Binet 5th ed, other)

• Adaptive behavior (Vineland Adaptive Behavior Scales)• Assessment of behaviors (Child Behavior Checklist,

CBCL; Sensory Profile; Children’s Sleep Habits Questionnaire, CSHQ; GI Symptom Inventory; PedsQL)

• Medical and developmental history, physical examination, pertinent lab studies

Externally Funded ATN Research

• Three projects funded thru Autism Speaks research program– GI disorders in children with ASD (Harland Winter,

MD, PI, MassGeneral Hospital for Children)• Collaborating sites: Columbia

– Improving sleep outcomes for children with ASD (Dan Glaze, MD, PI, Baylor)• Collaborating sites: Oregon, Columbia

– Developing quality of life measures for children with ASD and their parents (Karen Kuhlthau, PhD, PI, MassGeneral Hospital for Children)• Collaborating sites: UW, Oregon

ATN Registry Analyses

• “Use of Psychotropic Medications in Autism Spectrum Disorders”

• “Use of Complementary and Alternative Medicine in Autism Spectrum Disorders”

• “Factors Associated with Sleep Problems in Children with Autism Spectrum Disorders”

• “GI Symptoms in children with Autism Spectrum Disorders”

“Use of Psychotropic Medications in Autism Spectrum Disorders”

• Studies of psychotropic medication use in children with ASD based on national surveys and on claims data indicate rates of 24% to 57%, with even higher rates for older youths.

• We sought to determine the use of psychotropic medications in a well characterized cohort of children and adolescents with ASD.

• Psychotropic medication use was established by both parent and clinician report of use and entry into the registry. Clinicians were also asked to indicate reason

for medication use.


KEY FINDINGS• 112 of 415 subjects (27%) were receiving psychotropic

medications• 2 of 48 (4%) of children under age 3 years were on

medication• No one in the < 3 years group was on more than one

medication• As these children mature, we see a higher percentage

of them on medications


• 11% of children in 3-5 age group are on medication; 2% on multiple medications

• This rises to 44% of children in 6-10 age group with 22% on multiple medications (maximum 5)


• 59% of ATN subjects over age 10 are on medication

• 44% are on 2 or more medications (maximum 4 medications)


When compared to National Ambulatory Medical Care Survey (NAMCS) data for 2001-2005, children in ATN sites are

• Younger (87% <10 vs 40% in NAMCS)• Overall, less likely to be receiving meds (27%

vs 79%)• Highest ATN treated group reached 60% use


• Most common parental behavioral concerns, in order:

attention spanhyperactive behaviorsanxiety behaviorsrepetitive behaviors

• Most common medications prescribed, in order:stimulants (methylphenidate,

amphetamines)alpha agonists (guanfacine, clonidine)atypical antipsychotics (risperidone,

aripiprazole)


SIGNIFICANCE / RELEVANCE

• Overall lower rate of use perhaps due to proportion of newly diagnosed children

• Use in older youths similar to other reports• Patterns of use expected to change with new

data regarding effectiveness of certain medications, FDA approval, and other factors

Complementary and Alternative Medicine use in the U.S.

“Use of Complementary and Alternative Medicine in Autism Spectrum Disorders”

• Complementary and alternative medicine (CAM) is part of overall treatment plan for many people for a variety of conditions (arthritis, skin disorders, ADHD, bladder and bowel problems, etc)

• Several CAM treatments are promoted as helpful in treating autism spectrum disorders

• How commonly do we see this in the ATN?


• Complementary and alternative medicine (CAM) treatments are commonly reported as part of the overall management plan for children with ASD

• 250 of 1212 (21%) reported CAM use• 201 of 1212 (17%) reported special diet use• Most common treatment was gluten free, casein free

diet (53% of those using diets reported this diet)• Children with GI problems were most likely to be on

diets, and to be using other GI treatments (multivitamins, probiotics, digestive enzymes)

• Least common: chelation, HBOT, acupuncture


CAM TreatmentsSpecial Diets - 17% are on special diets• 8.4% are on gluten free, casein free (GFCF)• 2.2% on no processed sugars• 8.7% are on some other special diet such as

Feingoldno sugarsspecific carbohydrate


CAM dietary treatments• Children with ASD and with GI symptoms are

more likely to be receiving special diets• This ranges from two to five times the rate for

ASD children without GI symptoms• Families seem to be using special diets to treat

GI symptoms more than to treat ASD symptoms


Overall, 21% are using CAM treatmentsOral treatments• Vitamin supplements 14%• Vitamin B6 and magnesium 3.5%• Probiotics 8.8%• Digestive enzymes 3.6% • Essential fatty acids 6%• Amino acids 2.5%• Antifungal medication 1.5%• Glutathione 1.3%• Sulfation 0.3%

}more in GI symptoms


Other CAM treatments

• Chiropractics 2.4%• Acupuncture 0.5%• Chelation 0.5%• Hyperbaric oxygen treatment 0.4%

There is no relation to GI symptoms or type of ASD when families choose these treatments

“Factors Associated with Sleep Problems in Children with Autism Spectrum Disorders”

• Children with autism have been reported to have increased incidence of sleep problems, with estimates ranging from 44 – 83%

• Sleep problems have been associated with intellectual deficits, separate from autism diagnoses

• Sleep problems such as obstructive sleep apnea and fragmented sleep due to repeated arousals have been associated with poor neurocognitive function, including attention problems

• Sleep problems have been associated with challenging behavior


• Children’s Sleep Habits Questionnaire (CSHQ) was completed by 1056 parents

• 65% had scores in the range of clinical sleep problems• ASD children with sleep problems did not differ from

ASD children without sleep problems by gender, age, ASD category, race or IQ

• 70% of children with GI problems also report sleep problems; only 30% of children without GI problems report sleep problems


CSHQ SCALE Age < 6 yrs Age ≥ 6 yrs Community

Sleep delay 1.7 (0.8) 1.8 (0.8) 1.3 (0.5)

Sleep anxiety 6.2 (2.1) 6.0 (2.1) 4.9 (1.5)

Sleep duration ** 4.2 (1.6) 4.4 (1.8) 3.4 (0.9)

SDB 3.4 (0.9) 3.5 (0.9) 3.2 (0.6)

Parasomnias ** 9.7 (2.2) 9.2 (1.9) 8.11 (1.3)

Night awakenings * 4.5 (1.6) 4.3 (1.5) 3.5 (0.9)

Bedtime resistance *** 9.5 (8.6) 8.6 (2.9) 7.1 (1.9)

Daytime sleepiness *** 12.2 (3.3) 13.1 (3.7) 9.6 (2.8)

Total Score 48.1 (9.0) 48.0 (8.8)

* p=0.01 **p≤0.001 ***p≤0.0001


• Sleep factors are associated with problematic daytime behaviors in a large cohort of children with well-defined ASD (r=0.47).

• The behavioral domains of affective disorders and anxiety are associated with problematic sleep.


• The behavioral domains of affective disorders and anxiety are associated with problematic sleep (r=0.55).

“GI Symptoms in children with Autism Spectrum Disorders”

• The GI Symptom Inventory, the Child Behavior Check List (CBCL) and the Pediatric Quality of Life (PedsQL) questionnaire were completed by 1185 parents

• 45% reported GI symptoms; most common were abdominal pain (59% of those with symptoms), followed by constipation, diarrhea and nausea

• Children with GI symptoms had more overall behavioral abnormalities than those without

• Children with GI symptoms had lower health related quality of life than those without

Pediatric Quality of Life Inventory(PedsQL)

• Core domains are- physical functioning- social functioning- emotional functioning- school functioning

• There are norms for typically developing, healthy children

• Studies have shown differences in children with chronic conditions (asthma, obesity, arthritis, etc)

• Measures health-related quality of life• Higher scores = better functioning; lower scores =

poorer functioning

ATN Registry: Quality of LifeATN Sample

Healthy Sample*

Chronic Health Condition Sample*

N=1001 N=8,713 N=831

Parent Proxy Report

Mean (SD)

Mean (SD)

t Score Mean (SD) t Score

Total 65.4 (15.7)

82.3 (15.6)

-32.4** 73.1 (16.5) -10.2**

Physical health 74.4 (20.6)

84.1 (19.7)

-14.1** 77.0 (20.2) -2.7*

Psychosocial Health

60.3 (16.4)

81.2 (15.3)

-38.5** 71.0 (17.3) -13.6**

Emotional Functioning

65.9 (19.9)

81.2 (16.4)

-23.5** 71.1 (19.8) -5.6**

Social Functioning

53.1 (23.2)

83.1 (19.7)

-39.3** 75.1 (21.8) -20.7**

School Functioning

62.9 (19.7)

78.3 (19.6)

-23.4** 65.6 (20.8) -2.8*

* Data from Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL TM as a pediatric population health measure: feasibility, reliability, and validity. Ambulatory Pediatrics. 2003: 3:329-341.

** p-value < 0.001; *p-value < 0.01

CBCL Sample

XXXXX X XXXXXXxxxx

ATN Registry: Quality of Life

• PedsQL and Behavior (Child Behavior Checklist)• CBCL higher order scales (“Clinical” range: > 63) • Internalizing

– “Clinical” range• No: 77±3 versus Yes: 58±3; p-value <0.001

• Externalizing – “Clinical” range

• No: 72±3 versus Yes: 59±3; p-value <0.001

*Adjusted for age, gender and ASD


• PedsQL Subscale Scores by Total CBCL Score (“Clinical” range)


** All p-values < 0.0001

85

76

66

7672

67

50 49

5952

0

10

20

30

40

50

60

70

80

90

Physical Emotional Social School PsychosocialHealth

No Yes


• PedsQL Subscale Scores by Internalizing/Externalizing Groupings


** p-values < 0.001

8780

67

7974

65

48 4956

50

0

10

20

30

40

50

60

70

80

90

100

Physical Emotional Social School PsychosocialHealth

Non-disordered Internalizing Externalizing Comorbid

**

** ****

**

ATN 2010 Research Activities• Six AIR-P Research Projects underway funded by HRSA

• Nutrition in ASD • Improving sleep in children with ASD• Bone density in boys with ASD• Creatine deficiency in ASD• Iron problems in children with ASD• Co-existing behavioral problems and sleep in

children with ASD • Developed research agenda for GI disorders in ASD• Second round of possible AIR-P Research Projects under

review at this time; up to five to be funded

“Diet and Nutrition in Children with Autism Spectrum Disorders: An ATN Study”

• Lead PI: Susan Hyman, MD• Lead Site: University of Rochester • Collaborators: Jill James, PhD Arkansas

Cindy Molloy, MD CincinnatiAnn Reynolds, MD ColoradoCindy Johnson, PhD Pittsburgh

• Project Period: 09/01/2009 – 08/31/2011 • Study Aims:

– Assess nutritional intake and dietary patterns in a large and well characterized cohort of children with ASD

– Assess excess intake with nutritional supplementation– Compare iron status and vitamin D levels to dietary intake– Describe relationship of diet and nutrition to physical

symptoms related to sleep and GI function

“Parent-Based Sleep Education Program for Children with Autism Spectrum Disorders”

• Lead PI: Beth Malow, MD• Lead Site: Vanderbilt University Medical Center • Collaborators: Cindy Molloy, MD Cincinnati

Ann Reynolds, MD ColoradoWendy Roberts, MD Toronto

• Project Period: 03/01/2009 – 02/28/2012 • Study aims:

– To determine the efficacy of a sleep education pamphlet compared to no sleep education in children with ASD

– To compare two nurse-led sleep interventions in children with ASD

– To conduct a larger scale RCT comparing the more effective intervention developed in Phase 1, with the control intervention (sleep education pamphlet)

– To determine if the intervention improves sleep latency, as measured by actigraphy

“Markers of Iron Status and Metabolism in Children with ASD”

• Lead PI: Ann Reynolds, MD • Lead Site: University of Colorado • Collaborators: AIR-P Nutrition Sites

(Arkansas, Cincinnati, Pittsburgh, Rochester)

• Project Period: 12/01/2009 – 11/30/2010 (projected)• Study aims:

– To evaluate iron intake, iron status and associated sleep disorders in a large, well characterized sample of children with ASD

“Prevalence of Creatine Deficiency Syndromes and Genetic Variability in Creatine Metabolism

in Children with ASD: A Pilot Study”

• Lead PIs: Andreas Schulze, MD, PhD ; Alvin Loh, MD • Lead Site: University of Toronto• Collaborators: Margaret Bauman, MGH/LADDERS/Lurie

Center, BostonAnn Tsai, University of Colorado

• Project Period: 01/01/2010 – 12/31/2010 (projected)• Study aims:

– To identify the prevalence of creatine deficiency syndromes in children with autism spectrum disorder

– To treat individuals with ASD and a specific creatine deficiency syndrome with a defined protocol

– To compare the effects of creatine supplementation for children with ASD with low urinary creatine excretion vs children with ASD with normal urinary creatine excretion

“Defining the Relation of Sleep Disturbance in Autism Spectrum Disorder to Psychiatric and

Behavioral Co-morbidities”

• Lead PI: Suzanne Goldman, PhD • Lead Site: Vanderbilt University

Medical Center • Project Period: 10/01/2009 – 09/30/2010

• Study aims: – To define the psychiatric and behavioral co-

morbidities associated with disordered sleep in children with ASD

“Bone Mineral Density in Children with Autism Spectrum Disorders”

• Lead PI: Ann Neumeyer, MD • Lead Site: MGH/LADDERS/Lurie Center • Collaborators: Cindy Molloy, Cincinnati

Sue McGrew, Vanderbilt• Project Period: 12/01/2009 – 11/30/2010

(projected)• Study aims:

– To investigate the degree to which bone mineral density is impaired in children with autism and to explore specific additional risk factors

Registry Analyses under Development

• Psychiatric co-morbidity in ASD• Utility of various cognitive measures in

assessment of ASD• Effect of maternal fever during pregnancy on

functional status of child with ASD• Effect of parental age and functional status• Association of gestational age and adaptive

functioning, quality of life, and behavioral profiles

Summary

• The ATN is analyzing the Registry to better describe children with ASD

• Several prospective studies are underway• Future emphasis on improving care and

best practices through comparative effectiveness studies

Questions

medical findings from the autism treatment network

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