Understanding “the whirling ball of comorbidity”: Reading Disability and ADHD Erik Willcutt,...

Understanding “the whirling ball of comorbidity”:Reading Disability and ADHD

Erik Willcutt, Ph.D.University of Colorado, Boulder

Funding Colleagues in Training Collaborators at CU and other institutionsNIH Research Grants (PI) Graduate Students M. Banich E. Arnold J. Keenan

R01 MH 62120 (Willcutt) H. Barnard (DU) A. Bryan P. Asherson H. Kraemer

R01 MH 63941 (Willcutt) C. Bidwell G. CareyT.

Baneschewski J. Kuntsi

R01 HD 47264 (Willcutt) K. Brodsky N. Chhabildas J. Biederman B. Lahey

P50 HD 27802 (Olson) L. Duncan R. Corley B. Blachman J. Loney

R01 HD 38526 (Olson) R. Gaffney-Brown T. Curran B. Byrne K. McBurnett

R01 MH 63207 (Hewitt) C. Hartman J. DeFries L. Cardon R. Nicolson

R01 DC05190 (Wadsworth) K. Mackiewicz M. Ehringer C. Carlson J. Nigg

R01 MH 70037 (Banich) L. McGrath (DU) N. Friedman S. Cherny D. PaulsR01 MH 66115 (Ross) G. McHaffie J. Hewitt D. Davalos W. Pelham

L. Santerre-Lemmon (DU) C. Hopfer A. DePrince B. Pennington

NIH Training Grants J. Schacht K. Hutchison A. Doyle R. Plomin

T32 MH 16880 (Hewitt) M. Shanahan (DU) T. Ito J. Epstein S. Samuelsson

F31 MH 78514 (Bidwell) K. Krauter S. Faraone C. Schatschneider

F31 DC 008726 (McGrath) Postdoctoral Fellow D. Miklowitz J. Fletcher L. Seidman

F31 MH 77482 (Shanahan) R. Betjemann A. Miyake C. Francks J. Sergeant

Y. Munakata M. Frank S. ShirkNIH Project Officers Project Coordinators R. Olson M. Friedman S. SmalleyP. McArdle, B. Miller T. DiLeo R. O’Reilly J. Gayan S. SmithJ. Rumsey, F. Tuma S. Hitt-Laustsen S. H. Rhee J. Gruen E. Sonuga-Barke

J. Keith R. Ross C. Hartung J. Stevenson

Other Funding W. Legg A. Smolen D. Hay Jim Swanson

Ackerman Foundation M. Stallings W. Heller R. Todd

Australian Res. Counc. S. Wadsworth S. Hinshaw R. Tannock

University of Colorado S. Young P. Jensen I. Waldman

“That’s it! Just me, alone at home, trying to be a good parent for my little whirling ball of comorbidity”

Too active

Anxious

Learning

Aggressive Comorbidity

• What is comorbidity? Answer: Two or more disorders in the same individual.

• Why does comorbidity matter?

• What causes comorbidity between reading disability and ADHD?

• What are the implications of comorbidity for assessment and treatment?

• Suggestions for the future

Questions we will answer today

Why should we care about comorbidity?

Comorbidity is the rule, not the exception

0

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AcademicImpairment

Retained in school Social Impairment Occupationalimpairment

Justice System

Pe

rce

nt

Comorbidity is associated with greater initial impairment and more extensive and severe negative outcomes

Control ADHD RD+ADHDRD

Comorbidity has important implications for treatment

RD ADHD

ADHD RD

Shared risk factor RD + ADHD

Our ongoing studies most relevant to comorbiditybetween RD and ADHD

• Colorado Learning Disabilities Research Center (Director: Olson)

- 8 - 18 year old twins screened through schools• RD only (N = 400), ADHD only (N = 275), RD + ADHD (N = 125)

• Comparison group without RD or ADHD (N = 1,000)

- extensive initial testing and five-year follow-up assessment

• International Twin Study of Early Reading Development (PI: Olson)

- unselected sample of approximately 2,000 twins in US, Australia, Scand.- Tested yearly from preschool until 4th grade

• Validity of ADHD in adults (PI: Willcutt, Banich)

- screening: 4,000 undergraduates- individual testing: 200 students with ADHD, 100 without ADHD

Defining RD and ADHD

• Reading Disability- unexpected difficulty learning to read.- not explained by environmental deprivation, inadequate

education, or low cognitive ability.- 1.5 SD below the estimated population mean on a test of single-

word decoding (PIAT or WJ-III).

• ADHD- inattentive and / or hyperactivity-impulsive behaviors that are

inconsistent with an individual’s developmental level.- Parent interview (DICA-IV) and teacher ratings (DSM-IV)- Similar results for DSM-IV subtypes, so pooled for this

presentation.

What causes comorbidity?

more than 25 different explanations have been proposed(at last count)

Competing Explanations for Comorbidity(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995)

Clinical Sample Bias: Comorbidity is only present in clinical samples.

Comorbidity is present in our community samples

5%8%

3%

Tests of the Competing Hypotheses

Artifactual Hypothesis

Clinical Sample Bias

Results

Not supported



Method bias: Comorbidity occurs because both disorders are assessed with the same measure.




Method Bias

Results

Not supported

Not supported

Artifactual Hypotheses



Method bias: Comorbidity occurs because both disorders are assessed with the same measure.

Rater bias: raters are more likely to endorse symptoms of a second disorder if the child has the first disorder.

Secondary symptom (phenocopy) hypothesis: Disorder #1 causes an individual to exhibit the symptoms of disorder #2 when they do not actually have the disorder.

Attention Problems in Individuals With and Without RD(Willcutt, Chhabildas, & Pennington, 1998; Willcutt et al., under review)

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Mother Father Teacher Self-Report

Z-s

core

RD

Control

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ParentChildhood

ParentCurrent

SelfChildhood

Self Current

Z-s

core

RD

Control

8 - 18 year old twins Undergraduates




Method Bias

Rater Bias

Secondary Symptom

Results

Not supported

Not supported

Not supported

Not supported



Method bias: Comorbidity occurs only because both disorders are assessed with the same measure.



Causal Hypothesis: Disorder #1 directly causes disorder #2.

A plausible causal model

ADHDWeak phonological

developmentRD

Poor attention to instruction




Method Bias

Rater Bias

Secondary Symptom

“True Comorbidity” Models

Causal Hypothesis

Result

Not supported

Not supported

Not supported

Not supported

More work is needed



Method bias: Comorbidity occurs only because both disorders are assessed with the same measure.



Causal Hypothesis: Disorder #1 directly causes disorder #2.

Common Etiology Hypothesis: The two disorders co-occur due to shared risk factors.

Causes of RD and ADHD

• Family studies-RD and ADHD are each significantly familial (e.g., Wadsworth et al., 2000;

Willcutt et al., 2000)

-RD and ADHD run in the same families (Friedman et al., 2003)

Causes of RD and ADHD• Family studies

-RD and ADHD are each significantly familial (e.g., Wadsworth et al., 2000; Willcutt et al., 2000)


• Twin Studies: disentangle three causes of individual differences in reading or ADHD-Heritability: genetic influences-Shared environment: environmental factors that affect both twins in a similar way.-Nonshared environment: environmental factors that are specific to the child with the disorder.

Twin studies of individual differences in ADHD symptoms(N > 15,000 twin pairs)

Twin studies of individual differences in reading

Comorbidity of RD and ADHD is explained by shared genes(Trszenlewski et al., 2006; Willcutt et al., 2000, 2003, in press a and b)

Genetic and environmental risk factors specific to

RD

RD ADHD

Genetic and environmental risk factors specific to

ADHD

Shared Genes




• Twin Studies-ADHD: highly heritable, minimal shared environment-RD: highly heritable + shared environment-The association between reading deficits and inattention is due primarily to common genetic

influences (e.g., Willcutt et al., 2007)

-other genetic and environmental influences are unique to each disorder (Willcutt et al., 2007a, 2007b)




Method Bias

Rater Bias

Secondary Symptom

“True Comorbidity” Models

Causal Hypothesis

Common Etiology

Result

Not supported

Not supported

Not supported

Not supported

More work is needed

Supported:

Shared genetic risk factors

Sounds good, but one final detail...

Where are these shared genes and what do they do?

ADHD

G1

Cog 1

The “old school” model:

One Gene, One Deficit, One Disorder

RD

G2

Cog 2

Autism

G3

Cog 3

Schiz.

G4

Cog 4

• Dopamine genes– Dopamine transporter– Dopamine D2, D3, D4, D5 receptors– Dopamine-beta-hydroxylase

• Serotonin genes– Serotonin Transporter– Serotonin receptor 1A, 2B

• Other neurotransmitters– Monoamine oxidase A (Jiang et al., 2000)

• Genes whose exact location and function is still unknown– Chromosomes 2, 3, 4, 5, 11, 15, 16, 17

A Subset of the Genes Associated with ADHD

(send me an email if you would like the full list)




• Twin Studies-ADHD: highly heritable, minimal shared environment-RD: highly heritable + shared environment-The association between reading deficits and inattention is due primarily to common genetic influences (e.g., Willcutt et al., 2007)

-other genetic and environmental influences are unique to each disorder (Willcutt et al., 2007a, 2007b)

• Molecular genetics-RD and ADHD are each influenced by multiple genetic and environmental risk factors-Each of these risk factors accounts for a small amount of the variance in reading and/or ADHD symptoms

ADHDRD

A simplified hypothetical model of the genetic and environmental etiology of RD and ADHD

(see Shanahan et al., 2006; Willcutt et al., 2005b)

G E E

ADHD

G G EG G G G E G

RD

A large pool of genetic and environmental risk factors influence RD and ADHD

...

ADHD

G GG G

RD

Shared genetic influences increase risk for both disorders, sometimes leading to comorbidity

G E E

ADHD

G G EG G G G E G

RD

Additional genetic and environmental risk factors are specific to RD or specific to ADHD

How do these causal factors influence brain functioning?

G G E

ADHD

Cognitive Deficit 1

G G E

Cognitive Deficit 3

G G G

Cognitive Deficit 2

G E E

Cognitive Deficit 4

RD

What cognitive weaknesses are intermediate between the genes and the behavioral symptoms?

(see Shanahan et al., 2006; Willcutt et al., 2005b)

Four Key Cognitive Processes

Phonological processing: recognize and manipulate the phonemic constituents in speech.- say “plig” without the “l”



Working memory: retain information in short-term memory and manipulate that information.- repeat a series of digits in reverse order.




Response inhibition: suppress a response when it is not correct / appropriate.




Response inhibition: suppress a response when it is not correct / appropriate.

Processing Speed: process information rapidly and correctly.- name colors or common objects- rapidly process nonverbal material

G G E

ADHD

G G GG G G G E E

RD

What did we find?(Shanahan et al., 2006; Willcutt et al., 2005a, in press)

G G E

ADHD

G G GG G G G E E

RD

Weak phoneme awareness is specific to RD

PhonemeAwareness

G G E

ADHD

G G GG G G G E E

RD

Slow processing speed and weak working memory are associated with both RD and ADHD

PhonemeAwareness

ProcessingSpeed

Working Memory

G G E

ADHD

G G GG G G G E E

RD

Weakness in Response inhibition is specific to ADHD

PhonemeAwareness

ProcessingSpeed

Working Memory

Response Inhibition

Conclusions and Future Directions of our Group• RD and ADHD are frequently comorbid

– Future: longitudinal causal models

• Comorbidity is associated with multiple negative outcomes- Future: additional adult outcomes (Sally Wadsworth)

• Common genetic influences lead to comorbidity between RD and ADHD

• RD and ADHD are influenced by multiple genes, none of which is a necessary or sufficient cause- Future: What are these genes, what is their function, and how do they interact?

• These common genes may lead to slow processing speed or working memory difficulties.- Future: brain imaging

Clinical Implications and Practical Suggestions• When assessing RD or ADHD, clinicians should also screen

carefully for the other disorder– Quick ADHD screeners: Barkley, Conners, DuPaul, SNAP– More general psychopathology: Achenbach, BASC, Conners

• When RD and ADHD co-occur, both disorders are likely to require treatment:

• Needed: studies that test if comorbidity matters for treatment!– Add ADHD screener to ongoing studies

– Re-analyses of treatment studies that also measured ADHD

RD ADHD

ADHD RD

Shared risk factor RD + ADHD

Understanding “the whirling ball of comorbidity”: Reading Disability and ADHD Erik Willcutt,...

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