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Understanding “the whirling ball of comorbidity”: Reading Disability and ADHD Erik Willcutt, Ph.D. University of Colorado, Boulder. Anxious. “That’s it! Just me, alone at home, trying to be a good parent for my little whirling ball of comorbidity”. Too active.

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Understanding “the whirling ball of comorbidity”:

Reading Disability and ADHD

Erik Willcutt, Ph.D.

University of Colorado, Boulder


Anxious

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

Too active

Aggressive

Learning

Comorbidity





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

RD

RD+ADHD

Control

ADHD


Comorbidity has important implications for treatment
Comorbidity has important implications for treatment and more extensive and severe negative outcomes

RD  ADHD

ADHD  RD

Shared risk factor  RD + ADHD


Our ongoing studies most relevant to comorbidity between rd and adhd
Our ongoing studies most relevant to comorbidity and more extensive and severe negative outcomesbetween 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
Defining RD and ADHD and more extensive and severe negative outcomes

  • 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? and more extensive and severe negative outcomesmore than 25 different explanations have been proposed(at last count)


Competing explanations for comorbidity e g caron rutter 1991 neale kendler 1995
Competing Explanations for Comorbidity and more extensive and severe negative outcomes(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
Comorbidity is present in our community samples and more extensive and severe negative outcomes

8%

5%

3%


Tests of the competing hypotheses

Artifactual Hypothesis and more extensive and severe negative outcomes

Clinical Sample Bias

Results

Not supported

Tests of the Competing Hypotheses


Competing explanations for comorbidity e g caron rutter 1991 neale kendler 19951
Competing Explanations for Comorbidity and more extensive and severe negative outcomes(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995)

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

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


Tests of the competing hypotheses1

Artifactual Hypothesis and more extensive and severe negative outcomes

Clinical Sample Bias

Method Bias

Results

Not supported

Not supported

Tests of the Competing Hypotheses


Competing explanations for comorbidity e g caron rutter 1991 neale kendler 19952
Competing Explanations for Comorbidity and more extensive and severe negative outcomes(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995)

Artifactual Hypotheses

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

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 and more extensive and severe negative outcomes(Willcutt, Chhabildas, & Pennington, 1998; Willcutt et al., under review)

8 - 18 year old twins

Undergraduates


Tests of the competing hypotheses2

Artifactual Hypothesis and more extensive and severe negative outcomes

Clinical Sample Bias

Method Bias

Rater Bias

Secondary Symptom

Results

Not supported

Not supported

Not supported

Not supported

Tests of the Competing Hypotheses


Competing explanations for comorbidity e g caron rutter 1991 neale kendler 19953
Competing Explanations for Comorbidity and more extensive and severe negative outcomes(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995)

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

Method bias: Comorbidity occurs only 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.

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


A plausible causal model
A plausible causal model and more extensive and severe negative outcomes

Poor attention to instruction

Weak phonological development

RD

ADHD


Tests of the competing hypotheses3

Artifactual Hypothesis and more extensive and severe negative outcomes

Clinical Sample Bias

Method Bias

Rater Bias

Secondary Symptom

“True Comorbidity” Models

Causal Hypothesis

Result

Not supported

Not supported

Not supported

Not supported

More work is needed

Tests of the Competing Hypotheses


Competing explanations for comorbidity e g caron rutter 1991 neale kendler 19954
Competing Explanations for Comorbidity and more extensive and severe negative outcomes(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995)

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

Method bias: Comorbidity occurs only 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.

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
Causes of RD and ADHD and more extensive and severe negative outcomes

  • 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 adhd1
Causes of RD and ADHD and more extensive and severe negative outcomes

  • 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)

  • 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 and more extensive and severe negative outcomes

(N > 15,000 twin pairs)


Twin studies of individual differences in reading and more extensive and severe negative outcomes


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

Shared Genes

Genetic and environmental risk factors specific to RD

Genetic and environmental risk factors specific to ADHD

RD

ADHD


Causes of rd and adhd2
Causes of RD and ADHD and more extensive and severe negative outcomes

  • 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)

  • 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)


Tests of the competing hypotheses4

Artifactual Hypothesis and more extensive and severe negative outcomes

Clinical Sample Bias

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

Tests of the Competing Hypotheses


Sounds good, but one final detail... and more extensive and severe negative outcomes

Where are these shared genes and what do they do?


The “old school” model: and more extensive and severe negative outcomes

One Gene, One Deficit, One Disorder

G2

G1

G3

G4

Cog 2

Cog 1

Cog 3

Cog 4

RD

ADHD

Autism

Schiz.


A subset of the genes associated with adhd
A Subset of the Genes and more extensive and severe negative outcomesAssociated with ADHD

  • 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

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


Causes of rd and adhd3
Causes of RD and ADHD and more extensive and severe negative outcomes

  • 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)

  • 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


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

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

RD

ADHD


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

G

E

E

G

G

G

G

G

E

G

E

G

...

RD

ADHD


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

G

G

G

G

RD

ADHD


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

G

E

E

G

G

G

G

G

E

G

E

G

RD

ADHD



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

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

G

G

E

G

G

G

G

G

E

G

E

E

Cognitive Deficit 1

Cognitive Deficit 2

Cognitive Deficit 3

Cognitive Deficit 4

RD

ADHD


Four key cognitive processes
Four Key Cognitive Processes and the behavioral symptoms?

Phonological processing: recognize and manipulate the phonemic constituents in speech.

- say “plig” without the “l”


Four key cognitive processes1
Four Key Cognitive Processes and the behavioral symptoms?

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.


Four key cognitive processes2
Four Key Cognitive Processes and the behavioral symptoms?

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.


Xxxxx

XXXXX and the behavioral symptoms?


Xxxxx1

XXXXX and the behavioral symptoms?


Xxxxx2

XXXXX and the behavioral symptoms?


Xxxxx3

XXXXX and the behavioral symptoms?


Xxxxx4

XXXXX and the behavioral symptoms?


Xxxxx5

XXXXX and the behavioral symptoms?


Xxxxx6

XXXXX and the behavioral symptoms?


RED and the behavioral symptoms?


Four key cognitive processes3
Four Key Cognitive Processes and the behavioral symptoms?

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.

Processing Speed: process information rapidly and correctly.

- name colors or common objects

- rapidly process nonverbal material


What did we find? and the behavioral symptoms?

(Shanahan et al., 2006; Willcutt et al., 2005a, in press)

G

G

E

G

G

G

G

G

G

G

E

E

RD

ADHD


Weak phoneme awareness is specific to RD and the behavioral symptoms?

G

G

E

G

G

G

G

G

G

G

E

E

Phoneme

Awareness

RD

ADHD


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

G

G

E

G

G

G

G

G

G

G

E

E

Phoneme

Awareness

Processing

Speed

Working Memory

RD

ADHD


Weakness in Response inhibition is specific to ADHD with both RD and ADHD

G

G

E

G

G

G

G

G

G

G

E

E

Phoneme

Awareness

Processing

Speed

Working Memory

Response Inhibition

RD

ADHD


Conclusions and future directions of our group
Conclusions and Future Directions of our Group with both RD and ADHD

  • 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
Clinical Implications and Practical Suggestions with both RD and ADHD

  • 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


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