1. The Attention-Deficit Hyperactivity Disorder Paradox: 2. Phenotypic Variability in Prevalence and Cost of Comorbidity Larry Burd, PhD; Marilyn G. Klug, PhD; Matthew J. Coumbe, PhD; Jacob Kerbeshian, MD

2. Abstract The objective of this study was to use population-based data to estimate the cost and phenotypic variation of conditions comorbid with attention-deficit hyperactivity disorder (ADHD). The case population was 7745 children. We then examined the 10 most frequent comorbidities for a defined condition from the ICD-9. The observed prevalence of general health conditions was 12 to 70% less than expected. The presence of a comorbid condition resulted in increases in costs of care of $381 to $731 per case per year. The observed prevalence of comorbid mental health conditions was 97 to 5286% higher than expected. We identified an ADHD paradox: decreased rates of comorbid general health conditions and increased rates of comorbid mental disorders. Further research on comorbidity in ADHD is required. (J Child Neurol 2003;18:653-660). The objective of this study was to use population-based data to estimate the cost and phenotypic variation of conditions comorbid with attention-deficit hyperactivity disorder (ADHD). The case population was 7745 children. We then examined the 10 most frequent comorbidities for a defined condition from the ICD-9. The observed prevalence of general health conditions was 12 to 70% less than expected. The presence of a comorbid condition resulted in increases in costs of care of $381 to $731 per case per year. The observed prevalence of comorbid mental health conditions was 97 to 5286% higher than expected. We identified an ADHD paradox: decreased rates of comorbid general health conditions and increased rates of comorbid mental disorders. Further research on comorbidity in ADHD is required. (J Child Neurol 2003;18:653-660).

3. Study Population The original data set consisted of 1,509,980 visits made by children ages 0 to 21 years in North Dakota in 1996 and 1997. This included both inpatient and outpatient visits. For the 2 years combined, a total of 1,473,611 visits were included in this analysis. This represented (averaged over 1996 and 1997) visits made by 197,983 uniquely identified children (88,702 in 1996 and 109,281 in 1997). The original data set consisted of 1,509,980 visits made by children ages 0 to 21 years in North Dakota in 1996 and 1997. This included both inpatient and outpatient visits. For the 2 years combined, a total of 1,473,611 visits were included in this analysis. This represented (averaged over 1996 and 1997) visits made by 197,983 uniquely identified children (88,702 in 1996 and 109,281 in 1997).

4. Inclusion Criteria: Cases Patients were included in the study as cases with ADHD if at any time during either year they had an International Classification of Diseases, 9 th edition (ICD-9), code of 314.00 or (attention- deficit disorder not otherwise specified), 314.00 or (inattentive type), 314.01 (with hyperactivity/impulsiveness), or 314.8 (with other specific manifestations). The code 314.9 (attention-deficit hyperactivity disorder not otherwise specified) was also included to capture cases from the Diagnostic and Statistical Manual of Mental Diseases-IV (DSM-IV). Patients were included in the study as cases with ADHD if at any time during either year they had an International Classification of Diseases, 9 th edition (ICD-9), code of 314.00 or (attention- deficit disorder not otherwise specified), 314.00 or (inattentive type), 314.01 (with hyperactivity/impulsiveness), or 314.8 (with other specific manifestations). The code 314.9 (attention-deficit hyperactivity disorder not otherwise specified) was also included to capture cases from the Diagnostic and Statistical Manual of Mental Diseases-IV (DSM-IV).

5. Inclusion Criteria: Controls The control population consisted of all remaining subjects in the database who did not have an ICD-9 code of 314.00, 314.01, or 314.8 or the DSM-IV code of 314.9 in their diagnostic formulation at any time during the 2-year span of the study. There were 24.5 controls per case in this study. The control population consisted of all remaining subjects in the database who did not have an ICD-9 code of 314.00, 314.01, or 314.8 or the DSM-IV code of 314.9 in their diagnostic formulation at any time during the 2-year span of the study. There were 24.5 controls per case in this study.

6. Limitations The validity of the diagnosis reported needs to be considered. The validity of the diagnosis reported needs to be considered.  These data are from a single rural state, and the subjects are not currently traceable across years or type of claims.  The data set does not include uninsured children or children who did not access health care in the 2-year period included in this study.

7. Prevalence of ADHD by Age Group, Gender, and Payer Type 19961997Mean N (%) Age Group Infant to 5 yr Infant to 5 yr 334 (1.2) 190 (0.6) 262 (0.9) 6 to 13 yr 6 to 13 yr 2952 (10.8) 2387 (6.7) 2669 (8.7) 14 to 21 yr 14 to 21 yr 1031 (3.1) 851 (2.1) 941 (2.6) Gender Male Male 3247 (7.5) 2570 (4.8) 2908 (6.1) Female Female 1070 (2.4) 858 (1.6) 964 (2.0) Payer Type Public Public 1233 (5.8) 909 (6.0) 1071 (5.9) Private Private 3084 (4.6) 2519 (2.7) 2801 (3.6) ADHD = attention-deficit hyperactivity disorder

8. Results Prevalence and Base Costs of ADHD Prevalence and Base Costs of ADHD  The prevalence of ADHD in these claims data was 3.9% or 7,745 children (4,317 in 1996 and 3,428 in 1997).

9. Prevalence and Risk of 4 Most Common General and Neurologic Diagnoses in Children With ADHD Compared With Children Without ADHD (Controls) ObservedExpectedAdded Diagnosis N (%) NCasesAR% Respiratory illness 1996 ADHD Control Control 312 (7.2) 18,672 (22.1) 955-643-206.2 1997 ADHD Control Control 267 (7.8) 19,513 (18.4) 632-365-136.7 Acute pharyngitis 1996 ADHD Control Control 271 (6.3) 16,422 (19.5) 840-569-210.0 1997 ADHD Control Control 318 (9.3) 17,374 (16.4) 563-245-76.9 Respiratory illness: 465.xx; Acute pharyngitis: 462.xx ADHD = attention-deficit hyperactivity disorder; AR% = attributable risk percentage

10. Prevalence and Risk of 4 Most Common General and Neurologic Diagnoses in Children With ADHD Compared With Children Without ADHD (Controls)ObservedExpectedAdded Diagnosis N (%) NCasesAR% Vision 1996 ADHD Control Control 368 (8.5) 5146 (6.1) 26310528.5 1997 ADHD Control Control 181 (5.3) 30,006 (2.8) 978446.2 Suppurative otitis media 1996 ADHD Control Control 259 (6.0) 15,717 (18.6) 804-545-210.4 1997 ADHD Control Control 235 (6.9) 16,449 (15.5) 533-298-126.7 Vision: 367.xx; Suppurative otitis media: 382.xx ADHD = attention-deficit hyperactivity disorder; AR% = attributable risk percentage

11. Comorbidity With General and Neurologic Diagnosis Prevalence Prevalence  These data identify an important association between a diagnosis of ADHD and a decrease in the total risk of these comorbid conditions. This suggests the possibility of a protective effect from ADHD for several common illnesses.

12. Comparison of Mean Costs of Common General and Neurologic Illnesses Between Children With ADHD and Controls (Base Cost=$495, Cost Attributable to ADHD=$154) Mean Cost per Year ($) ADHDControl Mean Cost Attributable ($) Mean Cost of Comorbidity ($) Respiratory illness 1996 1996 1997 1997 Average Average 14298371133831488659222108164481159320 Acute pharyngitis 1996 1996 1997 1997 Average Average1385789108779244561818365123476153315 ADHD = attention-deficit hyperactivity disorder

13. Comparison of Mean Costs of Common General and Neurologic Illnesses Between Children With ADHD and Controls (Base Cost=$495, Cost Attributable to ADHD=$154) Mean Cost per Year ($) ADHDControl Mean Cost Attributable ($) Mean Cost of Comorbidity ($) Vison 1996 1996 1997 1997 Average Average10609401000589402495-20221354348351 Suppurative otitis media 1996 1996 1997 1997 Average Average14508871168838504671229124176494193343 ADHD = attention-deficit hyperactivity disorder

14. Costs The cost of care for these comorbid general health conditions was increased. The cost of care for these comorbid general health conditions was increased. The equation for the total annual cost of care ($1133) is composed of: The equation for the total annual cost of care ($1133) is composed of:  Base cost of care for a control child ($495)  Cost of care attributable to ADHD ($154)  Cost of care attributable to respiratory illness in controls without ADHD ($164)  The cost of comorbidity ($1133-$495-$154- $164=$320).

15. Comparison of Mean Costs of Common Mental Illnesses Between Children With ADHD and Controls (Base Cost=$495, Cost Attributable to ADHD=$154) Mean Cost per Year (%) ADHDControl Mean Cost Attributable (%) Mean Cost of Comorbidity (%) Depression 1996 199615191081586321 1997 199711421042547-91 Average Average13301061566115 Oppositional defiant disorder 1996 199616641366871181 1997 199712391148653-100 Average Average1451125776240 ADHD = attention-deficit hyperactivity disorder

16. Comparison of Mean Costs of Common Mental Illnesses Between Children With ADHD and Controls (Base Cost=$495, Cost Attributable to ADHD=$154) Mean Cost per Year (%) ADHDControl Mean Cost Attributable (%) Mean Cost of Comorbidity (%) Bipolar 1996 199619911382887492 1997 19971475127077515 Average Average17331326831253 Conduct disorders 1996 199618511279784454 1997 199713021140645-28 Average Average15761209714213 ADHD = attention-deficit hyperactivity disorder

17. Prevalence and Risk of 4 Most Common Mental Diagnoses in Children With ADHD Compared With Children Without ADHD DiagnosesObserved N (%) ExpectedNAddedCasesAR% Depression 1996ADHDControl 836 (19.4) 2690 (3.2) 13869883.5 1997ADHDControl 655 (19.1) 2139 (2.0) 6958689.4 Oppositional defiant disorder 1996ADHDControl 493 (11.4) 316 (0.4) 1647796.7 1997ADHDControl 377 (11.0) 218 (0.2) 737098.1 Depression: 293.83, 296.2x, 296.3x, 296.5x, 296.82, 298.0x, 300.4x, 301.12, 309.0x, 309.1x, 309.28, 311.xx, and 313.1x; Oppositional defiant disorder: 3131.81 ADHD = attention-deficit hyperactivity disorder; AR%= attributable risk percentage

18. Prevalence and Risk of 4 Most Common Mental Diagnoses in Children With ADHD Compared With Children Without ADHD DiagnosesObserved N (%) ExpectedNAddedCasesAR% Bipolar 1996ADHDControl 363 (8.4) 1148 (1.4) 5930483.8 1997ADHDControl 270 (7.9) 909 (0.9) 2924189.1 Conduct disorders 1996ADHDControl 329 (7.6) 437 (0.5) 2230793.2 1997ADHDControl 198 (5.8) 305 (0.3) 1018895.0 Bipolar: 296.xx; Conduct disorders: 312.xx ADHD = attention-deficit hyperactivity disorder; AR% = attributable risk percentage

19. Prevalence: Comorbidity With Mental and Neurologic Disorders The relative risks of a child with ADHD being diagnosed with an additional mental disease were all greater than 1, ranging from 3.2 (nondependent drug use) to 53.4 (oppositional defiant disorder). The relative risks of a child with ADHD being diagnosed with an additional mental disease were all greater than 1, ranging from 3.2 (nondependent drug use) to 53.4 (oppositional defiant disorder). Children with ADHD were 53 times more likely to have oppositional defiant disorder than controls. Children with ADHD were 53 times more likely to have oppositional defiant disorder than controls.

20. Four Disorders Oppositional defiant disorder, conduct disorders, learning disabilities, and tics Oppositional defiant disorder, conduct disorders, learning disabilities, and tics  Have an attributable risk percentage above 90%  This suggests that ADHD represents an important risk marker for multiple mental health disorders.

21. Policy Implications: Costs Attributable costs for mental disorders ranged from $204 (tic disorder) to $1262 (personality disorder). Attributable costs for mental disorders ranged from $204 (tic disorder) to $1262 (personality disorder). The cost of care attributable to depression in a control child was $566 ($1061-$495). The cost of care attributable to depression in a control child was $566 ($1061-$495). The cost of comorbidity in children with ADHD and depression was $115 ($1330- $495-$154-$566=$115). The cost of comorbidity in children with ADHD and depression was $115 ($1330- $495-$154-$566=$115).

22. Clinical Implications We have identified an ADHD comorbidity paradox We have identified an ADHD comorbidity paradox This was a decrease of 12 to 70% of the expected number of cases. This was a decrease of 12 to 70% of the expected number of cases. In contrast, there were 26 to 698 additional cases of vision problems, epilepsy, depression, oppositional defiant disorder, bipolar disorder, conduct disorder, adjustment disorder, anxiety disorder, nondependent drug use, tic disorders, personality disorders, epilepsy, and visual impairment. In contrast, there were 26 to 698 additional cases of vision problems, epilepsy, depression, oppositional defiant disorder, bipolar disorder, conduct disorder, adjustment disorder, anxiety disorder, nondependent drug use, tic disorders, personality disorders, epilepsy, and visual impairment. For these illnesses, the number of observed cases was increased by 97 to 5286% over the expected number For these illnesses, the number of observed cases was increased by 97 to 5286% over the expected number