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ADHD Comorbidity Findings From the MTA Study: Comparing Comorbid Subgroups
ADHD Comorbidity Findings From the MTA Study: Comparing Comorbid Subgroups PETER S. JENSEN, M.D., STEPHEN P. HINSHAW, PH.D., HELENA C. KRAEMER, PH.D., NILANTHA LENORA, B.S., JEFFREY H. NEWCORN, M.D., HOWARD B. ABIKOFF, PH.D., JOHN S. MARCH, M.D., L. EUGENE ARNOLD, M.D., DENNIS P. CANTWELL, M.D., C. KEITH CONNERS, PH.D., GLEN R. ELLIOTT, M.D., LAURENCE L. GREENHILL, M.D., LILY HECHTMAN, M.D., BETSY HOZA, PH.D., WILLIAM E. PELHAM, PH.D., JOANNE B. SEVERE, M.S., JAMES M. SWANSON, PH.D., KAREN C. WELLS, PH.D., TIMOTHY WIGAL, PH.D., AND BENEDETTO VITIELLO, M.D.
ABSTRACT Objectives: Previous research has been inconclusive whether attention-deficit/hyperactivity disorder (ADHD), when comorbid with disruptive disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]), with the internalizing disorders (anxiety and/or depression), or with both, should constitute separate clinical entities. Determination of the clinical significance of potential ADHD + internalizing disorder or ADHD + ODD/CD syndromes could yield better diagnostic decision-making, treatment planning, and treatment outcomes. Method: Drawing upon cross-sectional and longitudinal information from 579 children (aged 7–9.9 years) with ADHD participating in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), investigators applied validational criteria to compare ADHD subjects with and without comorbid internalizing disorders and ODD/CD. Results: Substantial evidence of main effects of internalizing and externalizing comorbid disorders was found. Moderate evidence of interactions of parent-reported anxiety and ODD/CD status were noted on response to treatment, indicating that children with ADHD and anxiety disorders (but no ODD/CD) were likely to respond equally well to the MTA behavioral and medication treatments. Children with ADHD-only or ADHD with ODD/CD (but without anxiety disorders) responded best to MTA medication treatments (with or without behavioral treatments), while children with multiple comorbid disorders (anxiety and ODD/CD) responded optimally to combined (medication and behavioral) treatments. Conclusions: Findings indicate that three clinical profiles, ADHD co-occurring with internalizing disorders (principally parent-reported anxiety disorders) absent any concurrent disruptive disorder (ADHD + ANX), ADHD co-occurring with ODD/CD but no anxiety (ADHD + ODD/CD), and ADHD with both anxiety and ODD/CD (ADHD + ANX + ODD/CD) may be sufficiently distinct to warrant classification as ADHD subtypes different from “pure” ADHD with neither comorbidity. Future clinical, etiological, and genetics research should explore the merits of these three ADHD classification options. J. Am. Acad. Child Adolesc. Psychiatry, 2001, 40(2):147–158. Key Words: attention-deficit/hyperactivity disorder, attention deficit, anxiety, comorbidity, treatment, outcomes, classification, diagnosis.
Accepted September 26, 2000. Dr. Jensen is Professor of Psychiatry, Department of Psychiatry, Columbia University College of Physicians and Surgeons; Dr. Hinshaw is Professor of Psychology, Department of Psychology, University of California at Berkeley; Dr. Kraemer is Professor of Biostatistics, Stanford University; Ms. Lenora is a medical student, George Washington University School of Medicine. Other authors’ affiliations are listed in the MTA Cooperative Group acknowledgment that appears at the end of the text. Reprint requests to Dr. Jensen, Center for the Advancement of Children’s Mental Health, Columbia University/NYSPI, 1051 Riverside Drive, Unit 78, New York, NY 10032; e-mail: [email protected]. 0890-8567/01/4002-0147䉷2001 by the American Academy of Child and Adolescent Psychiatry.
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The presence of comorbid disruptive behavior disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]) within children with attention-deficit/ hyperactivity disorder (ADHD) has been well established for several decades (e.g., see Bird et al., 1990; Hinshaw, 1987). Only in the past decade has it become apparent that internalizing disorders (both anxiety and depressive disorders) also commonly co-occur with ADHD. Thus, both clinical and epidemiological studies have consistently shown that as many as one third of children with ADHD have co-occurring anxiety dis147
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orders (Biederman et al., 1991; Bird et al., 1990; MTA Cooperative Group, 1999a; Woolston et al., 1989). This phenomenon appears “real” and cannot be attributed solely to factors such as referral biases or methodological artifacts (Angold et al., 1999). The overlap of ADHD with both the internalizing and disruptive disorders should be of substantial interest to researchers and clinicians. For example, if it can be shown that ADHD when comorbid with either the internalizing or disruptive disorders is unique with respect to its clinical correlates, etiology, course, and outcome (versus “pure” ADHD), it may be useful to consider such comorbid states as diagnostically meaningful subtypes or even as separate disorders. Also, if various comorbid forms of ADHD are actually of qualitatively different types from “pure” ADHD, better treatment planning and clinical prediction, as well as more valid etiological and genetic studies, should be possible. Validation of Subtypes
Cantwell (1995) outlined eight domains of clinical investigation that could be used to assess the discriminant validity of possible disorder types and subtypes. These criteria, modifications of the original Robins and Guze (1970) criteria, include (1) clinical phenomenology, (2) demographic correlates, (3) psychosocial correlates, (4, 5) family factors (both environmental and genetic), 6) biological factors, (7) response to treatment, and (8) clinical outcomes. Applying these criteria to ADHD comorbidity studies, Jensen, Martin, and Cantwell (1997) reported that seven of the eight validational criteria supported the hypothesis that ADHD comorbid with disruptive behavior disorders (ADHD + ODD/CD) constitutes a different ADHD subtype. However, applying these same criteria to ADHD comorbid with internalizing disorders (principally anxiety), they noted somewhat weaker evidence (four of eight criteria) in support of an ADHD + ANX subtype. In the past several years since the Jensen et al. (1997) review, two additional pertinent studies have been conducted that are of relevance to questions concerning the usefulness and validity of the ADHD + ANX subtype. Beginning with an initial dose titration, Diamond et al. (1999) followed stimulant-treated ADHD children over 4 months to determine the impact of comorbid anxiety on their response to medication. Unlike the preponderance of evidence from earlier studies (e.g., Buitelaar et al., 1995; DuPaul et al., 1994; Pliszka, 1989, 1992; Tannock et al., 1995), Diamond and colleagues found that children 148
with ADHD + ANX and those with ADHD/no ANX did not show any differential response to methylphenidate, either in terms of behavioral measures or side effects. Most recently, findings from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), a multisite randomized clinical trial testing four treatment groups in 579 children across six sites, indicated that ADHD children with comorbid parent-reported anxiety disorders have treatment responses that are qualitatively different from those of children without comorbid anxiety (MTA Cooperative Group, 1999a,b). Thus, among children with parent-identified anxiety disorders (33.5% of the sample), those children in the behavioral therapy condition (Beh) showed an enhanced response on outcome measures of parent-reported ADHD and internalizing symptoms, relative to nonanxious children. In addition, among anxious subjects combined treatments (Comb) yielded greater improvements than medication management alone (MedMgt) in several outcome domains. Among nonanxious participants, however, MedMgt and Comb both outperformed Beh and the community comparison group (CC) with regard to ADHD symptoms (MTA Cooperative Group, 1999b). Findings from the MTA study provide evidence of qualitatively different treatment responses in ADHD + ANX versus ADHD/no ANX children and may thus support the separate ADHD + ANX subtype hypothesis. In contrast, and to the surprise of the MTA investigators, the presence of comorbid ODD/CD did not moderate any differential treatment response to specific treatments. However, these first moderator analyses were restricted to examination of the main effects of comorbidity and did not explore possible interactions between ODD/CD and comorbid anxiety on MTA outcomes. Remarkably, only one study to date has examined these four potentially separate entities. In a study of 138 white males with DSM-III–defined ADHD, Livingston and colleagues (1990) found that boys with an internalizing disorder and ODD/CD differed along multiple dimensions from boys with ADHD + ODD/CD-only and ADHD + ANX-only, as well as from boys with ADHDonly. In most areas of functioning, doubly comorbid boys scored worse than ADHD + ODD/CD-only and ADHD + ANX-only boys, though in at least one instance doubly comorbid boys functioned somewhat better (e.g., teachercompleted aggression ratings). Unfortunately, given the study’s small sample size (n = 138) and its restriction to J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
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white males from one clinical setting, it could not be determined whether the differences between doubly comorbid boys and singly comorbid and ADHD-only boys were simply an additive function of the two comorbid conditions or whether these differences reflected unique clinical profiles. Thus, while mounting evidence does support the possibility that individuals with comorbid ADHD + ANX and those with ADHD + ODD/CD may have unique clinical profiles compared with children with noncomorbid ADHD, firm conclusions about these comorbid patterns cannot be derived from previous research, given the relatively small sample sizes and previous studies’ failure to tease apart the effects of the two comorbid conditions when they overlap. Furthermore, no previous investigations have used a comprehensive set of validational criteria (either Robins and Guze, 1970, or Cantwell, 1995) to examine these comorbidity subgroups, all within the same study. The MTA study (MTA Cooperative Group 1999a,b) offers a unique opportunity to examine whether children with ADHD + ANX, ADHD + ODD/CD, and ADHD + ANX + ODD/CD do indeed differ from each other and from children with noncomorbid ADHD, and whether such findings can be replicated across multiple settings. In this report, we examine four different groups of ADHD children (ADHD + ANX, ADHD + ODD/CD, ADHD + ANX + ODD/CD, ADHD-only), comparing them using the modified Cantwell validational criteria to determine whether the varying forms of comorbidity convey special diagnostic, therapeutic, or outcome significance beyond the presence of ADHD alone. METHOD Recruitment Procedures and Sample Characteristics MTA recruitment and screening procedures aimed to collect a carefully diagnosed, impaired sample of ADHD children with a wide range of comorbid conditions and demographic characteristics, representative of patients seen clinically (MTA Cooperative Group, 1999a). For eligibility, children (of either sex) were between ages 7.0 and 9.9 years, in first through fourth grades. All met DSM-IV criteria for ADHD, combined type, using the Diagnostic Interview Schedule for Children, parent report, version 3.0 (DISC-P) (Shaffer et al., 1996). The presence of comorbid disorders such as ODD, CD, internalizing disorders, or specific learning disabilities were not exclusions, as an important aim of the MTA study was to examine their interactions with treatment outcomes. In a four-group parallel design, 579 children were assigned randomly to (1) medication management (MedMgt), (2) behavioral treatment (Beh), (3) the combination (Comb), or (4) community comparison (CC) for 14 months. Demographic characteristics of the MTA partic-
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ipants were as follows: 80% male and 20% female; 61% white, 20% African American, and 19% Hispanic, racially mixed, or other ethnic origins. Mean age at study entry was 8.2 years. Extensive information concerning subject characteristics, study treatments, and outcomes is reported elsewhere (MTA Cooperative Group, 1999a,b). Assessments The major symptom and functioning domains originally used to assess baseline characteristics and 14-month outcomes (see MTA Cooperative Group, 1999a) were applied to test the Cantwell validational criteria on the various comorbidity profiles. Variables selected for the Cantwell criteria were as follows: (1) clinical phenomenology— inattentive, hyperactive/impulsive, and aggressive/oppositional symptoms (assessed via parent- and teacher-completed Swanson, Nolan, and Pelham scale [SNAP] scores) (MTA Cooperative Group, 1999a), Verbal and Performance IQ, impairment (measured via the Columbia Impairment Scale) (Bird et al., 1996), internalizing symptoms (assessed via the Multidimensional Anxiety Scale for Children [March et al., 1997], the Children’s Depression Inventory [Kovacs and Beck, 1977], and parent- and teacher-rated internalizing symptoms scales from the Social Skills Rating System [SSRS] [Gresham and Elliott, 1989]), and academic achievement (assessed via the Wechsler Individual Achievement Test [WIAT] [Wechsler, 1992]); (2) demographic factors—gender, age, single- versus two-parent status, income, and family occupational status; (3) psychosocial factors—social skills/peer relations (assessed via parent and teacher reports using the SSRS) and levels of life stressors; (4) family factors (both environmental and genetic)—family stress (using the Parent Stress Index), parent–child relations (using scales from the Parent–Child Relationship Questionnaire [Furman and Giverson, 1995]), parenting style based on an internally consistent and reliable factor derived from all MTA-administered parenting assessments (Wells et al., 2000), and maternal depression (using the Beck Depression Inventory); and (5) biological factors (history of pre- and perinatal difficulties). Of note, in the original Cantwell validational scheme family environment and family genetic factors are defined separately, but here we have combined them into a single criterion, as the MTA design did not allow any robust method for separating these two sources of familial effects. These five Cantwell criteria were all based on data collected at the baseline assessment, allowing us to examine what Kraemer (1995) has termed epidemiologic comorbidity. To examine the last two Cantwell criteria (outcomes, response to treatment—also termed clinical comorbidity by Kraemer, 1995), we constructed difference scores by subtracting 14-month endpoint scores from baseline scores of children’s symptoms and functioning ratings of those variables from the clinical phenomenology, psychosocial factors, and family factors domains that describe the child’s functioning. In addition to these outcome measures, we also used an overall composite outcome measure (see Conners et al., 2001) to examine outcomes and response to treatment. To avoid the potentially confounding effects of the MTA treatments on more “naturalistic” outcomes, analyses of outcomes were limited to CC subjects only (n = 146), while response to treatment analyses included all subjects. By way of caution in interpreting these data, our analyses of CC subjects’ “naturalistic” outcomes are should be viewed with caution, inasmuch as two thirds of these children obtained at least some treatment (including stimulants) over the course of the study. Comorbidity Subgroups Diagnoses and comorbidity groups were constructed on the basis of parent-reported DISC diagnoses at study baseline. Diagnoses were based on the previous 6 months, except for CD, which was based on
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the last 12 months according to DSM criteria. While our first reports concerning ADHD comorbid conditions (MTA Cooperative Group, 1999a,b) did not include simple phobia in the “anxiety disorders” category, other analyses have indicated that parent-reported simple phobias are in fact as likely to be validated by clinicians upon reinterview as other anxiety disorders (Jensen et al., 1999). Given these findings and the need to form large enough groups for the analyses for this report, we chose here to include subjects with simple phobia in the “anxiety disorders” category, resulting in somewhat higher rates of comorbid anxiety disorders (38.7% versus 33.5%). Each child was grouped into one of four categories: ADHD-only (31.8%, n = 184) ADHD + ANX (14.0%, n = 81), ADHD + ODD/ CD (29.5%, n = 171), and ADHD + ODD/CD + ANX (24.7%, n = 143). For the 22 cases of mood disorders in the MTA sample, all but 2 were comorbid with anxiety disorders. Given recent evidence presented by Angold et al. (1999) that comorbid mood disorders in children with ADHD occur principally via their association with anxiety disorders, we have named the overall category ADHD + ANX, though in fact this group also included two children with mood disorders without a full-blown anxiety disorder. All other comorbid conditions (e.g., enuresis, tics, etc.) were ignored for the purposes of forming the four comorbidity groups. Analytic Strategy To determine whether ADHD children with different comorbidity profiles differed meaningfully from “pure” ADHD subjects, our analytic strategy proceeded as follows. We first assigned two new variables to all subjects according to the presence or absence of the two comorbidity forms, i.e., presence (1) or absence (0) of anxiety comorbidity (Anx) and ODD/CD comorbidity (Cd ). Then, to examine the potential distinctions between the singly comorbid groups (e.g., ADHD + ANX) and the doubly comorbid group (ADHD + ANX + ODD/CD), it was necessary to determine whether the effects of each comorbidity applied equally across its single and doubly comorbid forms (termed a main effect of that comorbidity), or whether any interaction effects (Anx Cd ) existed. These issues were explored for all Cantwell criteria via multivariate analyses, examining the extent to which Anx, Cd, and Anx Cd effects could be found for specific indicators. If these analyses should demonstrate multiple Anx Cd interactions, or should indicate that when Anx and Cd effects are found they usually occur with different variables, such findings would provide evidence for the need to discriminate among the three potential comorbid subgroups versus “pure” ADHD-only subjects. To examine further the response to treatment criterion, we constructed unique codes for each of the MTA treatment group assignments. Then, using these codes in multivariate analyses of the difference scores described above, along with codes for the four comorbidity subgroups, we examined all interactions between comorbidity subtype and MTA treatment group status in the final model. Finding interactions between a given MTA treatment and any comorbidity group would have important implications for treatment planning and could enhance clinicians’ ability to match patients to specific treatments. Finally, to determine clinical significance of all findings, effect sizes were computed to examine the impact of comorbidity subtypes on baseline characteristics, outcomes, and response to treatment. Given our concern that too stringent methods might result in failure to identify modest to moderate effects within relatively small comorbidity groups stratified across six sites and four treatment conditions, p values are set at a modest p < .05 and no corrections for multiple tests are done here. After statistical consultation, we reasoned that this was a defensible strategy, since these are exploratory analyses and the interpretation of results should not rest not on any single statistical analysis
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per se. Readers are encouraged to exercise caution in the interpretation of findings. For all analyses, because previous analyses (March et al., 2000; MTA Cooperative Group, 1999b) demonstrated that neither gender nor ethnicity impacted significantly on results, these two variables were not included as covariates. In contrast, because important differences in baseline characteristics have been found across sites, site status was entered as a covariate for all analyses. RESULTS
Results are presented in the following order: (1) head-tohead comparisons of the two singly comorbid subgroups (to determine whether the specific kind of comorbidity [ANX or ODD/CD] makes a difference); (2) examination of Cd and Anx main, additive, and/or interaction effects by applying Cantwell criteria across baseline characteristics and outcomes; (3) examination of possible differential benefits of specific treatments on specific comorbid groups’ outcomes; and (4) examination of effect sizes. Do ADHD + ANX and ADHD + ODD/CD Subjects Differ? Table 1 presents the baseline means from each of the four groups constructed by comorbidity profiles. No analyses are presented for any baseline variables that simply reflect how the groups were formed (e.g., parent/teacher reports of aggression/oppositionality and internalizing symptoms). The comparisons of the two nonoverlapping ADHD comorbidity profiles (ADHD + ANX, ADHD + ODD/CD) can be seen in the second and third columns from the left in Table 1 (baseline characteristics, Cantwell criteria 1–5). Significant differences between these two groups are indicated by boldface type. Inspection of these columns indicates that these two singly comorbid groups differed in 11 instances on baseline characteristics (Table 1). Because of space considerations, analyses of the outcomes criterion are not presented here. Nonetheless, findings from ADHD + ANX versus ADHD + ODD/CD outcome comparisons overlapped substantially with and were consistent with the analogous differences noted between these two comorbid groups at baseline for five variables (parentrated subscale and total scores on the SNAP, overall impairment, WIAT math, and Conners composite scores). In addition, for three additional variables—all teachercompleted (SNAP inattention, total SNAP scores, and SSRS social skills), significant differences were found between ADHD + ANX and ADHD + ODD/CD subjects’ outcomes (tabled data available upon request). It is important to note that the differences between these two comorbid groups cross many areas of functioning, including domains where ADHD + ODD/CD subJ . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
Clinical phenomenology (baseline) Inattentive (T) Inattentive (P) Hyperactive-impulsive (T) Hyperactive-impulsive (P) Total SNAP (T) Total SNAP (P) CDI (child) MASC (child) Columbia Impairment Scale (P) Child needs services (P) LD diagnosis (yes/no) (proportion) Verbal IQ Performance IQ WIAT Math WIAT Spelling WIAT Reading Overall composite score Demographic factors (baseline) Gender (proportion male) Age (years) Minority (yes/no) (proportion) Two parents in home (proportion) (Mean no. of parents in home) Income (proportion on welfare status) Psychosocial factors (baseline) Social skills/peer relations SSRS (T) SSRS (P) No. of life stressors (all neg. events)b No. of life stressors (confounded) Family factors (environmental and genetic, baseline) Wells Parenting Index (P) Parenting Stress Index (P) Parent–child (power assertion) (P) Parent–child (positive affection) (P) Maternal depression (BDI) (P)
Variable 2.28 2.10 1.87 1.87 1.75 1.59 0.42 2.57 21.0 3.09 0.22 100 101 94.5 91.0 93.5 2.64 0.79 7.5 0.44 0.56 (1.5) 0.21 0.84 1.06 2.3 1.4 0.68 3.49 2.63 3.64 0.35
0.80 7.8 0.34 0.75 (1.7) 0.12 0.86 1.11 2.0 1.2 0.15 3.64 2.58 3.60 0.27
+Anx (81)
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–0.48 3.37 2.83 3.46 0.29
0.80 0.98 2.5 1.6
0.81 7.8 0.40 0.70 (1.7) 0.20
2.21 2.12 2.04 2.04 1.85 1.80 0.41 2.46 23.8 3.33 0.13 101 102 99.1 94.4 96.4 6.96
+ODD/CD (171)
Subtype Mean Scores
2.27 1.92 2.00 1.72 1.76 1.46 0.39 2.52 18.0 2.87 0.16 101 102 99.2 95.8 96.9 0.94
ADHD (184)a
0.03 3.20 2.82 3.57 0.39
.29** –.28*** –.09 .08 –.28**
–.07 –.21* –.12 –.11
–.34*** –.50*** –.46*** –.28* –.07
–.22 –.55*** –.21** –.21**
–.20
–.23* 0.80 0.94 3.1 2.0
.03 .00 –.12 .00
–.03 –.37* –.20 –.35**
0.81 7.9 0.41 0.59 (1.5) 0.27
.09 –.32 –.05 –.43*** –.18* –.69*** –.06 .11 –.74*** –.54*** .08 .00 .00 –.01 –.10 –.04 –.76**
Cd
–.02 –.29 .17 –.20 .02 –.26* –.10 –.09 –.38*** –.26* –.17*** –.07 –.06 –.34** –.34* –.24* –.21**
Anx
Effect Sizes
2.16 2.08 2.01 2.05 1.85 1.86 0.37 2.52 27.5 3.49 0.13 101 100 96.7 93.1 94.9 8.68
+Dual (143)
–.01 .04 .09 .14 –.07
.07 .04 –.12 –.11
.10
.03 .50* .18 .00
.09 .35 –.13 .19 .02 .14 .23 –.02 –.09 .07 .17 –.07 .06 .17 .25 .13 –.00
Cd Anx
TABLE 1 Validation Criteria by Comorbidity Subtype: Mean Scores and Effect Sizes
1.84 0.535 0.542 0.494 0.291
0.278 0.235 2.42 1.90
0.393
0.40 0.808 0.489 0.567
0.652 0.627 0.765 0.751 0.512 0.494 0.311 0.532 7.83 0.853 0.361 14.8 15.6 13.8 14.0 14.2 7.94
Pooled SD
–– Continued
F = 3.96, p < .001; 8,575 F = 8.78, p < .001; 8,515 F = 4.18, p < .001; 8,552 F = 1.61, p < .119; 8,552 F = 3.22, p < .001; 8,518
F = 2.15, p < .03; 8,531 F = 8.01, p < .001; 8,514 F = 2.84, p < .004; 8,560 F = 3.37, p < .001; 8,560
F = 7.07, p < .001; 8,570
F = 1.44, p < .18; 8,570 F = 2.27, p < .03; 8,570 F = 13.7, p < .001; 8,568 F = 3.79, p < .001; 8,570
F = 1.42, p < .20; 8,560 F = 2.74, p < .006; 8,563 F = 1.82, p < .07; 8,563 F = 4.94, p < .001; 8,565 F = 2.76, p < .005; 8,547 F = 10.5, p < .001; 8,551 F = 1.72, p < .09; 8,567 F = 1.32, p < .23; 8,536 F = 17.4, p < .001; 8,422 F = 5.10, p < .001; 8,422 F = 1.16, p < .33; 8,570 F = 1.89, p < .06; 8,564 F = 2.47, p < .012; 8,564 F = 3.38, p < .001; 8,570 F = 2.04, p < .04; 8,570 F = 1.43, p < .19; 8,570 F = 17.1, p < .001; 8,570
Statistics
ADHD COMORBID SUBGROUPS
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Note: For scale scores, higher scores and positive values indicate improvement/better functioning; negative scores indicate deterioration. ADHD, +Anx, +ODD/CD, and +Dual represent the four comorbidity groups, classified based on presence or absence of each comorbidity. Anx, Cd represent the dummy codes for presence/absence of each comorbidity coded and entered in multivariate analyses. Significant main effects and interactions (Anx Cd ) for comorbidity are denoted in the respective columns by asterisks to indicate level of statistical significance. * p .05; ** p .01; *** p .001. Significant differences between the ADHD + ANX and the ADHD + ODD/CD subgroups are indicated by boldface type. ADHD = attention-deficit/hyperactivity disorder; ANX = anxiety disorders; ODD/CD = oppositional defiant disorder or conduct disorder; T = teacher; P = parent; SNAP = Swanson, Nolan, and Pelham scale; CDI = Children’s Depression Inventory; MASC = Multidimensional Anxiety Scale for Children; LD = learning disability; WIAT = Wechsler Individual Achievement Test; SSRS = Social Skills Rating Scale; BDI = Beck Depression Inventory. a n’s. b Stress scores were computed first by summing only those events that were not potentially a result of subjects’ or families’ own functioning (“unconfounded”), then by summing only those events that may in fact result from families’ functioning, e.g., divorce or parental separation (“confounded”) (see Jensen et al., 1991).
1.37 0.77 1.72 1.11 F = 1.25, p < .27; 8,570 F = 2.23, p < .03; 8,570 F = 0.56, p < .81; 8,570 F = 1.39, p < .20; 8,530 .07 –.13 .06 .00 .07 .00 .00 .09 .07 –.13* –.06 –.18 1.2 0.7 1.9 2.1 1.4 0.5 1.9 1.9 1.4 0.6 2.0 2.2 1.5 0.5 1.9 2.0 Biological factors No. of prenatal problems No. of perinatal problems Total pre-perinatal problems Mat. postpartum depressive symptoms
Cd
+Dual (143) +ODD/CD (171) +Anx (81) Variable
ADHD (184)a
Subtype Mean Scores
TABLE 1 (Continued)
Anx
Effect Sizes
Cd Anx
Statistics
Pooled SD
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jects were more impaired (e.g., baseline hyperactiveimpulsive symptoms, overall impairment, parent–child relations, and the composite index), as well as other, quite different areas of functioning where ADHD + ANX subjects were more impaired (e.g., baseline academic performance scores, likelihood of a learning disability diagnosis, less improvement in teacher-rated inattention by 14 months, and less improvement in the composite index). Are the Two Forms of Comorbidity Simply “Additive”? Turning to the multivariate analyses to explore additive and interactive effects of the two forms of comorbidity, columns 5 through 7 in Table 1 indicate significant main (Anx, Cd ) and interactive (Anx Cd ) effects. Significant effects are labeled with asterisks to denote levels of significance. There were 22 variables in which there were significant effects of comorbidity on baseline characteristics and 7 additional instances of effects of comorbidity on outcomes (not shown here, but available upon request). Of note, across these variables, only 7 instances of additive effects of comorbidity were found (characterized by significant effects being noted in both columns 5 and 6—parent total SNAP scores, overall impairment, need for services, parent-rated social skills, the Parenting Stress Index, the Wells parenting factor, and the composite index). Note that none of the measures, except the parent total SNAP, attempt to measure psychopathology directly; rather, they are general indices of the overall impact of psychopathology on impairment, need for services, and families. These findings indicate that while the two different forms of comorbidity/psychopathology are not additive per se, their combined impacts on external factors such as overall impairment, family burden, and services use may be. Apart from the 7 variables for which additive effects were found, findings from Table 1 and our outcome criterion analyses revealed that Anx comorbidity exerted main effects on either baseline or outcome variables in 12 instances, while Cd exerted effects on 9 other variables. Thus, the most common main effects of Anx and Cd comorbidity were noted on different variables, suggesting quite different symptom profiles of subjects, depending on their particular comorbidity subgroup. Do Comorbid Subgroups Differ in Response to Specific Treatments? Table 2 presents findings concerning the response to treatment criterion among all three MTAdelivered interventions (versus CC), examined via the multivariate analyses. Turning first to the issue of unique effects of treatments on comorbid subgroups, such patterns are revealed by letters B (Beh), M (MedMgt), and C J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
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TABLE 2 Response to Treatment by Comorbidity Subtypes: Difference Scores (Baseline Minus 14 Months) Mean Scores ADHD (184)a
+Anx (81)
+ODD/CD (171)
+Dual (143)
Inattentive (T) Inattentive (P) Hyperactive-impulsive (T) Hyperactive-impulsive (P) Oppositional aggressive (T) Oppositional aggressive (P) Total SNAP symptoms (T) Total SNAP symptoms (P) Aggression (P) Internalizing symptoms (T) Internalizing symptoms (P) MASC (child) CDI (child) Columbia Impairment Scale Needs services (P) Social skills (T) Social skills (P) Overall composite
0.90 0.71 0.98 0.70 0.49 0.29 0.78 0.56 0.05 0.12 0.15 0.23 0.15 5.8 0.76 0.23 0.14 7.5
0.78B,M 0.77B 0.85 0.79B 0.42B 0.31 0.64B,M 0.59B 0.05 0.24M 0.14B 0.25 0.14 5.4B 0.95 0.24B 0.06 8.5B
0.83 0.81 0.93 0.86 0.54 0.55 0.75 0.70 0.09 0.15 0.22 0.25 0.14 7.6 0.67 0.25 0.16 9.1
0.91 0.78B 0.99 0.81C 0.62 0.58 0.85 0.70B 0.11 0.07 0.32B 0.16 0.11 9.7 0.92 0.30 0.17 8.6B
P-C power assertion P-C positive affection WIAT Math WIAT Spelling WIAT Reading LD at 14 mo (proportion) ADHD at 14 mo
0.22 0.01 2.5 0.7 1.4 0.10 0.42
0.20, 0.07 3.7B 2.7B,C 1.2 0.16 0.57
0.32 0.04 1.0B,M 1.0 1.4 0.08 0.50
0.31 0.05 2.5 1.0 1.2 0.16 0.55
Main Effects of Comorbid Group on Outcomes? ADHD+Anx
ADHD+Anx+ODD/CD ADHD+Anx+ODD/CD ADHD+ODD/CD ADHD+Anx ADHD+Anx+ODD/CD ADHD+Anx+ODD/CD
ADHD+Anx, ADHD+ Anx+ODD/CD
ADHD+Anx
Statistics F = 1.47, p < .09; 20,557 F = 3.44, p < .001; 20,555 F = 1.64, p < .04; 20,557 F = 4.01, p < .001; 20,555 F = 1.68, p < .03; 20,557 F = 3.08, p < .001; 20,555 F = 2.22, p < .002; 20,557 F = 4.45, p < .001; 20,555 F = 1.59, p < .05; 20,558 F = 1.55, p < .06; 20,524 F = 3.34, p < .001; 20,547 F = 1.17, p < .27; 20,524 F = 1.40, p < .12; 20,555 F = 4.23, p < .001; 20,470 F = 2.92, p < .001; 20,558 F = 1.68, p < .03; 20,519 F = 1.55, p < .05; 20,548 F = 4.41, p < .001; 20,558 F = 1.50, p < .08; 20,544 F = 0.70, p < .83; 20,554 F = 1.55, p < .06; 20,558 F = 0.94, p < .53; 20,558 F = 1.48, p < .08; 20,558 F = 1.28, p < .19; 20,558 F = 3.63, p < .001; 20,558
Note: Boldface values indicate that the MTA treatment type (B = behavioral therapy; M = medication management; C = combined treatment) exerted difference effects on the particular comorbidity groups in that column, compared with the overall effects of that same treatment for all subjects, irrespective of comorbidity profile. ADHD = attention-deficit/hyperactivity disorder; ANX = anxiety disorders; ODD/CD = oppositional defiant disorder or conduct disorder; T = teacher; P = parent; SNAP = Swanson, Nolan, and Pelham scale; MASC = Multidimensional Anxiety Scale for Children; CDI = Children’s Depression Inventory; WIAT = Wechsler Individual Achievement Test; LD = learning disability. a n’s.
(Comb) in the columns denoting the comorbidity subtypes. All comorbidity group effects are presented vis-à-vis comparisons to the ADHD-only group. Likewise, treatment effects are presented with reference to the CC group. Of note in the table are the commonly found, differentially beneficial effects of Beh interventions for the ADHD + ANX group. These interactions are indicative of treatment effects over and above the main effects of all treatments for the entire sample (irrespective of comorbidity), beyond Beh treatment benefits for the entire sample, and even distinct from the impact of Comb and MedMgt treatments on the ADHD + ANX subgroup itself. The second finding revealed in Table 2 is that dually comorbid subjects also evidenced a substantial benefit from specific treatments, sometimes Comb, sometimes J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RU A RY 2 0 0 1
Beh, while ADHD + ODD/CD subjects rarely showed a differential response to any of the treatments, compared with ADHD-only subjects. The right-hand column of Table 2 indicates whether there were any main effects of comorbidity subgroup on treatment outcomes. Of note, seven of these eight instances were found among subjects with comorbid anxiety (ADHD + ANX or ADHD + ANX + ODD/CD subtypes). Inspection of actual means revealed that these two groups generally showed the greatest response to treatments (not shown here, but tables available from the authors upon request), regardless of treatment type. How Large and Clinically Meaningful Are Comorbidity Subgroup Effects? The size and statistical significance of comorbidity effects on baseline characteristics (Table 1) 153
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can be seen in the right-hand column of the table. Review of Table 1 suggests that the effects of Cd comorbidity are generally more pronounced than Anx effects on baseline characteristics and are generally associated with greater levels of symptoms (e.g., hyperactive-impulsive symptoms), lower levels of functioning (teacher-rated social skills), and overall impairment. Important exceptions were noted in academic functioning, where ADHD + ANX subjects evidenced sizable effects with lower functioning levels. Further review of this table also indicates that in almost all instances of additive effects of the two comorbid conditions (parent total SNAP scores, impairment, need for services, teacher-rated social skills, and the composite index), effects exerted by Cd were 2-fold or more larger than those conveyed by Anx. Analyses of effect sizes of the outcomes criterion revealed few instances of comorbidity effects on outcomes independent of MTA treatments. Important exceptions are the relative lack of improvement over time in teacherreported inattention and the overall composite index among ADHD + ANX and ADHD + ANX + ODD/CD subjects (table available upon request). Effect sizes based on comorbidity profiles on the treatment response criterion are much more complex, since any given variable could have 12 different effect sizes (3 MTA treatments 4 comorbidity profiles). Therefore, effect sizes for selected variables where comorbidity treatment interactions were noted in Table 2 are presented in graphic form in Figure 1. Review of this figure indicates that ADHD + ANX subjects are particularly responsive to Beh, compared with subjects in other comorbidity groups, which rarely did as well (i.e., effect size > 0.4) with Beh alone. Figure 1 also indicates that ADHD + ANX + ODD/CD subjects were preferentially responsive to Comb interventions, as indicated by a robust response (effect size = 0.92) to Comb and much lower effect size for Beh (0.53) and MedMgt (.28) in the overall composite rating. By and large, the effect sizes of ADHD-only and ADHD + ODD/CD subjects were generally lower than those for ADHD + ANX and ADHD + ANX + ODD/CD subjects. For ADHD-only and ADHD + ODD/CD subjects, Beh alone interventions never appeared beneficial. DISCUSSION
Our findings suggest that ADHD children with and without ODD/CD and ANX differed on many baseline characteristics, outcomes, and response to treatment. 154
Though ODD/CD comorbidity commonly exerted fairly powerful main effects on baseline characteristics, it rarely interacted with treatment response or outcomes. In contrast, Anx conditions exerted somewhat less robust effects on baseline characteristics, but frequently interacted with response to specific treatments. Concerning our subtype hypothesis, while both Anx and Cd frequently exerted straightforward main effects, their effects usually did not operate on the same variables. Thus such effects were found in only six instances of all variables examined, and these variables pertained more to the impact of psychopathology than psychopathology per se. Taken together, our findings—consistent differences between ADHD + ANX and ADHD + ODD/CD groups, rarely found additive effects, the impact of Cd and Anx on different variables, and the differential impact of specific treatments on the four comorbidity types, with some but not all treatments yielding effects of sizable magnitude—indicate that the overall clinical profiles of the comorbidity types are sufficiently distinct to support the need to discriminate among the comorbid subgroups. Consistent with our first report of parent-reported anxiety as a moderating variable on outcomes (MTA Cooperative Group, 1999b), we found substantial, recurring indications of Anx comorbidity (either alone or in interaction with Cd ) moderating responses to treatment. In addition, however, this analysis, going well beyond our earlier report, suggests that anxiety may interact with treatment outcomes across many more variables than first described, more readily detectable here with Anx Cd interactions included in the analytic model. It is of interest to note that Anx exerted relatively modest effects on baseline characteristics and outcomes, yet exerted persistent, sometimes sizable effects on response to treatment findings. Reasons for this finding are unclear, but could be due to the fact simply that behavioral interventions are selectively effective for ADHD children with parent-defined anxiety and that these children are qualitatively different in terms of etiological processes and developmental trajectories. This possibility of qualitative differences in these children is further supported by the findings of WIAT score differences seen in these subjects at baseline, as well as evidence from other reports that such children may have different physiological reactions to methylphenidate (Urman et al., 1995). As a general rule, ANX status appeared to confer certain benefits on ADHD children, regardless of the presence of ODD/CD. Thus, inspection of Table 1 and our J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
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Fig. 1 Comorbidity type by treatment response: effect sizes across six variables. SNAP = Swanson, Nolan, and Pelham scale; ADHD = attention-deficit/hyperactivity disorder; DBD = disruptive behavior disorders; Beh = behavioral therapy; MedMgt = medication management; Comb = combined treatment.
outcomes criterion analyses (available upon request) indicates that most (40 of 58) Cd Anx interaction effects were positive (though rarely significant), that is, they exerted ameliorating effects on concurrent ODD/CD (i.e., ADHD + ANX + ODD/CD versus ADHD + ODD/CD subjects). Furthermore, review of Figure 1 indicates that children with Anx tended to be more treatment-responsive than ADHD + ODD/CD and even ADHD-only subjects, both in terms of absolute effect sizes and in terms of their relatively robust response to all J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RU A RY 2 0 0 1
treatment modalities. The ADHD + ANX group in particular responded to almost any of the three treatments, with the single exception of academic performance, where possible adverse effects of medication management were noted in the ADHD + ANX group, of some interest given historical reports of adverse effects of medication treatments on learning. In contrast, ADHD + ANX + ODD/ CD subjects in a number of important instances appeared to derive substantially greater benefits from Comb interventions compared with all other treatments, thus provid155
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ing some justification of their separate classification from ADHD + ANX subjects. ADHD-only and ADHD + ODD/CD subjects responded usually only to interventions that included medication. While ADHD-only and ADHD + ODD/CD subjects appeared quite similar in terms of degree of clinical change in response to treatment and outcomes, the sizable baseline differences in severity between these two groups indicates a more problematic prognosis for the ADHD/CD group. In fact, additional analyses of outcomes and response to treatment based solely on absolute levels of 14-month symptoms (rather than difference scores) revealed that these two groups continued to show substantial differences at endpoint on a number of critical variables, such as parent-reported aggression, need for services, impairment, social skills, parent–child relations, and the overall composite index (tables available from the authors upon request). These persistent differences in prognosis may justify the separate classification of these two profiles. Limitations
In consideration of our findings, a number of caveats must be carefully weighed. First, ours was a referred sample, so any inferences that these findings are applicable to ADHD comorbidity patterns in the general community are not warranted. In addition, our analyses of the outcomes criterion “independent of treatment” (i.e., with CC subjects only) must be viewed with caution because most CC subjects did indeed obtain some form of treatment, and our preliminary findings suggest that those seeking treatment benefited slightly more than those who did not seek care (MTA Cooperative Group, 1999a,b). Another word of caution is warranted concerning those analyses suggesting differential response to treatments as a function of comorbidity, particularly anxiety. As noted elsewhere, very little overlap is found between parentand child-identified anxiety syndromes (e.g., Jensen et al., 1999). This issue is of consequence because our additional analyses (March et al., 2000) of the moderator effects of anxiety on MTA outcomes indicate that in contrast to parent-reported anxiety comorbidity, childreported anxiety syndromes exert little if any moderating effects on MTA outcomes. Thus it remains unclear whether the moderating effects of anxiety reported here apply to anxiety disorders per se, or to some broader construct of parent-identified behavioral and affective dysregulation. Relatedly, it should be noted that we found 156
substantially lower rates of affective disorder in the MTA sample than have been reported in other clinical studies (e.g., Biederman et al., 1991), raising concerns about the possibility of underdiagnosis of these conditions, or alternatively, comorbidity differences between the MTA sample (which drew from a broad range of referral sources) versus samples that have drawn principally from mental health settings. We note that our decision to combine CD and ODD cases into a single disruptive disorder category is not without controversy. However, evidence from clinical studies suggests that most ADHD children with comorbid CD also often meet criteria for ODD, which has in fact usually preceded CD onset by several years (e.g., Biederman et al., 1996). On the other hand, a number of population-based studies have suggested that ODD and CD, while intercorrelated 0.70 to 0.76, may nonetheless constitute somewhat separate dimensions of psychopathology (Quay, 1999). Our decision to combine these two disorders reflects in part the substantial (but incomplete) overlap between the two disorders, as well the lack of power to examine CD as a separate disorder, given our sample sizes. A final note of caution concerns the use of clinical samples to explore comorbidity. As noted by Angold et al. (1999), clinical samples can be burdened by methodological artifacts, potentially leading to incorrect estimates of comorbidity rates and even mistaken etiological inferences. Nonetheless, clinical studies of comorbidity can be useful to the extent that the conclusions from such studies are intended to apply only to other clinical samples. In this regard, the MTA’s inclusion and exclusion criteria, such as admitting only children with ADHD combined type and excluding children with psychosis, with Tourette’s disorder, or concurrently being treated with antipsychotic medications, demarcate some of the possible limitations concerning inferences that might be drawn to more heterogenous clinical samples. Clinical Implications
Our findings may have considerable implications for future research and treatment studies, as well as for the clinical process of matching of patients to treatments. As constructed, our comorbidity groups appear to differ in a number of areas, including several notable baseline characteristics, response to treatment, and outcomes. ADHD children with parent-defined anxiety disorders, particularly those with no accompanying ODD/CD, may have a number of unique characteristics, most notably seen in WIAT J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
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performance scores at baseline (also reported by Livingston et al., 1990) and at 14 months. In addition, this group evinces a clinical profile that is not a simple function of how it was originally formed (persistent ADHD, teacherreported inattention at 14 months), and perhaps most importantly, in its differential response to treatment. While the discriminating responses to treatments (especially the behavioral components of Beh and Comb) were frequently shared between the ADHD + ANX and ADHD + ANX/ CD groups (suggesting a main effect of Anx status), additional interactions with treatment response were found by separating Anx children into the ADHD + ANX and ADHD + ANX/CD groups, compared with our original report (MTA Cooperative Group, 1999b). A simple “rule of thumb” that summarizes these findings suggests that if a child presents with an ADHD + ANX profile, all interventions are likely to be effective. If a child presents with ADHD-only or ADHD + ODD/ CD, treatments with medication appear especially indicated, and Beh alone strategies may be contraindicated. Finally, if a child presents with ADHD + ANX + ODD/ CD, Comb interventions may offer substantial advantages over other treatments, particularly in overall impairment and functioning outcomes. Our findings suggest that more precise matching of patients to treatment using patients’ comorbidity profiles may mitigate initial clinical uncertainty, reduce the number of therapeutic trials until a workable treatment is found, and yield larger treatment gains for specific patients. Future pathophysiological and genetic studies may benefit by these discriminations, to the extent that these clinical profiles reflect different etiological and developmental processes. The NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) is a cooperative treatment study performed by six independent research teams in collaboration with the staff of the Division of Services and Intervention Research of the NIMH, Rockville, MD, and the Office of Special Education Programs (OSEP) of the U.S. Department of Education (DOE). The NIMH Principal Collaborators are Peter S. Jensen, M.D., L. Eugene Arnold, M.Ed., M.D., John E. Richters, Ph.D., Joanne B. Severe, M.S., Donald Vereen, M.D., and Benedetto Vitiello, M.D. Principal Investigators and Coinvestigators from the six sites are as follows: University of California at Berkeley/San Francisco (UO1 MH50461): Stephen P. Hinshaw, Ph.D., Glen R. Elliott, M.D., Ph.D.; Duke University (UO1 MH50447): C. Keith Conners, Ph.D., Karen C. Wells, Ph.D., John S. March, M.D., M.P.H.; University of California at Irvine/Los Angeles (UO1 MH50440): James M. Swanson, Ph.D., Dennis P. Cantwell, M.D., Timothy Wigal, Ph.D.; Long Island Jewish Medical Center/Montreal Children’s Hospital (UO1 MH50453): Howard B. Abikoff, Ph.D., Lily Hechtman, M.D.; New York State Psychiatric Institute/Columbia
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University/Mount Sinai Medical Center (UO1 MH50454): Laurence L. Greenhill, M.D., Jeffrey H. Newcorn, M.D.; University of Pittsburgh (UO1 MH50467): William E. Pelham, Ph.D., Betsy Hoza, Ph.D. Helena C. Kraemer, Ph.D. (Stanford University) is statistical and design consultant. The OSEP/DOE Principal Collaborator is Ellen Schiller, Ph.D.
REFERENCES Angold A, Costello EJ, Erkanli A (1999), Comorbidity. J Child Psychol Psychiatry 40:57–87 Biederman J, Faraone SV, Milberger S et al. (1996), Is childhood oppositional defiant disorder a precursor to adolescent conduct disorder? Findings from a four-year follow-up study of children with ADHD. J Am Acad Child Adolesc Psychiatry 35:1193–1204 Biederman J, Newcorn J, Sprich S (1991), Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 148:564–577 Bird H, Gould M, Staghezza-Jaramillo B (1990), The comorbidity of ADHD in a community sample of children aged 6 through 16 years. J Child Fam Stud 3:365–378 Bird HR, Andrews H, Schwab-Stone M et al. (1996), Global measures of impairment for epidemiologic and clinical use with children and adolescents. Int J Methods Psychiatr Res 6:295–307 Buitelaar J, Van der Gaag R, Swaab-Barneveld HS, Kuiper M (1995), Prediction of clinical response to methylphenidate in children with attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 34:1025–1032 Cantwell DP (1995), Child psychiatry: introduction and overview. In: Comprehensive Textbook of Psychiatry/VI, Kaplan HI, Sadock BJ, eds. Baltimore: Williams & Wilkins, pp 2151–2154 Conners CK, Epstein JN, March JS et al. (2001), Multimodal treatment of ADHD in the MTA: an alternative outcome analysis. J Am Acad Child Adolesc Psychiatry Diamond I, Tannock R, Schachar R (1999), Response to methylphenidate in children with ADHD and comorbid anxiety. J Am Acad Child Adolesc Psychiatry 38:402–409 DuPaul G, Barkley R, McMurray M (1994), Response of children with ADHD to methylphenidate: interaction with internalizing symptoms. J Am Acad Child Adolesc Psychiatry 33:894–903 Furman W, Giverson R (1995), Identifying the links between parents and their children’s sibling relationships. In: Close Relationships and SocioEmotional Development, Shulman S, ed. Norwood, NJ: Ablex, pp 95–108 Gresham FM, Elliott SN (1989), Social Skills Rating System: Parent, Teacher, and Child Forms. Circle Pines, MN: American Guidance Systems Hinshaw SP (1987), On the distinction between attentional problems/ hyperactivity and conduct problems/aggression in child psychopathology. Psychol Bull 101:443–463 Jensen P, Martin C, Cantwell D (1997), Comorbidity in ADHD: implications for research, practice, and DSM-IV. J Am Acad Child Adolesc Psychiatry 36:1065–1079 Jensen PS, Rubio-Stipec M, Canino G et al. (1999), Parent and child contributions to diagnosis of mental disorder: are both informants always necessary? J Am Acad Child Adolesc Psychiatry 38:1569–1579 Jensen PS, Ussery T, Bloedau L, Richters J (1991), Stressful life events versus family processes: environmental predictors of child dysfunction. J Am Acad Child Adolesc Psychiatry 30:303–309 Kovacs M, Beck AT (1977), An empirical-clinical approach toward a definition of childhood depression. In: Depression in Childhood, Schulterbrandt JG, Raskin A, eds. New York: Raven, pp 1–25 Kraemer HC (1995), Statistical issues in assessing comorbidity. Stat Med 14:721–733 Livingston R, Dykman R, Ackerman P (1990), The frequency and significance of additional self-reported psychiatric diagnoses in children with ADD. J Abnorm Child Psychol 18:465–478 March JS, Parker JD, Sullivan K, Stallings P, Conners CK (1997), The Multidimensional Anxiety Scale for Children (MASC): factor structure, reliability, and validity. J Am Acad Child Adolesc Psychiatry 36:554–565
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March JS, Swanson JM, Arnold LE et al. (2000), Anxiety as a predictor and outcome variable in the MTA study: analysis using hierarchical linear modeling. J Abnorm Child Psychol 28:527–541 MTA Cooperative Group (1999a), 14-Month randomized clinical trial of treatment strategies for attention deficit hyperactivity disorder. Arch Gen Psychiatry 56:1073–1086 MTA Cooperative Group (1999b), Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 56:1088–1096 Pliszka S (1989), Effect of anxiety on cognition, behavior, and stimulant response in ADHD. J Am Acad Child Adolesc Psychiatry 28:882–887 Pliska S (1992), Comorbidity of ADHD and overanxious disorder. J Am Acad Child Adolesc Psychiatry 31:197–203 Quay H (1999), Classification of the disruptive behavior disorders. In: Handbook of Disruptive Behavior Disorders, Quay HC, Hogan AE, eds. New York: Kluwer Academic/Plenum Publishers, pp 3–21 Robins E, Guze SB (1970), Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 126:983–987
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Shaffer D, Fisher P, Dulcan M et al. (1996), The second version of the NIMH Diagnostic Interview Schedule for Children (DISC-2). J Am Acad Child Adolesc Psychiatry 35:865–877 Tannock R, Ickowicz A, Schachar R (1995), Differential effects of methylphenidate on working memory in ADHD children with and without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 34:886–896 Urman R, Ickowicz A, Fulford P, Tannock R (1995), An exaggerated cardiovascular response to methylphenidate in ADHD children with anxiety. J Child Adolesc Psychopharmacol 5:29–37 Wechsler D (1992), Wechsler Individual Achievement Test: Manual. San Antonio, TX: Psychological Corporation Wells CK, Epstein JN, Hinshaw SP et al. (2000), Parenting and family stress treatment outcomes in attention deficit hyperactivity disorder (ADHD): an analysis in the MTA study. J Abnorm Child Psychol 28:543–553 Woolston JL, Rosenthal SL, Riddle MA, Sparrow SS, Cicchetti D, Rosenthal LD (1989), Childhood comorbidity of anxiety/affective disorders and behavior disorders. J Am Acad Child Adolesc Psychiatry 28:707–713
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ABSTRACT Objectives: Previous research has been inconclusive whether attention-deficit/hyperactivity disorder (ADHD), when comorbid with disruptive disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]), with the internalizing disorders (anxiety and/or depression), or with both, should constitute separate clinical entities. Determination of the clinical significance of potential ADHD + internalizing disorder or ADHD + ODD/CD syndromes could yield better diagnostic decision-making, treatment planning, and treatment outcomes. Method: Drawing upon cross-sectional and longitudinal information from 579 children (aged 7–9.9 years) with ADHD participating in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), investigators applied validational criteria to compare ADHD subjects with and without comorbid internalizing disorders and ODD/CD. Results: Substantial evidence of main effects of internalizing and externalizing comorbid disorders was found. Moderate evidence of interactions of parent-reported anxiety and ODD/CD status were noted on response to treatment, indicating that children with ADHD and anxiety disorders (but no ODD/CD) were likely to respond equally well to the MTA behavioral and medication treatments. Children with ADHD-only or ADHD with ODD/CD (but without anxiety disorders) responded best to MTA medication treatments (with or without behavioral treatments), while children with multiple comorbid disorders (anxiety and ODD/CD) responded optimally to combined (medication and behavioral) treatments. Conclusions: Findings indicate that three clinical profiles, ADHD co-occurring with internalizing disorders (principally parent-reported anxiety disorders) absent any concurrent disruptive disorder (ADHD + ANX), ADHD co-occurring with ODD/CD but no anxiety (ADHD + ODD/CD), and ADHD with both anxiety and ODD/CD (ADHD + ANX + ODD/CD) may be sufficiently distinct to warrant classification as ADHD subtypes different from “pure” ADHD with neither comorbidity. Future clinical, etiological, and genetics research should explore the merits of these three ADHD classification options. J. Am. Acad. Child Adolesc. Psychiatry, 2001, 40(2):147–158. Key Words: attention-deficit/hyperactivity disorder, attention deficit, anxiety, comorbidity, treatment, outcomes, classification, diagnosis.
Accepted September 26, 2000. Dr. Jensen is Professor of Psychiatry, Department of Psychiatry, Columbia University College of Physicians and Surgeons; Dr. Hinshaw is Professor of Psychology, Department of Psychology, University of California at Berkeley; Dr. Kraemer is Professor of Biostatistics, Stanford University; Ms. Lenora is a medical student, George Washington University School of Medicine. Other authors’ affiliations are listed in the MTA Cooperative Group acknowledgment that appears at the end of the text. Reprint requests to Dr. Jensen, Center for the Advancement of Children’s Mental Health, Columbia University/NYSPI, 1051 Riverside Drive, Unit 78, New York, NY 10032; e-mail: [email protected]. 0890-8567/01/4002-0147䉷2001 by the American Academy of Child and Adolescent Psychiatry.
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The presence of comorbid disruptive behavior disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]) within children with attention-deficit/ hyperactivity disorder (ADHD) has been well established for several decades (e.g., see Bird et al., 1990; Hinshaw, 1987). Only in the past decade has it become apparent that internalizing disorders (both anxiety and depressive disorders) also commonly co-occur with ADHD. Thus, both clinical and epidemiological studies have consistently shown that as many as one third of children with ADHD have co-occurring anxiety dis147
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orders (Biederman et al., 1991; Bird et al., 1990; MTA Cooperative Group, 1999a; Woolston et al., 1989). This phenomenon appears “real” and cannot be attributed solely to factors such as referral biases or methodological artifacts (Angold et al., 1999). The overlap of ADHD with both the internalizing and disruptive disorders should be of substantial interest to researchers and clinicians. For example, if it can be shown that ADHD when comorbid with either the internalizing or disruptive disorders is unique with respect to its clinical correlates, etiology, course, and outcome (versus “pure” ADHD), it may be useful to consider such comorbid states as diagnostically meaningful subtypes or even as separate disorders. Also, if various comorbid forms of ADHD are actually of qualitatively different types from “pure” ADHD, better treatment planning and clinical prediction, as well as more valid etiological and genetic studies, should be possible. Validation of Subtypes
Cantwell (1995) outlined eight domains of clinical investigation that could be used to assess the discriminant validity of possible disorder types and subtypes. These criteria, modifications of the original Robins and Guze (1970) criteria, include (1) clinical phenomenology, (2) demographic correlates, (3) psychosocial correlates, (4, 5) family factors (both environmental and genetic), 6) biological factors, (7) response to treatment, and (8) clinical outcomes. Applying these criteria to ADHD comorbidity studies, Jensen, Martin, and Cantwell (1997) reported that seven of the eight validational criteria supported the hypothesis that ADHD comorbid with disruptive behavior disorders (ADHD + ODD/CD) constitutes a different ADHD subtype. However, applying these same criteria to ADHD comorbid with internalizing disorders (principally anxiety), they noted somewhat weaker evidence (four of eight criteria) in support of an ADHD + ANX subtype. In the past several years since the Jensen et al. (1997) review, two additional pertinent studies have been conducted that are of relevance to questions concerning the usefulness and validity of the ADHD + ANX subtype. Beginning with an initial dose titration, Diamond et al. (1999) followed stimulant-treated ADHD children over 4 months to determine the impact of comorbid anxiety on their response to medication. Unlike the preponderance of evidence from earlier studies (e.g., Buitelaar et al., 1995; DuPaul et al., 1994; Pliszka, 1989, 1992; Tannock et al., 1995), Diamond and colleagues found that children 148
with ADHD + ANX and those with ADHD/no ANX did not show any differential response to methylphenidate, either in terms of behavioral measures or side effects. Most recently, findings from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), a multisite randomized clinical trial testing four treatment groups in 579 children across six sites, indicated that ADHD children with comorbid parent-reported anxiety disorders have treatment responses that are qualitatively different from those of children without comorbid anxiety (MTA Cooperative Group, 1999a,b). Thus, among children with parent-identified anxiety disorders (33.5% of the sample), those children in the behavioral therapy condition (Beh) showed an enhanced response on outcome measures of parent-reported ADHD and internalizing symptoms, relative to nonanxious children. In addition, among anxious subjects combined treatments (Comb) yielded greater improvements than medication management alone (MedMgt) in several outcome domains. Among nonanxious participants, however, MedMgt and Comb both outperformed Beh and the community comparison group (CC) with regard to ADHD symptoms (MTA Cooperative Group, 1999b). Findings from the MTA study provide evidence of qualitatively different treatment responses in ADHD + ANX versus ADHD/no ANX children and may thus support the separate ADHD + ANX subtype hypothesis. In contrast, and to the surprise of the MTA investigators, the presence of comorbid ODD/CD did not moderate any differential treatment response to specific treatments. However, these first moderator analyses were restricted to examination of the main effects of comorbidity and did not explore possible interactions between ODD/CD and comorbid anxiety on MTA outcomes. Remarkably, only one study to date has examined these four potentially separate entities. In a study of 138 white males with DSM-III–defined ADHD, Livingston and colleagues (1990) found that boys with an internalizing disorder and ODD/CD differed along multiple dimensions from boys with ADHD + ODD/CD-only and ADHD + ANX-only, as well as from boys with ADHDonly. In most areas of functioning, doubly comorbid boys scored worse than ADHD + ODD/CD-only and ADHD + ANX-only boys, though in at least one instance doubly comorbid boys functioned somewhat better (e.g., teachercompleted aggression ratings). Unfortunately, given the study’s small sample size (n = 138) and its restriction to J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
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white males from one clinical setting, it could not be determined whether the differences between doubly comorbid boys and singly comorbid and ADHD-only boys were simply an additive function of the two comorbid conditions or whether these differences reflected unique clinical profiles. Thus, while mounting evidence does support the possibility that individuals with comorbid ADHD + ANX and those with ADHD + ODD/CD may have unique clinical profiles compared with children with noncomorbid ADHD, firm conclusions about these comorbid patterns cannot be derived from previous research, given the relatively small sample sizes and previous studies’ failure to tease apart the effects of the two comorbid conditions when they overlap. Furthermore, no previous investigations have used a comprehensive set of validational criteria (either Robins and Guze, 1970, or Cantwell, 1995) to examine these comorbidity subgroups, all within the same study. The MTA study (MTA Cooperative Group 1999a,b) offers a unique opportunity to examine whether children with ADHD + ANX, ADHD + ODD/CD, and ADHD + ANX + ODD/CD do indeed differ from each other and from children with noncomorbid ADHD, and whether such findings can be replicated across multiple settings. In this report, we examine four different groups of ADHD children (ADHD + ANX, ADHD + ODD/CD, ADHD + ANX + ODD/CD, ADHD-only), comparing them using the modified Cantwell validational criteria to determine whether the varying forms of comorbidity convey special diagnostic, therapeutic, or outcome significance beyond the presence of ADHD alone. METHOD Recruitment Procedures and Sample Characteristics MTA recruitment and screening procedures aimed to collect a carefully diagnosed, impaired sample of ADHD children with a wide range of comorbid conditions and demographic characteristics, representative of patients seen clinically (MTA Cooperative Group, 1999a). For eligibility, children (of either sex) were between ages 7.0 and 9.9 years, in first through fourth grades. All met DSM-IV criteria for ADHD, combined type, using the Diagnostic Interview Schedule for Children, parent report, version 3.0 (DISC-P) (Shaffer et al., 1996). The presence of comorbid disorders such as ODD, CD, internalizing disorders, or specific learning disabilities were not exclusions, as an important aim of the MTA study was to examine their interactions with treatment outcomes. In a four-group parallel design, 579 children were assigned randomly to (1) medication management (MedMgt), (2) behavioral treatment (Beh), (3) the combination (Comb), or (4) community comparison (CC) for 14 months. Demographic characteristics of the MTA partic-
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RU A RY 2 0 0 1
ipants were as follows: 80% male and 20% female; 61% white, 20% African American, and 19% Hispanic, racially mixed, or other ethnic origins. Mean age at study entry was 8.2 years. Extensive information concerning subject characteristics, study treatments, and outcomes is reported elsewhere (MTA Cooperative Group, 1999a,b). Assessments The major symptom and functioning domains originally used to assess baseline characteristics and 14-month outcomes (see MTA Cooperative Group, 1999a) were applied to test the Cantwell validational criteria on the various comorbidity profiles. Variables selected for the Cantwell criteria were as follows: (1) clinical phenomenology— inattentive, hyperactive/impulsive, and aggressive/oppositional symptoms (assessed via parent- and teacher-completed Swanson, Nolan, and Pelham scale [SNAP] scores) (MTA Cooperative Group, 1999a), Verbal and Performance IQ, impairment (measured via the Columbia Impairment Scale) (Bird et al., 1996), internalizing symptoms (assessed via the Multidimensional Anxiety Scale for Children [March et al., 1997], the Children’s Depression Inventory [Kovacs and Beck, 1977], and parent- and teacher-rated internalizing symptoms scales from the Social Skills Rating System [SSRS] [Gresham and Elliott, 1989]), and academic achievement (assessed via the Wechsler Individual Achievement Test [WIAT] [Wechsler, 1992]); (2) demographic factors—gender, age, single- versus two-parent status, income, and family occupational status; (3) psychosocial factors—social skills/peer relations (assessed via parent and teacher reports using the SSRS) and levels of life stressors; (4) family factors (both environmental and genetic)—family stress (using the Parent Stress Index), parent–child relations (using scales from the Parent–Child Relationship Questionnaire [Furman and Giverson, 1995]), parenting style based on an internally consistent and reliable factor derived from all MTA-administered parenting assessments (Wells et al., 2000), and maternal depression (using the Beck Depression Inventory); and (5) biological factors (history of pre- and perinatal difficulties). Of note, in the original Cantwell validational scheme family environment and family genetic factors are defined separately, but here we have combined them into a single criterion, as the MTA design did not allow any robust method for separating these two sources of familial effects. These five Cantwell criteria were all based on data collected at the baseline assessment, allowing us to examine what Kraemer (1995) has termed epidemiologic comorbidity. To examine the last two Cantwell criteria (outcomes, response to treatment—also termed clinical comorbidity by Kraemer, 1995), we constructed difference scores by subtracting 14-month endpoint scores from baseline scores of children’s symptoms and functioning ratings of those variables from the clinical phenomenology, psychosocial factors, and family factors domains that describe the child’s functioning. In addition to these outcome measures, we also used an overall composite outcome measure (see Conners et al., 2001) to examine outcomes and response to treatment. To avoid the potentially confounding effects of the MTA treatments on more “naturalistic” outcomes, analyses of outcomes were limited to CC subjects only (n = 146), while response to treatment analyses included all subjects. By way of caution in interpreting these data, our analyses of CC subjects’ “naturalistic” outcomes are should be viewed with caution, inasmuch as two thirds of these children obtained at least some treatment (including stimulants) over the course of the study. Comorbidity Subgroups Diagnoses and comorbidity groups were constructed on the basis of parent-reported DISC diagnoses at study baseline. Diagnoses were based on the previous 6 months, except for CD, which was based on
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the last 12 months according to DSM criteria. While our first reports concerning ADHD comorbid conditions (MTA Cooperative Group, 1999a,b) did not include simple phobia in the “anxiety disorders” category, other analyses have indicated that parent-reported simple phobias are in fact as likely to be validated by clinicians upon reinterview as other anxiety disorders (Jensen et al., 1999). Given these findings and the need to form large enough groups for the analyses for this report, we chose here to include subjects with simple phobia in the “anxiety disorders” category, resulting in somewhat higher rates of comorbid anxiety disorders (38.7% versus 33.5%). Each child was grouped into one of four categories: ADHD-only (31.8%, n = 184) ADHD + ANX (14.0%, n = 81), ADHD + ODD/ CD (29.5%, n = 171), and ADHD + ODD/CD + ANX (24.7%, n = 143). For the 22 cases of mood disorders in the MTA sample, all but 2 were comorbid with anxiety disorders. Given recent evidence presented by Angold et al. (1999) that comorbid mood disorders in children with ADHD occur principally via their association with anxiety disorders, we have named the overall category ADHD + ANX, though in fact this group also included two children with mood disorders without a full-blown anxiety disorder. All other comorbid conditions (e.g., enuresis, tics, etc.) were ignored for the purposes of forming the four comorbidity groups. Analytic Strategy To determine whether ADHD children with different comorbidity profiles differed meaningfully from “pure” ADHD subjects, our analytic strategy proceeded as follows. We first assigned two new variables to all subjects according to the presence or absence of the two comorbidity forms, i.e., presence (1) or absence (0) of anxiety comorbidity (Anx) and ODD/CD comorbidity (Cd ). Then, to examine the potential distinctions between the singly comorbid groups (e.g., ADHD + ANX) and the doubly comorbid group (ADHD + ANX + ODD/CD), it was necessary to determine whether the effects of each comorbidity applied equally across its single and doubly comorbid forms (termed a main effect of that comorbidity), or whether any interaction effects (Anx Cd ) existed. These issues were explored for all Cantwell criteria via multivariate analyses, examining the extent to which Anx, Cd, and Anx Cd effects could be found for specific indicators. If these analyses should demonstrate multiple Anx Cd interactions, or should indicate that when Anx and Cd effects are found they usually occur with different variables, such findings would provide evidence for the need to discriminate among the three potential comorbid subgroups versus “pure” ADHD-only subjects. To examine further the response to treatment criterion, we constructed unique codes for each of the MTA treatment group assignments. Then, using these codes in multivariate analyses of the difference scores described above, along with codes for the four comorbidity subgroups, we examined all interactions between comorbidity subtype and MTA treatment group status in the final model. Finding interactions between a given MTA treatment and any comorbidity group would have important implications for treatment planning and could enhance clinicians’ ability to match patients to specific treatments. Finally, to determine clinical significance of all findings, effect sizes were computed to examine the impact of comorbidity subtypes on baseline characteristics, outcomes, and response to treatment. Given our concern that too stringent methods might result in failure to identify modest to moderate effects within relatively small comorbidity groups stratified across six sites and four treatment conditions, p values are set at a modest p < .05 and no corrections for multiple tests are done here. After statistical consultation, we reasoned that this was a defensible strategy, since these are exploratory analyses and the interpretation of results should not rest not on any single statistical analysis
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per se. Readers are encouraged to exercise caution in the interpretation of findings. For all analyses, because previous analyses (March et al., 2000; MTA Cooperative Group, 1999b) demonstrated that neither gender nor ethnicity impacted significantly on results, these two variables were not included as covariates. In contrast, because important differences in baseline characteristics have been found across sites, site status was entered as a covariate for all analyses. RESULTS
Results are presented in the following order: (1) head-tohead comparisons of the two singly comorbid subgroups (to determine whether the specific kind of comorbidity [ANX or ODD/CD] makes a difference); (2) examination of Cd and Anx main, additive, and/or interaction effects by applying Cantwell criteria across baseline characteristics and outcomes; (3) examination of possible differential benefits of specific treatments on specific comorbid groups’ outcomes; and (4) examination of effect sizes. Do ADHD + ANX and ADHD + ODD/CD Subjects Differ? Table 1 presents the baseline means from each of the four groups constructed by comorbidity profiles. No analyses are presented for any baseline variables that simply reflect how the groups were formed (e.g., parent/teacher reports of aggression/oppositionality and internalizing symptoms). The comparisons of the two nonoverlapping ADHD comorbidity profiles (ADHD + ANX, ADHD + ODD/CD) can be seen in the second and third columns from the left in Table 1 (baseline characteristics, Cantwell criteria 1–5). Significant differences between these two groups are indicated by boldface type. Inspection of these columns indicates that these two singly comorbid groups differed in 11 instances on baseline characteristics (Table 1). Because of space considerations, analyses of the outcomes criterion are not presented here. Nonetheless, findings from ADHD + ANX versus ADHD + ODD/CD outcome comparisons overlapped substantially with and were consistent with the analogous differences noted between these two comorbid groups at baseline for five variables (parentrated subscale and total scores on the SNAP, overall impairment, WIAT math, and Conners composite scores). In addition, for three additional variables—all teachercompleted (SNAP inattention, total SNAP scores, and SSRS social skills), significant differences were found between ADHD + ANX and ADHD + ODD/CD subjects’ outcomes (tabled data available upon request). It is important to note that the differences between these two comorbid groups cross many areas of functioning, including domains where ADHD + ODD/CD subJ . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
Clinical phenomenology (baseline) Inattentive (T) Inattentive (P) Hyperactive-impulsive (T) Hyperactive-impulsive (P) Total SNAP (T) Total SNAP (P) CDI (child) MASC (child) Columbia Impairment Scale (P) Child needs services (P) LD diagnosis (yes/no) (proportion) Verbal IQ Performance IQ WIAT Math WIAT Spelling WIAT Reading Overall composite score Demographic factors (baseline) Gender (proportion male) Age (years) Minority (yes/no) (proportion) Two parents in home (proportion) (Mean no. of parents in home) Income (proportion on welfare status) Psychosocial factors (baseline) Social skills/peer relations SSRS (T) SSRS (P) No. of life stressors (all neg. events)b No. of life stressors (confounded) Family factors (environmental and genetic, baseline) Wells Parenting Index (P) Parenting Stress Index (P) Parent–child (power assertion) (P) Parent–child (positive affection) (P) Maternal depression (BDI) (P)
Variable 2.28 2.10 1.87 1.87 1.75 1.59 0.42 2.57 21.0 3.09 0.22 100 101 94.5 91.0 93.5 2.64 0.79 7.5 0.44 0.56 (1.5) 0.21 0.84 1.06 2.3 1.4 0.68 3.49 2.63 3.64 0.35
0.80 7.8 0.34 0.75 (1.7) 0.12 0.86 1.11 2.0 1.2 0.15 3.64 2.58 3.60 0.27
+Anx (81)
J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RU A RY 2 0 0 1
–0.48 3.37 2.83 3.46 0.29
0.80 0.98 2.5 1.6
0.81 7.8 0.40 0.70 (1.7) 0.20
2.21 2.12 2.04 2.04 1.85 1.80 0.41 2.46 23.8 3.33 0.13 101 102 99.1 94.4 96.4 6.96
+ODD/CD (171)
Subtype Mean Scores
2.27 1.92 2.00 1.72 1.76 1.46 0.39 2.52 18.0 2.87 0.16 101 102 99.2 95.8 96.9 0.94
ADHD (184)a
0.03 3.20 2.82 3.57 0.39
.29** –.28*** –.09 .08 –.28**
–.07 –.21* –.12 –.11
–.34*** –.50*** –.46*** –.28* –.07
–.22 –.55*** –.21** –.21**
–.20
–.23* 0.80 0.94 3.1 2.0
.03 .00 –.12 .00
–.03 –.37* –.20 –.35**
0.81 7.9 0.41 0.59 (1.5) 0.27
.09 –.32 –.05 –.43*** –.18* –.69*** –.06 .11 –.74*** –.54*** .08 .00 .00 –.01 –.10 –.04 –.76**
Cd
–.02 –.29 .17 –.20 .02 –.26* –.10 –.09 –.38*** –.26* –.17*** –.07 –.06 –.34** –.34* –.24* –.21**
Anx
Effect Sizes
2.16 2.08 2.01 2.05 1.85 1.86 0.37 2.52 27.5 3.49 0.13 101 100 96.7 93.1 94.9 8.68
+Dual (143)
–.01 .04 .09 .14 –.07
.07 .04 –.12 –.11
.10
.03 .50* .18 .00
.09 .35 –.13 .19 .02 .14 .23 –.02 –.09 .07 .17 –.07 .06 .17 .25 .13 –.00
Cd Anx
TABLE 1 Validation Criteria by Comorbidity Subtype: Mean Scores and Effect Sizes
1.84 0.535 0.542 0.494 0.291
0.278 0.235 2.42 1.90
0.393
0.40 0.808 0.489 0.567
0.652 0.627 0.765 0.751 0.512 0.494 0.311 0.532 7.83 0.853 0.361 14.8 15.6 13.8 14.0 14.2 7.94
Pooled SD
–– Continued
F = 3.96, p < .001; 8,575 F = 8.78, p < .001; 8,515 F = 4.18, p < .001; 8,552 F = 1.61, p < .119; 8,552 F = 3.22, p < .001; 8,518
F = 2.15, p < .03; 8,531 F = 8.01, p < .001; 8,514 F = 2.84, p < .004; 8,560 F = 3.37, p < .001; 8,560
F = 7.07, p < .001; 8,570
F = 1.44, p < .18; 8,570 F = 2.27, p < .03; 8,570 F = 13.7, p < .001; 8,568 F = 3.79, p < .001; 8,570
F = 1.42, p < .20; 8,560 F = 2.74, p < .006; 8,563 F = 1.82, p < .07; 8,563 F = 4.94, p < .001; 8,565 F = 2.76, p < .005; 8,547 F = 10.5, p < .001; 8,551 F = 1.72, p < .09; 8,567 F = 1.32, p < .23; 8,536 F = 17.4, p < .001; 8,422 F = 5.10, p < .001; 8,422 F = 1.16, p < .33; 8,570 F = 1.89, p < .06; 8,564 F = 2.47, p < .012; 8,564 F = 3.38, p < .001; 8,570 F = 2.04, p < .04; 8,570 F = 1.43, p < .19; 8,570 F = 17.1, p < .001; 8,570
Statistics
ADHD COMORBID SUBGROUPS
151
152
Note: For scale scores, higher scores and positive values indicate improvement/better functioning; negative scores indicate deterioration. ADHD, +Anx, +ODD/CD, and +Dual represent the four comorbidity groups, classified based on presence or absence of each comorbidity. Anx, Cd represent the dummy codes for presence/absence of each comorbidity coded and entered in multivariate analyses. Significant main effects and interactions (Anx Cd ) for comorbidity are denoted in the respective columns by asterisks to indicate level of statistical significance. * p .05; ** p .01; *** p .001. Significant differences between the ADHD + ANX and the ADHD + ODD/CD subgroups are indicated by boldface type. ADHD = attention-deficit/hyperactivity disorder; ANX = anxiety disorders; ODD/CD = oppositional defiant disorder or conduct disorder; T = teacher; P = parent; SNAP = Swanson, Nolan, and Pelham scale; CDI = Children’s Depression Inventory; MASC = Multidimensional Anxiety Scale for Children; LD = learning disability; WIAT = Wechsler Individual Achievement Test; SSRS = Social Skills Rating Scale; BDI = Beck Depression Inventory. a n’s. b Stress scores were computed first by summing only those events that were not potentially a result of subjects’ or families’ own functioning (“unconfounded”), then by summing only those events that may in fact result from families’ functioning, e.g., divorce or parental separation (“confounded”) (see Jensen et al., 1991).
1.37 0.77 1.72 1.11 F = 1.25, p < .27; 8,570 F = 2.23, p < .03; 8,570 F = 0.56, p < .81; 8,570 F = 1.39, p < .20; 8,530 .07 –.13 .06 .00 .07 .00 .00 .09 .07 –.13* –.06 –.18 1.2 0.7 1.9 2.1 1.4 0.5 1.9 1.9 1.4 0.6 2.0 2.2 1.5 0.5 1.9 2.0 Biological factors No. of prenatal problems No. of perinatal problems Total pre-perinatal problems Mat. postpartum depressive symptoms
Cd
+Dual (143) +ODD/CD (171) +Anx (81) Variable
ADHD (184)a
Subtype Mean Scores
TABLE 1 (Continued)
Anx
Effect Sizes
Cd Anx
Statistics
Pooled SD
JENSEN ET AL.
jects were more impaired (e.g., baseline hyperactiveimpulsive symptoms, overall impairment, parent–child relations, and the composite index), as well as other, quite different areas of functioning where ADHD + ANX subjects were more impaired (e.g., baseline academic performance scores, likelihood of a learning disability diagnosis, less improvement in teacher-rated inattention by 14 months, and less improvement in the composite index). Are the Two Forms of Comorbidity Simply “Additive”? Turning to the multivariate analyses to explore additive and interactive effects of the two forms of comorbidity, columns 5 through 7 in Table 1 indicate significant main (Anx, Cd ) and interactive (Anx Cd ) effects. Significant effects are labeled with asterisks to denote levels of significance. There were 22 variables in which there were significant effects of comorbidity on baseline characteristics and 7 additional instances of effects of comorbidity on outcomes (not shown here, but available upon request). Of note, across these variables, only 7 instances of additive effects of comorbidity were found (characterized by significant effects being noted in both columns 5 and 6—parent total SNAP scores, overall impairment, need for services, parent-rated social skills, the Parenting Stress Index, the Wells parenting factor, and the composite index). Note that none of the measures, except the parent total SNAP, attempt to measure psychopathology directly; rather, they are general indices of the overall impact of psychopathology on impairment, need for services, and families. These findings indicate that while the two different forms of comorbidity/psychopathology are not additive per se, their combined impacts on external factors such as overall impairment, family burden, and services use may be. Apart from the 7 variables for which additive effects were found, findings from Table 1 and our outcome criterion analyses revealed that Anx comorbidity exerted main effects on either baseline or outcome variables in 12 instances, while Cd exerted effects on 9 other variables. Thus, the most common main effects of Anx and Cd comorbidity were noted on different variables, suggesting quite different symptom profiles of subjects, depending on their particular comorbidity subgroup. Do Comorbid Subgroups Differ in Response to Specific Treatments? Table 2 presents findings concerning the response to treatment criterion among all three MTAdelivered interventions (versus CC), examined via the multivariate analyses. Turning first to the issue of unique effects of treatments on comorbid subgroups, such patterns are revealed by letters B (Beh), M (MedMgt), and C J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
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TABLE 2 Response to Treatment by Comorbidity Subtypes: Difference Scores (Baseline Minus 14 Months) Mean Scores ADHD (184)a
+Anx (81)
+ODD/CD (171)
+Dual (143)
Inattentive (T) Inattentive (P) Hyperactive-impulsive (T) Hyperactive-impulsive (P) Oppositional aggressive (T) Oppositional aggressive (P) Total SNAP symptoms (T) Total SNAP symptoms (P) Aggression (P) Internalizing symptoms (T) Internalizing symptoms (P) MASC (child) CDI (child) Columbia Impairment Scale Needs services (P) Social skills (T) Social skills (P) Overall composite
0.90 0.71 0.98 0.70 0.49 0.29 0.78 0.56 0.05 0.12 0.15 0.23 0.15 5.8 0.76 0.23 0.14 7.5
0.78B,M 0.77B 0.85 0.79B 0.42B 0.31 0.64B,M 0.59B 0.05 0.24M 0.14B 0.25 0.14 5.4B 0.95 0.24B 0.06 8.5B
0.83 0.81 0.93 0.86 0.54 0.55 0.75 0.70 0.09 0.15 0.22 0.25 0.14 7.6 0.67 0.25 0.16 9.1
0.91 0.78B 0.99 0.81C 0.62 0.58 0.85 0.70B 0.11 0.07 0.32B 0.16 0.11 9.7 0.92 0.30 0.17 8.6B
P-C power assertion P-C positive affection WIAT Math WIAT Spelling WIAT Reading LD at 14 mo (proportion) ADHD at 14 mo
0.22 0.01 2.5 0.7 1.4 0.10 0.42
0.20, 0.07 3.7B 2.7B,C 1.2 0.16 0.57
0.32 0.04 1.0B,M 1.0 1.4 0.08 0.50
0.31 0.05 2.5 1.0 1.2 0.16 0.55
Main Effects of Comorbid Group on Outcomes? ADHD+Anx
ADHD+Anx+ODD/CD ADHD+Anx+ODD/CD ADHD+ODD/CD ADHD+Anx ADHD+Anx+ODD/CD ADHD+Anx+ODD/CD
ADHD+Anx, ADHD+ Anx+ODD/CD
ADHD+Anx
Statistics F = 1.47, p < .09; 20,557 F = 3.44, p < .001; 20,555 F = 1.64, p < .04; 20,557 F = 4.01, p < .001; 20,555 F = 1.68, p < .03; 20,557 F = 3.08, p < .001; 20,555 F = 2.22, p < .002; 20,557 F = 4.45, p < .001; 20,555 F = 1.59, p < .05; 20,558 F = 1.55, p < .06; 20,524 F = 3.34, p < .001; 20,547 F = 1.17, p < .27; 20,524 F = 1.40, p < .12; 20,555 F = 4.23, p < .001; 20,470 F = 2.92, p < .001; 20,558 F = 1.68, p < .03; 20,519 F = 1.55, p < .05; 20,548 F = 4.41, p < .001; 20,558 F = 1.50, p < .08; 20,544 F = 0.70, p < .83; 20,554 F = 1.55, p < .06; 20,558 F = 0.94, p < .53; 20,558 F = 1.48, p < .08; 20,558 F = 1.28, p < .19; 20,558 F = 3.63, p < .001; 20,558
Note: Boldface values indicate that the MTA treatment type (B = behavioral therapy; M = medication management; C = combined treatment) exerted difference effects on the particular comorbidity groups in that column, compared with the overall effects of that same treatment for all subjects, irrespective of comorbidity profile. ADHD = attention-deficit/hyperactivity disorder; ANX = anxiety disorders; ODD/CD = oppositional defiant disorder or conduct disorder; T = teacher; P = parent; SNAP = Swanson, Nolan, and Pelham scale; MASC = Multidimensional Anxiety Scale for Children; CDI = Children’s Depression Inventory; WIAT = Wechsler Individual Achievement Test; LD = learning disability. a n’s.
(Comb) in the columns denoting the comorbidity subtypes. All comorbidity group effects are presented vis-à-vis comparisons to the ADHD-only group. Likewise, treatment effects are presented with reference to the CC group. Of note in the table are the commonly found, differentially beneficial effects of Beh interventions for the ADHD + ANX group. These interactions are indicative of treatment effects over and above the main effects of all treatments for the entire sample (irrespective of comorbidity), beyond Beh treatment benefits for the entire sample, and even distinct from the impact of Comb and MedMgt treatments on the ADHD + ANX subgroup itself. The second finding revealed in Table 2 is that dually comorbid subjects also evidenced a substantial benefit from specific treatments, sometimes Comb, sometimes J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RU A RY 2 0 0 1
Beh, while ADHD + ODD/CD subjects rarely showed a differential response to any of the treatments, compared with ADHD-only subjects. The right-hand column of Table 2 indicates whether there were any main effects of comorbidity subgroup on treatment outcomes. Of note, seven of these eight instances were found among subjects with comorbid anxiety (ADHD + ANX or ADHD + ANX + ODD/CD subtypes). Inspection of actual means revealed that these two groups generally showed the greatest response to treatments (not shown here, but tables available from the authors upon request), regardless of treatment type. How Large and Clinically Meaningful Are Comorbidity Subgroup Effects? The size and statistical significance of comorbidity effects on baseline characteristics (Table 1) 153
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can be seen in the right-hand column of the table. Review of Table 1 suggests that the effects of Cd comorbidity are generally more pronounced than Anx effects on baseline characteristics and are generally associated with greater levels of symptoms (e.g., hyperactive-impulsive symptoms), lower levels of functioning (teacher-rated social skills), and overall impairment. Important exceptions were noted in academic functioning, where ADHD + ANX subjects evidenced sizable effects with lower functioning levels. Further review of this table also indicates that in almost all instances of additive effects of the two comorbid conditions (parent total SNAP scores, impairment, need for services, teacher-rated social skills, and the composite index), effects exerted by Cd were 2-fold or more larger than those conveyed by Anx. Analyses of effect sizes of the outcomes criterion revealed few instances of comorbidity effects on outcomes independent of MTA treatments. Important exceptions are the relative lack of improvement over time in teacherreported inattention and the overall composite index among ADHD + ANX and ADHD + ANX + ODD/CD subjects (table available upon request). Effect sizes based on comorbidity profiles on the treatment response criterion are much more complex, since any given variable could have 12 different effect sizes (3 MTA treatments 4 comorbidity profiles). Therefore, effect sizes for selected variables where comorbidity treatment interactions were noted in Table 2 are presented in graphic form in Figure 1. Review of this figure indicates that ADHD + ANX subjects are particularly responsive to Beh, compared with subjects in other comorbidity groups, which rarely did as well (i.e., effect size > 0.4) with Beh alone. Figure 1 also indicates that ADHD + ANX + ODD/CD subjects were preferentially responsive to Comb interventions, as indicated by a robust response (effect size = 0.92) to Comb and much lower effect size for Beh (0.53) and MedMgt (.28) in the overall composite rating. By and large, the effect sizes of ADHD-only and ADHD + ODD/CD subjects were generally lower than those for ADHD + ANX and ADHD + ANX + ODD/CD subjects. For ADHD-only and ADHD + ODD/CD subjects, Beh alone interventions never appeared beneficial. DISCUSSION
Our findings suggest that ADHD children with and without ODD/CD and ANX differed on many baseline characteristics, outcomes, and response to treatment. 154
Though ODD/CD comorbidity commonly exerted fairly powerful main effects on baseline characteristics, it rarely interacted with treatment response or outcomes. In contrast, Anx conditions exerted somewhat less robust effects on baseline characteristics, but frequently interacted with response to specific treatments. Concerning our subtype hypothesis, while both Anx and Cd frequently exerted straightforward main effects, their effects usually did not operate on the same variables. Thus such effects were found in only six instances of all variables examined, and these variables pertained more to the impact of psychopathology than psychopathology per se. Taken together, our findings—consistent differences between ADHD + ANX and ADHD + ODD/CD groups, rarely found additive effects, the impact of Cd and Anx on different variables, and the differential impact of specific treatments on the four comorbidity types, with some but not all treatments yielding effects of sizable magnitude—indicate that the overall clinical profiles of the comorbidity types are sufficiently distinct to support the need to discriminate among the comorbid subgroups. Consistent with our first report of parent-reported anxiety as a moderating variable on outcomes (MTA Cooperative Group, 1999b), we found substantial, recurring indications of Anx comorbidity (either alone or in interaction with Cd ) moderating responses to treatment. In addition, however, this analysis, going well beyond our earlier report, suggests that anxiety may interact with treatment outcomes across many more variables than first described, more readily detectable here with Anx Cd interactions included in the analytic model. It is of interest to note that Anx exerted relatively modest effects on baseline characteristics and outcomes, yet exerted persistent, sometimes sizable effects on response to treatment findings. Reasons for this finding are unclear, but could be due to the fact simply that behavioral interventions are selectively effective for ADHD children with parent-defined anxiety and that these children are qualitatively different in terms of etiological processes and developmental trajectories. This possibility of qualitative differences in these children is further supported by the findings of WIAT score differences seen in these subjects at baseline, as well as evidence from other reports that such children may have different physiological reactions to methylphenidate (Urman et al., 1995). As a general rule, ANX status appeared to confer certain benefits on ADHD children, regardless of the presence of ODD/CD. Thus, inspection of Table 1 and our J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
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Fig. 1 Comorbidity type by treatment response: effect sizes across six variables. SNAP = Swanson, Nolan, and Pelham scale; ADHD = attention-deficit/hyperactivity disorder; DBD = disruptive behavior disorders; Beh = behavioral therapy; MedMgt = medication management; Comb = combined treatment.
outcomes criterion analyses (available upon request) indicates that most (40 of 58) Cd Anx interaction effects were positive (though rarely significant), that is, they exerted ameliorating effects on concurrent ODD/CD (i.e., ADHD + ANX + ODD/CD versus ADHD + ODD/CD subjects). Furthermore, review of Figure 1 indicates that children with Anx tended to be more treatment-responsive than ADHD + ODD/CD and even ADHD-only subjects, both in terms of absolute effect sizes and in terms of their relatively robust response to all J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RU A RY 2 0 0 1
treatment modalities. The ADHD + ANX group in particular responded to almost any of the three treatments, with the single exception of academic performance, where possible adverse effects of medication management were noted in the ADHD + ANX group, of some interest given historical reports of adverse effects of medication treatments on learning. In contrast, ADHD + ANX + ODD/ CD subjects in a number of important instances appeared to derive substantially greater benefits from Comb interventions compared with all other treatments, thus provid155
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ing some justification of their separate classification from ADHD + ANX subjects. ADHD-only and ADHD + ODD/CD subjects responded usually only to interventions that included medication. While ADHD-only and ADHD + ODD/CD subjects appeared quite similar in terms of degree of clinical change in response to treatment and outcomes, the sizable baseline differences in severity between these two groups indicates a more problematic prognosis for the ADHD/CD group. In fact, additional analyses of outcomes and response to treatment based solely on absolute levels of 14-month symptoms (rather than difference scores) revealed that these two groups continued to show substantial differences at endpoint on a number of critical variables, such as parent-reported aggression, need for services, impairment, social skills, parent–child relations, and the overall composite index (tables available from the authors upon request). These persistent differences in prognosis may justify the separate classification of these two profiles. Limitations
In consideration of our findings, a number of caveats must be carefully weighed. First, ours was a referred sample, so any inferences that these findings are applicable to ADHD comorbidity patterns in the general community are not warranted. In addition, our analyses of the outcomes criterion “independent of treatment” (i.e., with CC subjects only) must be viewed with caution because most CC subjects did indeed obtain some form of treatment, and our preliminary findings suggest that those seeking treatment benefited slightly more than those who did not seek care (MTA Cooperative Group, 1999a,b). Another word of caution is warranted concerning those analyses suggesting differential response to treatments as a function of comorbidity, particularly anxiety. As noted elsewhere, very little overlap is found between parentand child-identified anxiety syndromes (e.g., Jensen et al., 1999). This issue is of consequence because our additional analyses (March et al., 2000) of the moderator effects of anxiety on MTA outcomes indicate that in contrast to parent-reported anxiety comorbidity, childreported anxiety syndromes exert little if any moderating effects on MTA outcomes. Thus it remains unclear whether the moderating effects of anxiety reported here apply to anxiety disorders per se, or to some broader construct of parent-identified behavioral and affective dysregulation. Relatedly, it should be noted that we found 156
substantially lower rates of affective disorder in the MTA sample than have been reported in other clinical studies (e.g., Biederman et al., 1991), raising concerns about the possibility of underdiagnosis of these conditions, or alternatively, comorbidity differences between the MTA sample (which drew from a broad range of referral sources) versus samples that have drawn principally from mental health settings. We note that our decision to combine CD and ODD cases into a single disruptive disorder category is not without controversy. However, evidence from clinical studies suggests that most ADHD children with comorbid CD also often meet criteria for ODD, which has in fact usually preceded CD onset by several years (e.g., Biederman et al., 1996). On the other hand, a number of population-based studies have suggested that ODD and CD, while intercorrelated 0.70 to 0.76, may nonetheless constitute somewhat separate dimensions of psychopathology (Quay, 1999). Our decision to combine these two disorders reflects in part the substantial (but incomplete) overlap between the two disorders, as well the lack of power to examine CD as a separate disorder, given our sample sizes. A final note of caution concerns the use of clinical samples to explore comorbidity. As noted by Angold et al. (1999), clinical samples can be burdened by methodological artifacts, potentially leading to incorrect estimates of comorbidity rates and even mistaken etiological inferences. Nonetheless, clinical studies of comorbidity can be useful to the extent that the conclusions from such studies are intended to apply only to other clinical samples. In this regard, the MTA’s inclusion and exclusion criteria, such as admitting only children with ADHD combined type and excluding children with psychosis, with Tourette’s disorder, or concurrently being treated with antipsychotic medications, demarcate some of the possible limitations concerning inferences that might be drawn to more heterogenous clinical samples. Clinical Implications
Our findings may have considerable implications for future research and treatment studies, as well as for the clinical process of matching of patients to treatments. As constructed, our comorbidity groups appear to differ in a number of areas, including several notable baseline characteristics, response to treatment, and outcomes. ADHD children with parent-defined anxiety disorders, particularly those with no accompanying ODD/CD, may have a number of unique characteristics, most notably seen in WIAT J . A M . A C A D . C H I L D A D O L E S C . P S YC H I AT RY, 4 0 : 2 , F E B RUA RY 2 0 0 1
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performance scores at baseline (also reported by Livingston et al., 1990) and at 14 months. In addition, this group evinces a clinical profile that is not a simple function of how it was originally formed (persistent ADHD, teacherreported inattention at 14 months), and perhaps most importantly, in its differential response to treatment. While the discriminating responses to treatments (especially the behavioral components of Beh and Comb) were frequently shared between the ADHD + ANX and ADHD + ANX/ CD groups (suggesting a main effect of Anx status), additional interactions with treatment response were found by separating Anx children into the ADHD + ANX and ADHD + ANX/CD groups, compared with our original report (MTA Cooperative Group, 1999b). A simple “rule of thumb” that summarizes these findings suggests that if a child presents with an ADHD + ANX profile, all interventions are likely to be effective. If a child presents with ADHD-only or ADHD + ODD/ CD, treatments with medication appear especially indicated, and Beh alone strategies may be contraindicated. Finally, if a child presents with ADHD + ANX + ODD/ CD, Comb interventions may offer substantial advantages over other treatments, particularly in overall impairment and functioning outcomes. Our findings suggest that more precise matching of patients to treatment using patients’ comorbidity profiles may mitigate initial clinical uncertainty, reduce the number of therapeutic trials until a workable treatment is found, and yield larger treatment gains for specific patients. Future pathophysiological and genetic studies may benefit by these discriminations, to the extent that these clinical profiles reflect different etiological and developmental processes. The NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) is a cooperative treatment study performed by six independent research teams in collaboration with the staff of the Division of Services and Intervention Research of the NIMH, Rockville, MD, and the Office of Special Education Programs (OSEP) of the U.S. Department of Education (DOE). The NIMH Principal Collaborators are Peter S. Jensen, M.D., L. Eugene Arnold, M.Ed., M.D., John E. Richters, Ph.D., Joanne B. Severe, M.S., Donald Vereen, M.D., and Benedetto Vitiello, M.D. Principal Investigators and Coinvestigators from the six sites are as follows: University of California at Berkeley/San Francisco (UO1 MH50461): Stephen P. Hinshaw, Ph.D., Glen R. Elliott, M.D., Ph.D.; Duke University (UO1 MH50447): C. Keith Conners, Ph.D., Karen C. Wells, Ph.D., John S. March, M.D., M.P.H.; University of California at Irvine/Los Angeles (UO1 MH50440): James M. Swanson, Ph.D., Dennis P. Cantwell, M.D., Timothy Wigal, Ph.D.; Long Island Jewish Medical Center/Montreal Children’s Hospital (UO1 MH50453): Howard B. Abikoff, Ph.D., Lily Hechtman, M.D.; New York State Psychiatric Institute/Columbia
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University/Mount Sinai Medical Center (UO1 MH50454): Laurence L. Greenhill, M.D., Jeffrey H. Newcorn, M.D.; University of Pittsburgh (UO1 MH50467): William E. Pelham, Ph.D., Betsy Hoza, Ph.D. Helena C. Kraemer, Ph.D. (Stanford University) is statistical and design consultant. The OSEP/DOE Principal Collaborator is Ellen Schiller, Ph.D.
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