Using the 18 VAS-P items for inattention, impulsivity, and hyperactivity, we produced similar clustering patterns (i.e., six to eight clusters and similar cluster definitions), as shown in other LCA studies of ADHD symptoms.8,10–14,46
Because the VAS-P has not been used for this purpose in adults and symptom severities are known to differ among age groups, we performed LCA separately for children, adolescents, and adults. Although the age groups differed on certain hyperactivity symptoms, overall the symptom-clustering patterns between age groups were strikingly similar.
Adding comorbidities had little effect on the cluster distributions. This comparability of symptom profiles among age groups with a broad range of internalizing and externalizing symptoms supports the use of LCA in genetic cohorts that include both adults and children.
We used a specific ascertainment process, particular features of which are recruitment of patients based on a voluntary agreement to participate in a study that did not involve help seeking or interventions, making the presence of familial clustering a condition for participating in the study, recruitment not targeting any particular population (participating families came from throughout the United States), most families were successfully enrolled in a standard program of clinical support and were not actively seeking additional support or intervention, and prevalence of comorbidities such as CD was low (3%) compared to clinically referred samples, but similar to the epidemiological prevalence.25
A limitation of our study is that because this sample is family based, the LCA independence assumption is violated. To address this, we created a covariate controlling for coancestry. Maximization of models while considering this covariate did not incur any qualitative change in clustering. Differences among models with the coancestry covariate present and absent were compared by means of parametric bootstrap. In addition, empirical analyses on multigenerational and extended pedigrees in which only a small number of categories are present have confirmed our view that this violation of LCA assumption is not fatal (data not shown).
Beyond replicating the basic clustering pattern found in other studies, we also confirmed the observation47
that a substantial proportion of individuals who are classified as unaffected according to DSM-IV
criteria nevertheless cluster in latent categories exhibiting symptoms associated with clinical impairment. These results suggest that the application of DSM-IV
ADHD criteria likely underestimates the prevalence of clinically impaired individuals, some of whom may carry genetic risk factors for ADHD. Volk et al.15
also found that despite not meeting formal DSM-IV
criteria, individuals clustering in the mild combined latent class, a form of ADHD undetected by current DSM-IV
criteria, showed evidence of educational and psychological impairment. Thus, the extension of LCA methods to clinical settings may have utility in allowing the identification of individuals who could benefit from clinical attention. Results from LCA using Dutch twins with the Conners Rating Scale show stability across informants, suggesting that more stable phenotypes may be accessible for genotyping using a multi-informant approach.48
In addition, LCAs have already demonstrated the utility of the population-based phenotype approach to identified potential genetic markers for ADHD.49,50
The traditional classification according to the DSM-IV
criteria, useful in clinical assessment, may introduce uncertainty into studies of subtype etiology. Todd et al.49,50
reported a significant association between specific clusters using LCA and some ADHA
candidate genes. Those associations were not previously found in the same data using the traditional approach and subtype classification according to the DSM-IV
. Use of alternative population-based defined ADHD subtypes may help to resolve some of the variation in results presented for candidate gene association studies in ADHD.
Although adding the symptoms of common comorbid conditions did not have much effect on the underlying clustering patterns, LCA supports some observations regarding comorbid conditions. Our group has already demonstrated the presence of genetic linkage between ODD, CD, and alcohol and nicotine abuse with specific genetic markers in a sample ascertained in a genetic isolate from ADHD probands.17
ADHD plus CD is a comorbid subgroup characterized by earlier age at onset, poor school performance, high male-to-female ratio, greater risk for drinking while driving, subsequent substance abuse, development of antisocial personality, and decreased likelihood of eventual remission compared to individuals affected by ADHD alone.51
Although consensus has yet to be attained regarding whether ADHD plus CD should be considered a separate entity, some have suggested that it is a distinct clinical subtype.52
In our population, the frequency of CD is lower compared with other studies.22,53
However, the distribution of clusters still fits similar patterns described by other investigators.22
In our population, most of the individuals affected with CD correspond to the combined subtype in all ages.
Another interesting finding in our clinical sample was the pattern of splitting of the severe combined ADHD cluster when externalizing (ODD and CD) and internalizing (anxiety disorders and depression) symptoms were included in the LCA. A previous LCA study in a sample of female twins also found that ODD symptoms are not only associated in the context of ADHD combined type but also in a subgroup of ADHD predominantly inattentive type.14
Different patterns of splitting were noted in the three age groups. In children, severe cases of ADHD with high levels of ODD endorsement appeared to differ primarily to internalizing behaviors, particularly in those items most directly related to anxiety. This pattern was not seen in adolescents and adults. In these age groups, severe cases were largely distinguished by the presence or absence of externalizing behaviors.
We did not find correlations between the diagnosis of dysthymic disorder per the DICA and the screening criteria for internalizing disorders in the VAS-P.34
Similar patterns of behaviors may represent different psychopathologies, and parents sometimes underreport internalizing symptoms in their children or adolescents.24,54
The causal relationship between anxiety disorder and ADHD is unclear, although its implications for diagnosis, etiology, and intervention have long been described in the literature.24,28,29,54
One possibility is that common genetic loci may confer increased risk of both internalizing disorders and ADHD. Levy55
suggested a mechanism whereby differences in mesolimbic system function may play a role in the expression of anxiety in patients with ADHD.
In summary, our data suggest that LCA can feasibly allow the combination of internalizing and externalizing symptoms for future tests of hypotheses regarding specific genetic risk factors.