Six limitations are noteworthy. First, diagnoses were based on fully-structured lay interviews. These typically produce more reliable (i.e., reproducible across multiple interviewers) diagnoses than semi-structured clinical interviews46
and their prevalence estimates typically correspond well with those based on clinical interviews.47
However, fully-structured interviews, unlike semi-structured clinical interviews, are unable to clarify symptom responses or check questions across disorders to facilitate differential diagnosis, potentially leading to inflated estimates of comorbidity. Second, disorders were assessed dichotomously rather than dimensionally, presumably reducing our ability to detect for subtle aspects of structure in the data. This might help explain why we did not detect higher-order sub-factors in the two-factor exploratory factor analysis model. Third, data were combined across countries with very different cultures and across surveys with very different response rates (which could have introduced variation in sample selection bias), different rates of sample exclusion (due to cross-national differences in rates of suicide, homelessness, and institutionalization), and different languages in which interviews were administered. Even though every effort was made to make the translations as comparable as possible,34
residual variation in meaning almost certainly contributed to cross-national variation in results.
Fourth, lifetime diagnoses were based on retrospective reports rather than prospective assessments, probably leading to recall bias that under-estimated prevalence48
and distorted age-of-onset estimates49
despite the use of special memory priming methods.38
Bias in model coefficients might have varied across disorders as a function of age of onset and/or recency. Given the importance of this potential bias, it is noteworthy that the onset distributions based on these retrospective data are quite consistent with those based on prospective studies and studies carried out at separate life course stages.50
In addition, model coefficients in subsamples defined by life course stage are very consistent, suggesting that variation in recall across the sample age range does not importantly influence results. Fifth, models were based on the simplifying assumptions that the time-lagged associations among mental disorders are constant across countries and gender, stable across the life course, and unrelated either to age-of-onset or time-since-onset of the predictor disorders. Preliminary analyses showed that these assumptions are a reasonable first approximation, but the investigation of these specifications needs to be a focus of ongoing WMH analysis. Sixth, we did not take history of treatment into consideration even though early treatment, which varies in frequency across countries,51
might interrupt the progression of comorbidity and thereby distort estimates of predictive associations.
In the context of these limitations, our finding of a two-factor internalizing-externalizing structure among WMH disorders is consistent with previous research,4–9
but does not support the distinction in some previous studies between distress (e.g., depression, GAD, PTSD) and fear (i.e., panic and phobias) disorders. As noted in the introduction, others also failed to find a distinction between distress and fear disorders.16, 52
This less differentiated structure in the WMH data might be due to our focus on lifetime disorders, whereas 12-month disorders were the focus of most studies that distinguished distress and fear disorders.
Our finding of significant time-lagged associations across virtually all pairs of the disorders considered here is broadly consistent with evidence of associations between earlier and later disorders in previous longitudinal studies,18–23
although most previous studies focused on prevalent cases whereas we studied first onsets. We found, again consistent with previous studies, stronger and more consistent time-lagged associations within than between the internalizing and externalizing domains. However, again like previous studies, we also found significant between-domain time-lagged associations.22, 23
Our analysis then went beyond previous studies to investigate the role of latent variables in the development of comorbidity. We showed that the vast majority of the 306 pair-wise time-lagged associations among the 18 disorders considered here can be explained by a model that assumes the existence of mediating latent internalizing and externalizing variables. This finding extends previous cross-cultural work on the structure of comorbidity.53
The fact that the predictive associations across this large number of disorders is mediated by two higher-order variables makes the internalizing and externalizing spectrum dimensions compelling targets for inquiry aimed at reducing burden of mental disorder around the world by interrupting the processes leading to the onset of comorbidity.
Specific phobia and OCD stood out as the most important internalizing predictors and HD and ODD the most important externalizing predictors. The time-lagged associations involving these four predictors were largely mediated by the latent variables, with only two of the 13 significant residual associations involving these four strongest predictors (HD predicting AD and BPD). Both of these were positive, showing that the comparatively high ORs of these four predictor disorders are relatively constant across the range of WMH outcomes. Although it is unclear why specific phobia and OCD should be the most important predictors among the internalizing disorders or HD and ODD among the externalizing disorders, the fact that all four are typically early-onset disorders50
means they might be useful markers of youth at high risk for progression to later disorders. Even this possibility requires further analysis, though, as we did not investigate non-proportional hazards that might include differential predictive associations related to age-of-onset or time-since-onset. These more in-depth analyses go beyond the scope of this first report, but will be pursued in ongoing WMH analyses.
Our finding of 13 significant residual associations shows that the latent variables do not explain all the comorbidity among the disorders considered here. The four negative residual associations are most plausibly interpreted as suggesting the existence of more differentiated dimensions underlying internalizing and externalizing disorders. The negative association of IED with subsequent drug abuse, for example, could be due to externalizing disorders being made up of multiple dimensions, one or more of which is significantly more strongly related to drug abuse than to IED. Evidence consistent with this possibility exists in the literature54–56
The negative residual association of CD2 (overt CD) with subsequent PTSD, in comparison, might be related to the findings that blunted
psychophysiological and emotional reactivity to fear stimuli are predictors of CD57, 58
physiological reactivity to trauma-related stress cues is a predictor of PTSD.59, 60
These observations suggest that a more differentiated latent variable model that includes internalizing and externalizing sub-dimensions might explain the significant negative associations found here in the less differentiated WMH latent variable model.
The positive residual associations in the WMH data, in comparison, are most plausibly interpreted as disorder subtypes rather than comorbidities, including the reciprocal associations between CD1 (covert CD) and CD2 (overt CD) and between AD and HD, or a severity marker in the association between panic disorder and subsequent agoraphobia. At least one other association, between agoraphobia and subsequent specific phobia, could be due to diagnostic confusion in the CIDI. The same kind of confusion might account at least in part for the positive association between HD and subsequent BPD, as differentiation between these two disorders can be difficult, especially within the constraints of a fully-structured diagnostic interview,61, 62
although a number of common neurobiological correlates have also been found for HD and BPD,63, 64
arguing that ADHD might be a risk marker for BPD. The WMH finding that this association is specific to HD and does not apply to AD has not to our knowledge been investigated previously.
It is important to caution that these few unique significant residual pair-wise associations should be treated as no more than preliminary due to the problem of multiple testing and the limitations noted at the beginning on this section. Replication in other datasets, most importantly prospective datasets, is needed before these associations should be considered reliable. Furthermore, even if they are subsequently found to be reliable, their existence should not deflect attention from our main finding: that the consistently significant comorbidities found among the 306 disorder-pairs considered here are likely due to common underlying processes that should be a major focus of future research on the development of comorbidity. One important implication of this finding is that future research on specific pair-wise comorbid associations needs to guard against interpreting results as unique without first demonstrating, as we did here, that they are specific rather than mere realizations of larger processes involving all internalizing and/or externalizing disorder. The fact that we found only two factors, finally, does not mean that only two underlying processes are at work, as multiple processes could underlie each factor and these diverse processes need to be studied in order to enrich our understanding of the causal influences leading to the higher-order structure found here.