Objective Identify diagnostic risk factors of mania/hypomania in the offspring of parents with bipolar disorder (“high-risk offspring”). Method High-risk offspring aged 6-18 years (n=391) and demographically-matched offspring (n=248) of community parents without bipolar disorder were assessed longitudinally with standardized diagnostic instruments by staff blind to parental diagnoses. Follow-up assessments were completed in 91% of the offspring (mean interval 2.5 years; mean duration 6.8 years). Results High-risk offspring, as compared to community offspring, had significantly higher rates of subthreshold (hypo)manic (13.3% vs. 1.2%, p<.0001), manic/hypomanic (9.2% vs. 0.8%, p=.0003) and major depressive episodes (32.0% vs. 14.9%, p<.0001). They also had higher rates of attention-deficit hyperactivity (30.7% vs. 18.2%, p=.01), disruptive behavior (27.4% vs. 15.3%, p=.03), anxiety (39.9% vs. 21.8%, p=.0002), and substance use disorders (20.0% vs. 10.1%, p=.008), but not unipolar major depressive disorder (major depression with no bipolarity; 18.9% vs. 13.7%; p=.10). Multivariate Cox regressions in the high-risk offspring showed that subthreshold (hypo)manic episodes (Hazard Ratio 2.29, p=.03), major depressive episodes (Hazard Ratio 1.99, p=.05), and disruptive behavior disorders (Hazard Ratio 2.12, p=.03) were associated with subsequent mania/hypomania. Only subthreshold (hypo)manic episodes (Hazard Ratio 7.57, p<.0001) were associated when analyses were restricted to prospective data. Conclusions Subthreshold (hypo)manic episodes were a diagnostic risk factor for the development of mania/hypomania in the offspring of parents with bipolar disorder, and should be a target for clinical assessment and future treatment research. Major depressive episodes and disruptive behavior disorders are also indications for close clinical monitoring of emergent bipolarity in high-risk offspring.

The effects of psychotropic medications, when present, are predominantly normalizing and thus do not seem to provide an alternative explanation for differences in volume, white matter tracts, or BOLD signal between BD participants and healthy subjects. However, the normalizing effects of medication could obfuscate differences between BD and healthy subjects, and thus might lead to type II errors.

Objective We aimed to assess dimensional symptomatic predictors of new-onset bipolar spectrum disorder in youth at familial risk of bipolar disorder (“at-risk” youth). Method Offspring aged 6–18 of parents with bipolar-I/II disorder (n=391) and offspring of community controls (n=248) were recruited without regard to non-bipolar psychopathology. At baseline, 8.4% (33/391) of offspring of bipolar parents had bipolar spectrum; 14.7% (44/299) of offspring with follow-up developed new-onset bipolar spectrum (15 with bipolar-I/II) over eight years. Scales collected at baseline and follow-up were reduced using factor analyses; factors (both at baseline and visit proximal to conversion or last contact) were then assessed as predictors of new-onset bipolar spectrum. Results Relative to community control offspring, at-risk and bipolar offspring had higher baseline levels of anxiety/depression, inattention/disinhibition, externalizing, subsydromal manic, and affective lability symptoms (p<.05). The strongest predictors of new-onset bipolar spectrum were: baseline anxiety/depression, baseline and proximal affective lability, and proximal subsyndromal manic symptoms (p<.05). While affective lability and anxiety/depression were elevated throughout follow-up in those who later developed bipolar spectrum, manic symptoms increased up to the point of conversion. A path analysis supported the hypothesized model that affective lability at baseline predicted new-onset bipolar spectrum, in part, through increased manic symptoms at the visit prior to conversion; earlier parental age of mood disorder onset also significantly increased risk of conversion (p<.001). While youth without anxiety/depression, affective lability, and mania (and with a parent with older age of mood disorder onset) had a 2% predicted chance of conversion to bipolar spectrum, those with all risk factors had a 49% predicted chance of conversion. Conclusions Dimensional measures of anxiety/depression, affective lability, and mania are important predictors of new-onset bipolar spectrum in this population of at-risk youth. These symptoms emerged from among numerous other candidates, underscoring the potential clinical and research utility of these findings.

Recent criticism of epidemiologic methods has focused on the limitations of 'black box' epidemiology, a pejorative label given to the simple identification of exposure-disease relationships. The assessment of mediation is an important tool for addressing this criticism. By using mediation analysis to open the black box, underlying mechanisms of the observed associations can be described and causal inference improved. An explicit theoretical motivation for such an analysis has been missing from the epidemiological literature. To provide this motivation, we integrate literature from epidemiology and other social sciences to describe the reasons that an investigator might want to assess mediation. We then describe the connections between these reasons and specific measures of indirect and direct effects that have been previously described.

This risk calculator provides a practical tool for assessing the probability that a youth at familial risk for BPSD will develop new-onset BPSD within the next 5 years. Such a tool may be used by clinicians to inform frequency of monitoring and treatment options and for research studies to better identify potential participants at ultra high risk of conversion.

BackgroundManganese is a common natural contaminant of groundwater in Bangladesh. In this cross-sectional study we assessed the association between water manganese and all-cause infant mortality in the offspring of female participants in the Health Effects of Arsenic Longitudinal Study Cohort.MethodsIn 2001, drinking water samples were collected, a history of well use was obtained, and a history of birth outcomes was ascertained. To avoid misclassification of exposure, women were included only if they had been drinking from the same well for most of their childbearing years (marriage years – well years ≤ 2). Of a total of 26,002 births (among 6,537 mothers), 3,837 children were born to women with this profile. The current analysis was based on the portion of these infants (n = 3,824) with recorded exposure and outcome status, 335 of whom died before reaching 1 year of age.ResultsInfants exposed to water manganese greater than or equal to the 2003 World Health Organization standard of 0.4 mg/L had an elevated mortality risk during the first year of life compared with unexposed infants [odds ratio (OR) = 1.8; 95% confidence interval (CI), 1.2–2.6]. Adjustment for water arsenic, indicators of social class, and other variables did not appreciably alter these results. When the population was restricted to infants born to recently married parents (marriage year 1991 or after), this elevation was more pronounced (OR = 3.4; 95% CI, 1.5–7.9).ConclusionsThese preliminary findings indicate a possible association between manganese exposure and infant mortality. However, given the methodologic limitations of this study, the association needs to be confirmed through future work.

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