Abstract
BackgroundAnxiety is associated with mood disorders including bipolar disorder. Two statistical modelling frameworks were compared to investigate the longitudinal relationship between repeatedly measured anxiety symptoms and the onset of depression and bipolar disorder in youth at confirmed familial risk.MethodsProspectively collected data on 156 offspring of a parent with confirmed bipolar disorder participating in the Canadian Flourish high-risk offspring longitudinal cohort study were used for this analysis. As part of the research protocol at approximately yearly visits, a research psychiatrist completed the HAM-A and a semi-structured diagnostic research interview following KSADS-PL format. Diagnoses using DSM-IV criteria were made on blind consensus review of all available clinical information. We investigated two statistical approaches, Cox model and Joint model, to evaluate the relationship between repeated HAM-A scores and the onset of major depressive or bipolar disorder. The Joint model estimates the trajectory of the longitudinal variable using a longitudinal sub-model and incorporates this estimated trajectory into a Cox sub-model.ResultsThere was evidence of an increased hazard of major mood disorder for high-risk individuals with higher HAM-A scores under both modelling frameworks. After adjusting for other covariates, a one-unit increase in log-transformed HAM-A score was associated with a hazard ratio of 1.74 (95% CI (1.12, 2.72)) in the Cox model compared to 2.91(95% CI (1.29, 6.52)) in the Joint model. In an exploratory analysis there was no evidence that family clustering substantially affected the conclusions.ConclusionsEstimated effects from the conventional Cox model, which is often the model of choice, were dramatically lower in this dataset, compared to the Joint model. While the Cox model is often considered the approach of choice for analysis, research has shown that the Joint model may be more efficient and less biased. Our analysis based on a Joint model suggests that the magnitude of association between anxiety and mood disorder in individuals at familial risk of developing bipolar disorder may be stronger than previously reported.
Highlights
Anxiety is associated with mood disorders including bipolar disorder
In R, the Cox model by default assumes that the Hamilton Anxiety (HAM-A) scores are constant from one time of assessment to the
These findings are consistent with our prior findings and the extant literature showing a predictive association between clinically significant anxiety symptoms or anxiety disorders and subsequent mood disorder in high-risk offspring of bipolar parents (Duffy et al 2013, 2014, 2018; Nurnberger et al 2011)
Summary
Two statistical modelling frameworks were compared to investigate the longitudinal relationship between repeatedly measured anxiety symptoms and the onset of depression and bipolar disorder in youth at confirmed familial risk. We and others (Hafeman et al 2016) have shown that anxiety disorders and clinically significant anxiety symptoms are associated with and predict the onset of major mood disorder (Duffy et al 2013, 2018; Nurnberger et al 2011). In this manuscript, we compared two different statistical approaches to study the longitudinal relationship between repeatedly measured antecedent anxiety symptoms and the diagnosis of major depression or bipolar disorder in high-risk individuals
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