Development of a Risk Calculator for Major Mood Disorders Among the Offspring of Bipolar Parents Using Information Collected in Routine Clinical Practice

Abstract

Background: Family history is a significant risk factor for bipolar disorders (BD), but the magnitude of risk varies considerably between individuals within and across families. Accurate risk estimation may increase motivation to reduce modifiable risk exposures and identify individuals appropriate for monitoring over the peak risk period. Our objective was to develop and independently replicate an individual risk calculator for major mood disorders among the offspring of BD parents using data collected in routine clinical practice. Methods: The longitudinal Canadian High-Risk Offspring cohort study was used to develop a 5 and 10-year risk calculator using parametric time-to-event models with a cure fraction and a generalized gamma distribution. The calculator was then externally validated using data from the Lausanne–Geneva High-Risk Offspring cohort study. A Time-varying C-index by age in years was used to estimate the probability that the model correctly classified risk. Bias corrected estimates and 95% confidence limits were derived using a jackknife resampling approach. Outcomes: The primary outcome was age of onset of a major mood disorder. The risk calculator was most accurate at classifying risk in mid to late adolescence in the Canadian cohort, and a similar pattern was replicated in the Swiss cohort. Specifically, the time-varying C-index indicated that there was approximately a 70% chance that the model would correctly predict which of two 15-year-olds would be more likely to develop a bipolar spectrum mood disorder in the future. Interpretation: Findings suggest that this model may be a useful clinical tool in routine practice for improved individualized risk estimation of bipolar spectrum disorders among the adolescent and offspring of a BD parent; however, accurate risk estimation in younger high-risk children is less precise reflecting the evolving nature of psychopathology at this early developmental stage. Funding: Funding: The Canadian High-Risk Study has been funded by consecutive operating grants from the Canadian Institutes for Health Research, currently CIHR PJT Grant 152976 The Lausanne-Geneva high-risk study was and is supported by five grants from the Swiss National Foundation (#3200-040677, #32003B-105969, #32003B-118326, #3200-049746 and #3200-061974), three grants from the Swiss National Foundation for the National Centres of Competence in Research project “The Synaptic Bases of Mental Diseases” (#125759, #158776, and #51NF40 – 185897), and a grant from GlaxoSmithKline Clinical Genetics. The funders had no involvement in any aspect of this study. Declaration of Interest: MISSING Ethical Approval: The two studies have been approved by respective research ethics boards at each site: the Ottawa Independent Research Ethics Board (Pro00011514), the Queens University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (PSIY-561-17) and the Ethics Committee for Clinical Research of the Canton de Vaud.