2·1 Study design and participants
Participants were drawn from the PLS-BD, an ongoing cohort study of BD that has been continuously gathering phenotypic and biological data over the naturalistic course of BD beginning in 2006. Participants are recruited via advertisements, psychiatric clinics, mental health centers, and community outreach events in Michigan. Participants are excluded if diagnosed with neurological disease or alcohol or substance use that would interfere with the ability to complete research (e.g., attending interviews intoxicated). The present study included 603 participants (MeanAge = 39, SDAge= 14, 65·7% female, 78·6% White, 21·4% non-Caucasian, Meanenrollment = 13 years, Rangeenrollment = 10–17) who had completed at least 10 years of follow-up in the study. Participants in the BD group had a DSM-IV-TR diagnosis of BD I (n = 258), BD II (n = 80), BD Not Otherwise Specified (n = 30), or Schizoaffective BD (n = 17). Participants in the PC group had a DSM-IV-TR diagnosis of major depressive disorder (n = 20), non-affective diagnoses (n = 23), or other affective diagnoses (n = 28). The HC included individuals (n = 147) who had no psychiatric history and no first-degree relatives with BD. Diagnosis was assessed using the Diagnostic Interview for Genetic Studies, version 4 (21). A team of at least two doctoral-level psychologists or psychiatrists confirmed diagnosis using criteria from the DSM-IV-TR and all available medical history from electronic health records. Demographic and descriptive information regarding each group is presented in Supplemental Tables 1–4. Written informed consent was obtained from participants and all study procedures were approved by the Institutional Review Board at Michigan Medicine.
2·2 Choice of primary measure
The full longitudinal protocol and procedures of the PLS-BD are outlined elsewhere (19). We focus on measures related to the current investigation which include mood and functioning measures that are administered every two months for the duration of the study. Demographics including sex at birth, race, ethnicity, and age of onset are collected annually on the participants’ anniversary of enrollment while age was calculated as of November 1, 2023 the date at which data was extracted for analysis.
Self-reported depression symptoms over the past two weeks were measured using the gold-standard nine-item Patient Health Questionnaire (PHQ-9) (22). Items are answered on a Likert Scale from 0 (Not at all) to 3 (Nearly every day) with a scale score range from 0 to 27. Scores of 5 to 9 indicate mild depression, 10–14 moderate depression, 15–19 moderately severe depression, and 20–27 severe depression. Self-reported manic symptoms over the past two weeks were measured using the five-item Altman Self-Rating Mania Scale (ASRM) (23). Items are answered on a scale from 1 to 5 with scale scores ranging from 5 to 25. A score of 6 or higher indicates a concern for manic or hypomanic presentations. Self-reported anxiety symptoms were measured using the gold-standard seven-item Generalized Anxiety Disorder Scale (GAD-7) (24). Items are answered on a scale from 0 (Not at all) to 3 (Nearly every day). Scores range from 0 to 21 (0–4: minimal, 5–9: mild, 10–14: moderate, >= 15: severe anxiety). General health and functioning were measured using the short form of the SF-36, the SF-12 (25). The SF-12 is a widely used measure to assess quality of life in health-sciences. The SF-12 results in two normed T scores (mean = 50, SD = 10), the mental component summary (MCS) and physical component summary (PCS), with higher scores indicating better-than-average functioning. Internal consistency for all measures were good to excellent in the current sample (Chronbach’s a = 0·82 − 0·92).
2·3 Analytical Strategy
Rolling variance of the PHQ-9, ASRM, and GAD-7 was calculated for each participant using three window widths; 3, 6, and 12 corresponding to 3, 6, and 12 independent measures captured over 6-months, 1-year, and 2-years, respectively. Visual inspection with a LOESS (Locally Weighted Scatterplot Smoothing) line was completed along with calculation of the Mean Squared Error (MSE) and standard deviation (SD) to examine responsiveness of each window width. One-year of rolling variance was selected as it had the lowest MSE but highest SD across 20 random selected participants representing 12:4:4 ratio of BD:PC:HC. Raw rolling variances were z-scaled so that the distributions were similar and comparable across participants (continuous measure of instability). To identify categorical thresholds of low, moderate, and high instability based on rolling variances, independent of diagnostic group, ranked percentiles were created (n = 100). Thresholds were determined from ranked percentiles so that </= 60-%tile was considered “low”, 61-94-%tile was “moderate” and >/= 95-%tile was considered “high” instability for each measured scale. As such, each participant had a continuous index and categorical threshold of instability for each mood measure.
To account for multiple comparisons and reduce chances of type I error with a large number of within-person observations, we adjusted the alpha level to .001 across all models. To examine whether diagnostic groups differed in terms of continuous measures of instability, linear mixed-effects models were used in the lmer package in R. To examine pair-wise group differences, we completed post-hoc contrasts with Tukey correction for multiple comparisons. To test whether there were proportional differences in the low, moderate, and high thresholds by diagnosis, we ran pair-wise chi-square tests. To test whether thresholds predicted longitudinal functioning outcomes (mental and physical health functioning from the SF-12), over and above other important covariates (diagnosis, sex, race, age), we ran linear mixed-effect models robust to missingness. An example formula is provided below:
$$\left(1\right) {SF12\_MCS}_{ij}={{\rm Y}}_{00} + {{\rm Y}}_{01}{\left(diagnostic group\right)}_{j} +{{\rm Y}}_{02}{\left(sex\right)}_{j}+{{{\rm Y}}_{03}{\left(race\right)}_{j}+{{\rm Y}}_{04}{\left(age\right)}_{j}+{\rm Y}}_{10}{\left(instability threshold\right)}_{ij} + {U}_{0j} + {R}_{ij}$$
Note
SF12_MCS = mental health functioning. Diagnostic group (0 = HC), sex (0 = male), race (0 = White). represents a random intercept for each participant.