How to Ensure Inclusivity in Large-Scale General Population Cohort Studies?:Lessons Learned with Regard to Including and Assessing Sex, Gender, and Sexual Orientation

Despite recent advances in the measurement of sex, gender, and sexual orientation in large-scale cohort studies, the three concepts are still gaining relatively little attention, may be mistakenly equated, or non-informatively operationalized. The resulting imprecise or lacking information hereon in studies is problematic, as sex, gender, and sexual orientation are important health-related factors. Omission of these concepts from general population cohort studies might dismiss participants’ identity and experiences and pushes research on sexual or gender minority populations toward purposive sampling, potentially introducing selection bias. It also reinforces the unintentional notion of irrelevance of these concepts to health research, ultimately disadvantaging sexual and gender minority populations. Similarly, a lack of uniform measures on sex, gender, and sexual orientation hampers multi-cohort studies in which data from multiple studies are combined, facilitating increased statistical power. This paper discusses the encountered pitfalls and lessons learned on including and assessing sex, gender, and sexual orientation in large-scale general population cohort studies, exemplified by the Dutch Lifelines Cohort Study. Additionally, we propose hands-on strategies on how to operationalize these concepts in an inclusive manner that is useful for large-scale general population cohort studies

The association of sex, age and FKBP5 genotype with common somatic symptoms:A replication study in the lifelines cohort study

OBJECTIVE: Our aim was to replicate a recent study that reported an association between the rs9470080 CC-genotype and common somatic symptoms in women, but not in men. Additionally, we quantified the genetic contribution to phenotypic variation in common somatic symptom levels. METHODS: We used data from the Lifelines Cohort Study, including 28,299 participants (60.0% female; 44.2% CC-genotype; mean age 42.9 (14.2) years). Common somatic symptoms were measured with the SCL-90 SOM subscale. To assess the association between the rs9470080 genotype and SCL-90 SOM scores we applied similar analyses as the original study, including independent t-tests, two-way ANOVAs and a mixed ANOVA. To estimate the proportion of phenotypic variance in SCL-90 SOM scores explained by single nucleotide polymorphisms (SNPs), we used a genomic-relatedness-based restricted maximum-likelihood method. RESULTS: We could not replicate the original study's findings. We found no association between the rs9470080 genotype and common somatic symptom levels in either female or male participants (F(1, 8775) = 1.07, p = 0.30 and F(1,13,903) = 0.01, p = 0.93, respectively). Genome-wide heritability analyses show that 12.1% (p = 2.1e-08) of the phenotypic variance in common somatic symptom levels in Lifelines can be explained by SNPs. The genetic contribution to common somatic symptom levels was higher in male participants (SNP-h2 = 20.5%; p = 9.1e-08) than in female participants (SNP-h2 = 12.0%, p = 2.8e-05). CONCLUSION: Our findings of significant SNP-h2 and the sex-specific differences herein, does warrant further sex-stratified research of individual genetic variants associated with common somatic symptoms. Preferably, further research should be performed within the analytic framework of a genome-wide association study

Female sex and femininity independently associate with common somatic symptom trajectories

BACKGROUND: Multiple predictors have been associated with persistent somatic symptoms. However, previous studies problematically defined the persistence of symptoms, conflated participants' sex and gender, and focused on patient populations. Therefore, we studied associations between predictors, especially sex and gender, and longitudinal patterns of somatic symptoms in the general adult population. We also assessed whether predictors for persisting symptoms differ between sexes. METHOD: To identify developmental trajectories of somatic symptoms, assessed by the SCL-90 SOM, we used latent class trajectory modeling in the Dutch Lifelines Cohort Study [N = 150 494; 58.6% female; median time to follow-up: 46.0 (min-max: 22.0-123.0) months]. To identify predictors of trajectories, we applied multiple logistic regression analyses. Predictors were measured by surveys at baseline and a composite gender index was previously developed. RESULTS: A five-class linear LCGA model fitted the data best: 93.7% of the population had a stable symptom trajectory, whereas 1.5% and 4.8% of the population had a consistently increasing or decreasing symptom trajectory, respectively. Female sex predicted severe, stable symptom severity (OR 1.74, 95% CI 1.36-2.22), but not increasing symptom severity (OR 1.15, 95% CI 0.99-1.40). Femininity was protective hereof (OR 0.60, 95% CI 0.44-0.82 and OR 0.66, 95% CI 0.51-0.85, respectively). Merely a few predictors of symptom severity, for instance hours of paid employment and physical functioning, differed in strength between sexes. Yet, effect sizes were small. CONCLUSION: Female sex and femininity predict symptom trajectories. No large sex differences in the strength of additional predictors were found, thus it may not be clinically useful to distinguish between predictors specific to male or female patients of persistent somatic symptoms

Sex differences in the trajectories to diagnosis of patients presenting with common somatic symptoms in primary care:an observational cohort study

Objective: Little insight exists into sex differences in diagnostic trajectories for common somatic symptoms. This study aims to quantify sex differences in the provided primary care diagnostic interventions for common somatic symptoms, as well as the consequences hereof for final diagnoses. Methods: In this observational cohort study, we used real-world clinical data from the Dutch Family Medicine Network (N = 34,268 episodes of care related to common somatic symptoms; 61,4% female). The association between patients' sex on the one hand, and diagnostic interventions and disease diagnoses on the other hand, were assessed using multilevel multiple logistic regression analyses. Structural equation modelling was used to estimate a mediation model with multiple parallel mediators to assess whether the fewer disease diagnoses given to female patients were mediated by the fewer diagnostic interventions female patients receive, compared to male patients. Results: Women received fewer physical examinations (OR = 0.84, 95%CI = 0.79-0.89), diagnostic imaging (OR = 0.92, 95%CI = 0.84-0.99) and specialist referrals (OR = 0.85, 95%CI = 0.79-0.91) than men, but more laboratory diagnostics (OR = 1.27, 95%CI = 1.19-1.35). Women received disease diagnoses less often than men for their common somatic symptoms (OR = 0.94, 95%CI = 0.89-0.98). Mediation analysis showed that the fewer disease diagnosis in female patients were mediated by the fewer diagnostic interventions conducted in women compared to men. Conclusion: This study shows that sex inequalities are present in primary care diagnostic trajectories of patients with common somatic symptoms and that these lead to unequal health outcomes in terms of diagnoses between women and men. FPs have to be aware of these inequalities to ensure equal high-quality care for all patients

Gender and sex independently associate with common somatic symptoms and lifetime prevalence of chronic disease

Contains fulltext : 225526.pdf (Publisher’s version ) (Open Access)Sex and gender influence health differently. Associations between sex and health have been extensively studied, but gender (i.e. psychosocial sex) has been largely neglected, partly due to the absence of gender measures in cohort studies. Therefore, our objective was to test the unique associations of gender and sex with common somatic symptoms and chronic diseases, using a gender index created from existing cohort data. We applied LASSO logistic regression to identify, out of 153 unique variables, psychosocial variables that were predictive of sex (i.e. gender-related) in the Dutch LifeLines Cohort Study. These psychosocial variables covered gender roles and institutionalized gender. Using the estimated coefficients, gender indexes were calculated for each adult participant in the study (n = 152,728; 58.5% female; mean age 44.6 (13.1) years). We applied multiple ordinal and logistic regression to test the unique associations of the gender index and sex, and their interactions, with common somatic symptoms assessed by the SCL-90 SOM and self-reported lifetime prevalence of chronic diseases, respectively. We found that in 10.1% of the participants the gender index was not in line with participants' sex: 12.5% of men and 8.4% of women showed a discrepancy between gender index and sex. Feminine gender characteristics are associated with increased common somatic symptoms and chronic diseases, especially in men. Female sex is associated with a higher common somatic symptom burden, but not with a higher prevalence of chronic diseases. The study shows that gender and sex uniquely impact health, and should be considered in epidemiological studies. Our methodology shows that consideration of gender measures in studies is necessary and feasible, based on data generally present in cohort studies

Discordance between Adolescents and Parents in Functional Somatic Symptom Reports:Sex Differences and Future Symptom Prevalence

Functional somatic symptoms, i.e., physical complaints that cannot be sufficiently explained by an objectifiable biomedical abnormality, become increasingly more prevalent in girls than in boys during adolescence. Both parents and adolescents report more functional somatic symptoms in girls, but their reports correspond only limitedly. It remains unknown whether parent-adolescent discordance contributes to the higher symptom prevalence in girls. This study investigated parent-adolescent discordance in reported functional somatic symptoms throughout adolescence, examined the longitudinal association of parent-adolescent discordance with symptom prevalence in early adulthood and focused on sex differences in these processes. Participants included 2229 adolescents (50.7% female) from four assessments (age 11 to 22 years) of the TRAILS population cohort. Parents and adolescents reported significantly more symptoms in girls than in boys during adolescence. Variance analyses showed that throughout adolescence, parents reported fewer symptoms than girls self-reported and more than boys self-reported. Regression analyses using standardized difference scores showed that lower parent-report than self-report was positively associated with symptom prevalence in early adulthood. Polynomial regression analyses revealed no significant interaction between parent-reported and adolescent self-reported symptoms. Associations did not differ between boys and girls. The findings show that lower parent-reported than self-reported symptoms predict future symptom prevalence in both sexes, but this discordance was more observed in girls. The higher functional somatic symptom prevalence in girls might be partly explained by parental underestimation of symptoms.</p