Donghao Lu

Around 4% of middle-aged women have breast implants, the large majority for cosmetic reasons. There are rising concerns for adverse health effects of breast implants, yet comprehensive research efforts are needed to determine if the indicated health risks are preexisting or caused by the procedure itself. Therefore, the aim of the BRISK study is to leverage unique Swedish population-based data to determine risks of mental disorders, autoimmune disease, chronic fatigue, and other medical conditions among women with cosmetic breast implants. In this three-year project, we will identify 29 011 women with cosmetic breast implants through the Breast Implant Quality Register (operated 2014-22) and ongoing mammography studies (identified 2008-21), as well as ~5 000 women undergoing permanent removal of breast implants (1997-2022). By record linkage to the population-based Patient, Primary Care- and Prescription Registers, we will compare the rates of the studied health risks of women with breast implants to that of their full sisters and an age- and region matched cohort of women. We will assess pre-surgery rates of these conditions and take them into account when assessing post-surgery rates. Solid evidence on major health outcomes of breast implant surgery is currently lacking, leaving women considering this surgery option largely uninformed on long-term health effects. The BRISK study will provide valuable evidence for this patient group and health care policy worldwide.

The MoodMAP project targets the challenge of diagnosing and treating reproductive mood disorders (RMDs), such as premenstrual disorder and postpartum depression, which significantly affect women’s health and contribute to the mental health gender gap. Emerging evidence including our own indicate that these disorders, linked to hormonal changes, may be influenced by genetic predisposition, chronic inflammation, and metabolic dysfunction. Our goals are to uncover new biomarkers, understand the biological underpinnings of women’s susceptibility to mood disorders, and improve strategies for diagnosis, prevention, and treatment. Utilizing data from three Nordic cohorts, the project will:1) integrate genomic, inflammatory proteomic, and metabolomic data to map RMDs’ molecular architecture

2) identify functional and causal biomarkers through hormone-manipulated cell data and epidemiological methods

3) predict clinical prognosis using multi-omics data and machine learning.By studying RMDs in concert, MoodMAP aims to reveal the biological basis of female vulnerability to mood disorders, employing advanced omics techniques and state-of-the-art design and analytic methods. The research team is experienced and interdisciplinary in nature, with specific milestones mapped out for each aim over five years. This project is poised to transform our understanding of RMDs, enhancing diagnostic and therapeutic approaches and ultimately addressing the gender gap in mental health.

Research problem and specific questions: Approximately 4% of middle-aged women in Sweden have breast implants, the large majority (~80%) for cosmetic reasons. At the same time there are rising concerns for adverse health effects, including reports of multiple adverse symptoms (‘breast implant illness’) as well as some psychiatric- and autoimmune conditions among women with breast implants. Yet, comprehensive research efforts are still needed to determine if these risks are preexisting or caused by the procedure itself. Therefore, the aim of the BRISK study is to leverage unique Swedish population-based data sources to determine pre- and post- implant procedure risks of: 1) mental disorders and psychotropic drug use

2) autoimmune and chronic fatigue conditions

3) sick-leave and disability pension among women with cosmetic breast implants. Data and method: We will identify 28 835 women with cosmetic breast implants through the Breast Implant Register (BRIMP

N=20 779 operated 2014-22) and ongoing mammography studies (N=8 056 with breast implants, identified 2008-21). By record linkage to the population-based Patient, Primary Care- and Prescription Medicines Registers, and Databases for Health Insurance and Labor Market, we will compare the rates of psychiatric- and autoimmune conditions as well as sick leave and disability pension among women with breast implants to that of their full sisters and an age- and region matched cohort of women (1:10 unexposed women). We will assess pre-surgery rates of these conditions and take them into account when assessing the post-surgery rates of the studied health outcomes.Societal relevance and utilization: Solid evidence on major health outcomes associated with breast implant surgery is currently lacking, leaving women considering this surgery option largely uninformed on long-term health effects. This comprehensive investigation will provide valuable information for health care policy and the growing population of women with breast implants. Plan for project realization:  We seek three years of funding for a post-doc, record linkages, database management and presentation of the results to stakeholders and the scientific community. Implementation of record linkages and preliminary analyses will be completed during the first year (2025), statistical analyses during the second year (2026), and publication of three scientific papers in leading international scientific journals by the end of the third year (2027).

Research problem and specific questionsSex/gender differences in mental health among adolescents and young adults (AYAs) are well documented. Yet, the driving forces are poorly understood. Premenstrual disorders (PMDs) are common yet under-investigated mental/behavioral conditions emerging during adolescence, with a significant psychosocial impact on young women. Our recent work based on cross-sectional data revealed that the higher prevalence rates of depression and anxiety in adolescent girls than boys did not emerge until menarche and were almost fully attributable to PMDs. However, prospective data are urgently needed to demonstrate the causal relations between PMDs and mental ill-health in young women, and subsequently the contribution to the sex disparities in AYAs mental health.Data and methodsLeveraging the nationwide Swedish register data and two large prospective cohorts (the LifeGene and CATSS), this proposal aims to develop a strategy roadmap for future interventions reducing mental health sex/gender disparities among AYAs through novel prevention programs for PMDs. Specifically, we aim to: 1) assess the association of PMDs and subsequent risks of depression and anxiety using population and sibling analyses

2) quantify the mediating role of PMDs in the sex differences in mental health and suicidal behavior using mediation analysis

and 3) determine modifiable childhood causal risk factors for PMDs using Mendelian randomization (MR) analysis.Plan for project realizationThe research team consists of multidisciplinary experts from epidemiology, OB/GYN, psychology/psychiatry, and genetics from Iceland, Sweden, and the US. The applicant has extensive experience in conducting cutting-edge studies on women´s mental health, particularly among AYAs, using registers and large population-based cohorts with advanced methods integrating omics data. One full-time PhD student and 70% of a postdoc will be financed to implement the projects over 3 years under the applicant´s supervision. RelevanceMental ill-health is the leading cause of disease burden among AYAs in Sweden and the sex/gender disparity is alarmingly concerning. However, very limited progress has been implemented so far. Through this program, we will fill an important knowledge gap in the contribution of PMDs to the sex/gender disparities in AYAs mental health, and provide innovative guidelines for future interventions targeted to reduce such disparities.