COVID-19 experiences predicting high anxiety and depression among a sample of BRCA1/BRCA2-positive women in the US

During the COVID-19 pandemic, breast and ovarian cancer survivors experienced more anxiety and depression than before the pandemic. Studies have not investigated the similarities of this trend among BRCA1/2-positive women who are considered high risk for these cancers. The current study examines the impact of COVID-19 experiences on anxiety and depression in a sample of BRCA1/2-positive women in the U.S. 211 BRCA1/2-positive women from medically underserved backgrounds completed an online survey. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression for associations between COVID-19 experiences and self-reported anxiety and depression stratified by demographic factors. Overall, women who reported COVID-19 stigma or discrimination (aOR, 5.14, 95% CI [1.55, 17.0]) experienced significantly more depressive symptoms than women who did not report this experience. Racial/ethnic minority women caring for someone at home during COVID-19 were 3.70 times more likely (95% CI [1.01, 13.5]) to report high anxiety while non-Hispanic white women were less likely (aOR, 0.34, 95% CI [0.09, 1.30], p interaction = 0.011). To date, this is the first study to analyze anxiety and depression considering several COVID-19 predictors among BRCA1/2-positive women. Our findings can be used to inform future research and advise COVID-19-related mental health resources specific to these women.

Statistical methods. All analyses were performed using Stata statistical software, version 16 38 . Frequency and percentages were analyzed to identify missingness; cases that were missing were dropped for that specific model. Missingness is outlined in Table 1. Chi-square tests for categorical variables and independent samples t tests for continuous variables were conducted to determine potential covariates for demographic characteristics of interest. These analyses compared characteristics by income and racial/ethnic minority status) and are included in Table 1. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated with multivariable logistic regression models to measure the association between each COVID-19 experience/predictor and outcomes (anxiety and depression), while adjusting for age at survey completion, number of comorbid conditions, years since genetic testing, education, marital status, survivor/control status, geographic location, race/ ethnicity, and income status. To examine the effect of experiences during COVID-19 on anxiety and depressive symptomology by income status and racial/ethnicity among BRCA1/2-positive women, models were stratified by these factors and an interaction term was created for COVID-19 experience combined with income status (did/did not experience during COVID-19 × income status) and race/ethnicity (did/did not experience during COVID-19 × race/ethnicity) within appropriate models. Analyses in Table 1 were two-sided and statistical significance was indicated if p values were below 0.05. For multivariable logistic regression models, the level of statistical significance was restricted to p values less than or equal to 0.02 to account for multiple tested models.
Ethics approval. This study was performed in line with the principles of the Declaration of Helsinki.
Approval was granted by the Johns Hopkins Bloomberg School of Public Health Institutional Review Board. Consent to participate. Informed consent was obtained from all individual participants included in the study.

Results
Characteristics of the study sample. Description of the study population and characteristics are shown in Table 1. A total of 211 BRCA1/2-positive women, both with and without a history of cancer meeting inclusion criteria were included in the current study. The sample ranged in age from 18 to 75 (M = 39.5, SD = 10.6) and most women did not have a history of cancer (n = 138, 65.4%). The composition of originally polynomial predictor variables was as follows: race (American Indian or Alaska Native [   Missing Missing

Changes in life due to COVID-19
Caring for someone at home     . Most of the current sample completed a college degree or above (64.5%) and was married or living as married (62.6%). Some of the women did report having at least one physical disability (40.8%) and most reported having more than one comorbid condition including cancer (61.6%). Most women reported ≥ $40,000/year for their household incomes (77%) A total of 49 participants identified as being lesbian, gay, bisexual, transgender, queer/questioning, or something else (LGBTQ+). Study characteristics among NHW and racial/ethnic minority women differed significantly. Racial/ ethnic minority women were more often 49 years of age or younger (p = 0.011), whereas NHW women had reported significantly more comorbid conditions than racial/ethnic minority women (p = 0.027). Some demographic characteristics also differed significantly by income status. Women with household incomes ≥ $40,000/ year more often reported a college degree or above (p ≤ 0.001) and being married or lived as married (p ≤ 0.001). COVID-19 experiences also differed by income status and racial/ethnic minority status, as depicted in Table 1. Missing

Confusion about COVID-19
No Giving to the greater good by following mandates Getting emotional support from loved ones

Mean (SD) Mean (SD) p value Mean (SD) Mean (SD) p value Mean (SD)
Age at survey completion 40.5 (11.5) 37. 5   There was an additional significant interaction between changes in healthcare services and race/ethnicity (p interaction = 0.02); however, aORs were not statistically significant. No other interactions were observed by race/ethnicity. Table 3 presents the association between the COVID-19-related experiences and the odds of reporting more depressive symptoms, overall and by income status and race/ethnicity. Women reporting stigma or discrimination (aOR, 5.14, 95% CI [1.55, 17.0]) or sleep issues (aOR, 2.52, 95% CI [1.24, 5.13]) during the COVID-19 pandemic were significantly more likely to have more symptoms of depression than women who did not experience these experiences. In models stratified by income status, women with lower incomes who reported sleep issues during the pandemic (aOR, 3.16, 95% CI [1.44, 6.94]) were significantly more likely to report increased depressive symptoms in comparison with women of average/high income (aOR, 0.96, 95% CI [0. 21, 4.25], p interaction = 0.15). There was a significant interaction between women who reported quarantining/isolation and low income status (p interaction = 0.01), where women with higher incomes were significantly less likely to have depressive symptoms (aOR, 0.08, 95% CI [0.01, 0.43]) than women of lower incomes (aOR, 0.73, 95% CI [0.35, 1.52]). No other significant interactions were observed by income.

Depression and COVID-19 experiences by income status and race/ethnicity.
In models stratified by race/ethnicity (Table 3), minority women who experienced stigma or discrimination related to COVID-19 had 6.20 times the odds of reporting more depressive symptoms (95% CI [1.60, 24.0]) while NHW women had 2.66 times the odds (95% CI [0. 26, 26.6]) of this outcome, although this association was not significantly different. The association between sleep issues due to the pandemic and depression symptoms was significantly modified by race/ethnicity (p interaction = 0.01). NHW women reporting sleep issues during the pandemic were 7.77 more likely (95% CI [2.31, 26.1]) to experience more depressive symptoms while minority women were only 1.40 times more likely (95% CI [0.59, 3.29]), although this finding among minorities was not statistically significant. There were also statistically significant racial/ethnic differences among women caring for someone at home during the COVID-19 pandemic and odds of depression. NHW women were less likely (aOR, 0.24, 95% CI [0.06, 0.97]) to report more depressive symptoms, while racial/ethnic minority women were 3.52 times more likely (95% CI [1.11, 11.0]) to experience depression symptomology, although neither relationship was significant (p interaction = 0.003). No other significant interactions were observed by race/ethnicity.

Discussion
Among BRCA1/2-positive women residing in the US, the current study analyzed relationships between experiencing COVID-19-related instances and odds of reporting anxiety and depression overall and stratified by sociodemographic factors. Historically, women with BRCA1/2 mutations have been difficult to recruit in large numbers, partly due to the rarity of the prevalence of these mutations. In past literature, women with these mutations have been primarily recruited from hospital genetics programs or gynecologists offices in small numbers 39 . Due to the nature of the COVID-19 pandemic and with hospital outpatient non-essential care halting, the current study piloted recruitment through online Facebook BRCA1/2-oriented support groups, which were very successful in reaching our recruitment ceiling of 225 consented participants in 3.5 months.
Demographically, most of the sample was younger than age 50, consistent with past literature suggesting that women are being genetically tested at younger ages 40,41 . Most women were NHW and educated, but there was some diversity where as much as 40.8% reported a physical disability and 61.6% a chronic condition. The current study is novel in its relation to COVID-19, however research remains limited regarding the pandemic and its impact on at-risk cancer populations such as those with BRCA1/2 mutations. Commonalities existed with several COVID-19-related experiences predicting increases in anxiety and depression symptomologies among women with BRCA1/2 mutations. It appears reporting stigma or discrimination or sleep issues during the pandemic resulted in significantly increased chances of having more anxiety and depression symptoms than www.nature.com/scientificreports/ women who did not report these instances. Although it is well-known that BRCA1/2-positive women report on average, higher levels of anxiety and depression than the general population, these increases have not been directly connected to the COVID-19 pandemic, but within past literature have focused on the stress of ongoing surveillance and prophylactic risk-reducing surgeries 18,42,43 and cancer patients generally 44 . Among women of the general population, previous literature has found that both anxiety and depression symptomologies were heightened during the pandemic, highlighting the impact on the impact of mental health in various communities 45 . Specifically, risk factors for worsened mental health distress included female gender, being below the age of 40, having additional chronic or psychiatric illnesses, unemployment, student status, and/or frequent exposure to COVID-19-related social media or news coverage 46 . Additionally, one study posited that those in fair/poor health, of below-average income, and those who knew someone infected with COVID-19 experienced higher levels of mental health distress. However, NHW individuals, those of above-average income, and those who spent less than 8 h on electronic screeners per day were likely to experience lower levels of distress 47 . While some of these risk factors may overlap with women of the current sample, future research should focus on discerning these factors from the US general female population. Not surprisingly, there were differences in income status, where women with average/high income were less likely to report depressive symptoms if they quarantined due to COVID-19. As we know, individuals who have both the resources and time to seek mental healthcare are more likely to utilize such care 48,49 , but does not account for COVID-19-related barriers. Interestingly, for those caring for someone at home during the pandemic, there were differences by race/ethnicity, where NHW were less likely to experience depression, but minority women were almost three times more likely. Past literature has found that among caregivers, depression and anxiety were higher in Black or African Americans than NHW women 50 , but other literature has reported that mental health symptoms increased with level of care 51 . It is also possible that COVID-19 experiences vary based upon geographic location within the US (urban, suburban, rural), and although not the case within the current study perhaps due to invariability, has been highlighted in past literature among the general population 45,52 and reproductive cancer patients 53,54 , noting that those living in rural areas were more likely to experience greater anxiety than those living in urban areas. Due to the recency of the COVID-19 pandemic in conjunction with its effect on both cancer patients, survivors, and those at increased risk for cancer like the women in this study, this topic remains relatively new and suggests the importance of researching this further.
To our knowledge, no studies have been conducted focusing on BRCA1/2-positive women's mental health and their relation to the COVID-19 pandemic. In current literature, healthcare utilization in relation to genetic testing 55 and cancer-related diagnostic delays 56 has been introduced in recent years, but not many have highlighted how the pandemic has impacted cancer patients or survivors' mental health. In one such study, Wang and colleagues 20 published that among 6213 cancer patients, 23.4% experienced depression and 17.7% had anxiety. In relation to COVID-19, individuals showing a history of mental health adversities, alcohol consumption, and continuous cancer worry were predominant factors for mental health symptomology among this population 20 . The Table 2. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the association between COVID-19 experiences and odds of high anxiety among BRCA1/2-positive women from disadvantaged health populations, overall and by income status and race/ethnicity. Missing values: anxiety (15), change in life due to COVID-19 (15), age (3), and cancer status (3). Bold font indicates statistically significant with corresponding p < 0.02. p interaction terms are between income status, racial/ethnic minority status, and predictor(s). Covariates/stratifications: age (continuous), number of comorbid conditions (continuous), years since genetic testing (continuous), education (some college or less, college graduate or above), marital status (married/ living as married, other), cancer status (no cancer history, cancer history), income status (average/high income, low income), geographic location (urban/suburban, rural), and race/ethnicity (non-Hispanic white [NHW], Hispanic or racial minority).  www.nature.com/scientificreports/ recent pandemic's impact on the mental health of the general population has been published more often, noting that both the direct and indirect psychological impact of COVID-19 on the general public and vulnerable groups (e.g., elderly, people with pre-existing mental health issues, etc.) 57 should be studied in more detail. Similarly, symptoms of mental health during COVID-19 have been exacerbated by lower quality of life and focusing on the negative aspects of the pandemic 58 . The recency of the COVID-19 pandemic in the US has focused research on the general population and its mental health, while very little, to our knowledge, has been implemented among cancer patients or survivors, and none regarding BRCA1/2-positive women. It is apparent that the COVID-19 pandemic had variable effects on certain groups such as BRCA1/2-positive racial/ethnic minority women and those with low income. While research is continuing to emerge in response to the COVID-19 pandemic in relation to cancer and cancer risk, future studies should focus on stratifying by groups who are at higher risk for cancer and those who have survived it. Larger, more inclusive nationwide studies may provide the framework necessary to distinctly analyze subgroups such as these so resources following this pandemic may be of benefit to all in the US. Longitudinal studies could be implemented to discover the impact of COVID-19 on the cancer care continuum, from screening to survivorship. Resources should be made available to individuals experiencing compounded disparities, like those mentioned in the current study, to help alleviate the adverse mental health symptoms that may arise due to COVID-19, surveillance, and surgery. The National Cancer Institute (NCI) 59 and American Cancer Society (ACS) 16,60 , and even several large hospital systems such as Johns Hopkins Medicine in collaboration with the National Comprehensive Cancer Network (NCCN) 61 have published websites to assist cancer patients and survivors navigate the COVID-19 pandemic. Clinically, mental health screening at routine healthcare appointments may be beneficial to this population in combination with available mental health resources and recommendations. However, because this is a new realm of research, additional research is needed to accurately describe the relationship between COVID-19, anxiety, and depression among at-risk cancer groups such as women with BRCA1/2 mutations.
Study strengths. The current study has several strengths. Our study attempted to recruit from a combination of hard-to-reach populations and those with rare cancer hereditary genetic mutations not easily recruited in-person. The online nature of this study acted as a pilot to test if these populations could be recruited successfully and from areas across the US. We were able to recruit a female sample from diverse backgrounds, allowing for limited generalizability to subpopulations such as racial/ethnic minorities, those with low income, and those with cancer. Future studies can use these approaches to recruit other hard-to-reach populations for rare or stigmatized health conditions.

Limitations.
The current study's findings should be interpreted with consideration of its limitations. Overall, while the current study provided a moderately large sample, the data is cross-sectional and self-reported, www.nature.com/scientificreports/ which may introduce misclassification or recall bias. While we did collect information on the presence of physical disability, we did not gauge severity, subtype, or impact on activities of daily living (ADLs) based upon reported physical disability. We also did not collect information on COVID-19 severity or recency to include in these analyses. This study recruited BRCA1/2-positive women during various stages of the COVID-19 pandemic, where hospitalization, deaths, and vaccination rates varied both nationally and at community levels. We were unable to account for these variables in the current analysis, but future studies should capture these data to account for these distinctions. Stratified results should be interpreted with caution due to limited sample sizes among the subgroups of interest. Our findings should be replicated in a larger study with a similar study population to confirm similarities. It is also possible that by using predictors that were originally dichotomous may limit the implication of detailed information, as future studies may ask about the severity of COVID-19 experiences in addition to incidence. These participants were recruited from online support groups, which may introduce bias by being more open and willing to share experiences than others not in support groups 62 . Therefore, generalization of these findings is limited to the populations analyzed in the current sample.

Conclusion
The current study provides a unique view in beginning to understand the impact of the COVID-19 pandemic on anxiety and depression among women with BRCA1/2 mutations. This perspective allowed the identification of several COVID-19-related experiences in relation to mental health outcomes, stratified by income status and race/ethnicity, showing that there are distinct disparities among both groups. Future research can target the development of anxiety and depressive symptom relief during and after the COVID-19 pandemic utilizing prospective longitudinal study designs, while interventions can focus on recurrent training for medical professionals working with this population. Clinically, medical professionals should offer referrals to mental health counselling for all patients, not only those who are visibly struggling during this pandemic. With genetic testing becoming more widely available, especially with the utilization of telemedicine, it is possible that women may require ongoing mental healthcare that are not currently widely available for those of low income and racial/ ethnic minority groups to reduce the inequities among those with BRCA1/2 mutations.

Data availability
The datasets generated during and/or analyzed the current study are available at the Principal Investigator (PI)'s discretion upon reasonable request.