Stress-And-Gene-Analysis cohort about Icelandic women

The Stress-And-Gene-Analysis (SAGA) cohort is a study of women aged 18–69 years residing in Iceland in 2018.^{Reference Valdimarsdóttir and Hauksdóttir11–Reference Yang, Þórðardóttir, Hauksdóttir, Aspelund, Jakobsdóttir and Halldorsdottir13} All Icelandic-speaking women with an address or telephone number (approximate n  104 197) were invited to participate in the study between March 2018 and July 2019. The participants of the SAGA cohort answered an extensive web-based questionnaire including questions on for example, demographic factors, psychological trauma history (in childhood and adulthood), psychological health and history of various diseases. As shown in a previous study about the SAGA cohort, the participants represent the general population of Icelandic women in terms of age, education, geographic location of residence and monthly wages.^{Reference Daníelsdóttir, Aspelund, Thordardottir, Fall, Fang and Tómasson12} A total of 29 367 women (mean age 44 years) with sufficient information on ACEs and childhood deprivation were included in the present study (Fig. 1). All participants signed an informed consent. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All procedures involving patients were approved by the National Bioethics Committee of Iceland (reference number: 17–238) and the Icelandic Data Protection Authority.

Fig. 1 The flow chart of study population. ACE-IQ, Adverse Childhood Experience International Questionnaire; SAGA, Stress-And-Gene-Analysis.

Information on schizophrenia and bipolar disorder diagnoses

Women reported whether they had ever been diagnosed by a healthcare professional (e.g. a psychologist or medical doctor) with either schizophrenia or bipolar disorder. A total of 108 women (0.4%) reported a diagnosis of schizophrenia and 479 (1.6%) of bipolar disorder, with 53 of these women reporting being diagnosed with both disorders, resulting in 534 women with schizophrenia or bipolar disorder. We had no information on the date of the diagnosis nor specific diagnostic details. Self-report information on severe mental disorders has been shown to represent valid information relevant for research purposes.^{Reference Supina and Patten14} For the overall analyses, we grouped women with schizophrenia or bipolar disorder together as having severe mental disorders. Women who did not report a schizophrenia or bipolar disorder diagnosis are referred to as the reference group.

Measurement of ACEs and childhood deprivation

ACEs were measured with a modified version of the ACE International Questionnaire (ACE-IQ) developed by the World Health Organization.¹⁵ The ACE-IQ consists of 39 items assessing the frequency of exposure to 13 types of ACEs before the age of 18 years: emotional neglect, physical neglect, emotional abuse, physical abuse (the latter four items were referring specifically to abuse/neglect by parents or a guardian), sexual abuse, domestic violence, living with a household member who misuses drugs and/or alcohol, living with a household member who is mentally ill or suicidal, incarceration of a household member, parental death or separation/divorce, being bullied, witnessing community violence and exposure to war/collective violence. Response options varied between items and could either be answered on a five-point scale (ranging from 0 (never) to 4 (always)), on a four-point scale (from 0 (never) to 3 (many times)) or answered dichotomously 0 (no) and 1 (yes). In the main analysis, the response option ‘cannot/will not answer’ was treated as no childhood adversity for that respective question. In the present study, we followed the recommended frequency scoring system, which takes into account the level of exposure for each ACE. We then generated three types of exposure variables:

1. (a) a continuous ACE-IQ total score ranging from 0 to 13, reflecting the number of ACEs the participants were exposed to;

2. (b) the total score categorised based on the distribution of the sample (0–2, 3–4 and ≥5 ACEs); and

3. (c) binary variables for each individual ACE type, coded as 0 (unexposed) and 1 (exposed).

Childhood deprivation was assessed with the question: ‘Was your family's economic situation ever so bad that you suffered any deprivation as a consequence? For example, this could apply to deprivation of nutritious food and/or deprivation of warm clothes and appropriate footwear during the winter months’, with response options ranging from 0 (never) to 3 (often). For analytical purposes, we grouped childhood deprivation into ‘no’ (never and rarely occurring) and ‘yes’ (sometimes and often), as has been done previously.^{Reference Daníelsdóttir, Aspelund, Thordardottir, Fall, Fang and Tómasson12}

Measurements of psychological functioning

Questions on psychological functioning covered present-state mental symptoms and coping ability. Women reported their symptoms via the following measures, with higher scores indicating greater symptom severity: depressive symptoms were assessed with the nine-item Patient Health Questionnaire (PHQ-9) with a score ≥10 representing a well-established validated cut-off for a probable diagnosis of depression.^{Reference Kroenke, Spitzer and Williams16} Symptoms of anxiety were assessed with the Generalized Anxiety Disorder 7-item scale (GAD-7) with a score ≥10 representing a well-established validated cut-off for clinically relevant anxiety symptoms.^{Reference Spitzer, Kroenke, Williams and Löwe17} Sleep disturbances were assessed with the Pittsburgh Sleep Quality Index (PSQI), with 19 individual items generating seven component scores and with a PSQI ≥6 indicating clinically significant sleep disturbances.^{Reference Buysse, Reynolds, Monk, Berman and Kupfer18}

We imputed data for women who responded to more than 75% of items on the PHQ-9, GAD-7 and PSQI. Mean scores were used to replace missing values in both PHQ-9 and GAD-7 questionnaires. For the PSQI questionnaire, we replaced missing values with single imputation using predictive mean matching (PMM, with default d = 5 and 20 iterations).^{Reference Buuren19}

Perceived coping ability was assessed with the 10-item version of the Connor–Davidson Resilience scale (CD-RISC-10),^{Reference Campbell-Sills and Stein20} measuring individuals’ perceptions of their ability to cope effectively with stress and adversity. The CD-RISC-10 scale has demonstrated good reliability and validity.^{Reference Campbell-Sills and Stein20} Items were summed to create a total score ranging from 0 to 40 with a higher score indicating higher levels of perceived coping ability.

Covariates

We included the following covariates: age at responding; civil status (divided into married or in a relationship and single or widowed); educational level categorised as primary education, secondary education (high school or vocational education), tertiary education A (BSc or equivalent) and tertiary education B (MSc or above); current personal monthly income (categorised into low (≤US$2527/month), moderate (US$2528 to US$5897/month), high (>US$5898); conversion rates according to Central Bank of Iceland, 17 October 2018); body mass index (BMI); and smoking status (never, previous and current).

Statistical analysis

We compared the study population's characteristics between women with and without severe mental disorders using the t-test for age (as continuous variables) and the chi²-test for other variables and determined correlations between specific types of ACEs via rank-order correlations.

For the primary analyses, we grouped women with schizophrenia or bipolar disorder as one group, i.e. women with a severe mental disorder. We estimated prevalence ratios (PRs) including 95% CI of a continuous ACE-IQ total score via Poisson log-binomial regression models with the sandwich variance estimators.^{Reference Chen, Qian, Shi and Franklin21} We also compared women who endorsed different numbers of ACEs (3–4 and ≥5 ACEs) with women with 0–2 ACEs and women with childhood deprivation to women without childhood deprivation. We used the group of women with 0–2 ACEs as the comparison group because the majority of women (79.7% among women without a severe mental disorder v. 95.7% among women with a severe mental disorders) reported at least one ACE. We conducted a model adjusted for age and a model additionally adjusted for all other covariates.

Next, we estimated the associations of type-specific ACEs and severe mental disorders. To determine the independent associations of type-specific ACEs and severe mental disorders, we first ran type-specific analyses separately adjusted for all covariates, then re-ran the analysis additionally adjusted for other types of ACEs.^{Reference Yang, Thornorethardottir, Hauksdottir, Aspelund, Jakobsdottir and Halldorsdottir22}

Finally, we performed analyses specifically among women with a severe mental disorder studying the association of ACEs (0–2, 3–4 and ≥5 ACEs) and childhood deprivation with psychological functioning (i.e. the severity of symptoms of depression, anxiety, sleep disturbances and resilience). We used both linear regression and Poisson log-binomial regression models to calculate the beta coefficient and PR adjusted for all covariates, respectively.

We performed several sensitivity and subgroup analyses. First, we re-ran all analysis separately for women with schizophrenia or bipolar disorder, respectively. Second, to assess the effect of missingness on our results, we re-ran our analysis restricted to participants without the ‘cannot/will not answer’ option on the ACE-IQ. Third, we replaced ‘cannot/will not answer’ with single imputation using PMM (with default d = 5 and 20 iterations).^{Reference Buuren19} Fourth, as divorce is frequently occurring in Nordic societies and might not necessarily represent a severe ACE, we performed all analyses excluding this variable as an ACE. Fifth, as women with schizophrenia or bipolar disorder were younger and since recall bias might increase with age, we performed the analyses stratified by age.