Identifying modifiable factors and their joint associations on late-onset schizophrenia risk in the UK Biobank: a prospective exposure-wide association study

Associations between residential environments and late-onset schizophrenia in UK Biobank: Interaction with genetic risk factor

Despite extensive research, significant uncertainty remains regarding the associations between various risk factors and ischemic stroke (IS). This study aimed to systematically identify and validate a broad range of potential modifiable risk factors for IS. Utilizing genetic and phenotypic data from the UK Biobank (UKB; N = 418,236), we conducted a phenome-wide association study (PheWAS) and Cox regression analysis to identify modifiable factors across sociodemographics, physical measures, lifestyles, medical history, mental health, and biological assays associated with both polygenic risk scores for IS (IS-PRS) and incident IS. To assess potential causal relationships, two-sample Mendelian randomization (MR) analysis was further performed. Among the 1,023 modifiable factors examined, 145 were significantly associated with both IS-PRS and incident IS. Notably, better lung function and more computer use were associated with decreased IS risk, whereas more summer outdoor exposure, sleep-related factors, mental health factor, and facial ageing were linked to increased IS risk. The strongest association was observed for pneumonitis due to solids and liquids, with a hazard ratio (HR) and 95% confidence interval (CI) of 7.65 (7.06- 8.28). MR analysis provided further causal evidence supporting 31 of the identified risk factors and confirmed the casual associations of worse lung function, greater summer outdoor exposure and longer daytime napping with increased IS risk. The study comprehensively identified a wide range of novel modifiable risk factors for IS, including physical, lifestyle, and mental health indicators. These findings may contribute to the development of more targeted and effective prevention strategies for IS.

Previous hypothesis-driven research has identified many risk factors linked to dementia. However, the multiplicity and co-occurrence of risk factors have been underestimated. Here we analysed data of 344,324 participants from the UK Biobank with 15 yr of follow-up data for 210 modifiable risk factors. We first conducted an exposure-wide association study and then combined factors associated with dementia to generate composite scores for different domains. We then evaluated their joint associations with dementia in a multivariate Cox model. We estimated the potential impact of eliminating the unfavourable profiles of risk domains on dementia using population attributable fraction. The associations varied by domain, with lifestyle (16.6%), medical history (14.0%) and socioeconomic status (13.5%) contributing to the majority of dementia cases. Overall, we estimated that up to 47.0%-72.6% of dementia cases could be prevented.

The aim of this study was to determine whether puberty plays a mediating role in onset of schizophrenia. The hypothesis was that there is an inverse relation between age at puberty (menarche) and age at onset in women. Competent and consenting individuals with DSM-IV-defined schizophrenia or schizoaffective disorder and their mothers underwent a 45-minute interview to ascertain age at first odd behavior, age at first psychotic symptoms, age at first hospitalization, and ages at various indices of puberty. Information about substance use, head injury, perinatal trauma, and first-degree family history of schizophrenia was also obtained. In the women (N = 35), the earlier the age at menarche, the later the ages at both the first psychotic symptoms and the first hospitalization. There was no significant association between puberty and onset in the men (N = 45). Other than gender, none of the examined variables played a role in the interaction of puberty and onset of illness. In women, early puberty (whether through hormonal or social influence) was associated with later onset of schizophrenia. This effect was not found in men; in fact, the trend was in the opposite direction.

Objectives: Given the escalating global prevalence of age-related cognitive impairments, identifying modifiable factors is crucial for developing targeted interventions. Methods: After excluding participants with dementia and substantial missing data, 453,950 individuals from UK Biobank (UKB) were included. Cognitive decline was assessed across four cognitive domains. The top 10% exhibiting the greatest decline were categorized as the "Cognitively At-Risk Population". Eighty-three potential factors from three categories were analyzed. Univariate and multivariate Cox proportional hazards models were employed to assess the independent and joint effects of these factors on cognitive decline. Population Attributable Fractions (PAFs) were calculated to estimate the potential impact of eliminating each risk category. Results: Our findings revealed a significant impact of unfavorable medical and psychiatric histories on processing speed and visual episodic memory decline (Hazard Ratio (HR) = 1.34, 95% CI: 1.20-1.51, p = 6.06 × 10⁻7; HR = 1.50, 95% CI: 1.22-1.86, p = 1.62 × 10⁻4, respectively). Furthermore, PAF analysis indicated that physiological and biochemical markers were the most critical risk category for preventing processing speed decline (PAF = 7.03%), while social and behavioral factors exerted the greatest influence on preventing visual episodic memory decline (PAF = 9.68%). Higher education, socioeconomic status, and handgrip strength emerged as protective factors, whereas high body mass index (BMI), hypertension, and depression were detrimental. Conclusions: By identifying this high-risk group and quantifying the impact of modifiable factors, this study provides valuable insights for developing targeted interventions to delay cognitive decline and improve public health outcomes in middle-aged and older adults.

Modifiable risk factors for schizophrenia and autism — Shared risk factors impacting on brain development

ICD-11 (International Classification of Diseases, 11th Revision) is the next major revision of the ICD by the World Health Organization (WHO). ICD-11 differs dramatically from historical versions, as it is based on an underlying semantic network of terms and meaning, called the Foundation. To function as a mutually exclusive and exhaustive statistical classification, ICD-11 creates derivative linearizations from the network that is a monohierarchy with residual categories such as Not Elsewhere Classified. ICD-11 also introduces the widespread post-coordination of terms, which allows for highly expressive representation of detailed patient descriptions. Phenotyping features are included in many subchapters or the signs and symptoms chapter. Composite phenotype descriptions of specific presentations or syndromes can be represented though post-coordination. Rare diseases are well represented in the Foundation, though not all appear in the relatively shallow linearization hierarchies.

Population attributable fraction of lung cancer due to genetic variants, modifiable risk factors, and their interactions: a nationwide prospective cohort study

In April 2003 the Alberta government integrated specialized mental health services, formerly organized independently, with the health regions, which are responsible for general health services. The objective of this article is to determine whether the transfer was associated with an increase or decrease in the share of resources in the region allocated to mental health care relative to total spending for health care. The measure of the share for mental health care is the total costs for mental health care resources as a percentage of total health care spending. Resources and spending examined were those that were actually or potentially under the regions' control. Annual costs for mental health services in the province were obtained for a seven-year period (fiscal year [FY] 2000 through FY 2006) from provincial utilization records for all residents in the province. Unit costs were assigned to each visit. The trend in the share measure was plotted for each year. The share for mental health care increased overall from FY 2000 (7.6%) to FY 2003 (8.2%), but returned to pre-FY 2003 levels in the three years after the transfer (7.6%). Despite concerns expressed before the transfer by federal and provincial reports over the level of expenditures devoted to mental health care, the integration of mental health services with other health services did not result in an increase of the share for mental health care.

The repetition of hospital-treated self-harm by young people is common. However, little work has summarised the modifiable factors associated with this. A thorough understanding of those factors most strongly associated with repetition could guide the development of relevant clinical interventions. We systematically reviewed four databases (EMBASE, Medline, PubMed and PsycINFO) until 15 April 2016 to identify all observational studies of factors for the repetition of self-harm or suicide reattempts (together referred to as 'self-harm behaviour') in young people. We quantified the magnitude of association with odds ratios (OR) and 95% confidence intervals (CIs) and calculated the population attributable risk (PAR) and population preventable fraction (PPF) for modifiable factors to provide an indication of the potential impact in reducing subsequent self-harm behaviour in this population. Seventeen studies were included comprising 10,726 participants. Borderline personality disorder (OR 3.47, 95% CI 1.84-6.53; PAR 42.4%), any personality disorder (OR 2.54, 95% CI 1.71-3.78; PAR 16.3%), and any mood disorder (OR 2.16, 95% CI 1.09-4.29; PAR 42.2%) are important modifiable risk factors. Severity of hopelessness (OR 2.95, 95% CI 1.74-5.01), suicidal ideation (OR 2.01, 95% CI 1.43-2.81), and previous sexual abuse (OR 1.52, 95% CI 1.02-2.28; PAR 12.8%) are also associated with repetition of self-harm. We recommend that clinical services should focus on identifying key modifiable risk factors at the individual patient level, whilst the reduction of exposure to child and adolescent sexual abuse would also be a useful goal for public health interventions.

A thorough understanding and identification of potential determinants leading to frailty are imperative for the development of targeted interventions aimed at its prevention or mitigation. We investigated the potential determinants of frailty in a cohort of 469,301 UK Biobank participants. The evaluation of frailty was performed using the Fried index, which encompasses measurements of handgrip strength, gait speed, levels of physical activity, unintentional weight loss, and self-reported exhaustion. EWAS including 276 factors were first conducted. Factors associated with frailty in EWAS were further combined to generate composite scores for different domains, and joint associations with frailty were evaluated in a multivariate logistic model. The potential impact on frailty when eliminating unfavorable profiles of risk domains was evaluated by PAFs. A total of 21,020 (4.4%) participants were considered frailty, 192,183 (41.0%) pre-frailty, and 256,098 (54.6%) robust. The largest EWAS identified 90 modifiable factors for frailty across ten domains, each of which independently increased the risk of frailty. Among these factors, 67 have the potential to negatively impact health, while 23 have been found to have a protective effect. When shifting all unfavorable profiles to intermediate and favorable ones, overall adjusted PAF for potentially modifiable frailty risk factors was 85.9%, which increases to 86.6% if all factors are transformed into favorable tertiles. Health and medical history, psychosocial factors, and physical activity were the most significant contributors, accounting for 11.9%, 10.4%, and 10.1% respectively. This study offers valuable insights for developing population-level strategies aimed at preventing frailty.

The causes of racial disparities in epithelial ovarian cancer (EOC) incidence remain unclear. Differences in the prevalence of ovarian cancer risk factors may explain disparities in EOC incidence among African American (AA) and White women. We used data from 4 case-control studies and 3 case-control studies nested within prospective cohorts in the Ovarian Cancer in Women of African Ancestry Consortium to estimate race-specific associations of 10 known or suspected EOC risk factors using logistic regression. Using the Bruzzi method, race-specific population attributable risks (PAR) were estimated for each risk factor individually and collectively, including groupings of exposures (reproductive factors and modifiable factors). All statistical tests were 2-sided. Among 3244 White EOC cases and 9638 controls and 1052 AA EOC cases and 2410 controls, AA women had a statistically significantly higher PAR (false discovery rate [FDR] P < .001) for first-degree family history of breast cancer (PAR = 10.1%, 95% confidence interval [CI] = 6.5% to 13.7%) compared with White women (PAR = 2.6%, 95% CI = 0.8% to 4.4%). After multiple test correction, AA women had a higher PAR than White women when evaluating all risk factors collectively (PAR = 61.6%, 95% CI = 48.6% to 71.3% vs PAR = 43.0%, 95% CI = 32.8% to 51.4%, respectively; FDR P = .06) and for modifiable exposures, including body mass index, oral contraceptives, aspirin, and body powder (PAR = 36.0%, 95% CI = 21.0% to 48.8% vs PAR = 13.8%, 95% CI = 4.5% to 21.8%, respectively; FDR P = .04). Collectively, the selected risk factors accounted for slightly more of the risk among AA than White women, and interventions to reduce EOC incidence that are focused on multiple modifiable risk factors may be slightly more beneficial to AA women than White women at risk for EOC.

Stroke prevention requires effective treatment of its causes. Many etiological factors for stroke have been identified, but the potential gain of effective intervention on these factors in terms of numbers of actually prevented strokes remains unclear because of the lack of data from cohort studies. We assessed the impact of currently known potentially modifiable etiological factors on the occurrence of stroke. This population-based cohort study was based on 6,844 participants of the Rotterdam Study who were aged ≥55 y and free from stroke at baseline (1990-1993). We computed population attributable risks (PARs) for individual risk factors and for risk factors in combination to estimate the proportion of strokes that could theoretically be prevented by the elimination of etiological factors from the population. The mean age at baseline was 69.4 y (standard deviation 6.3 y). During follow-up (mean follow-up 12.9 y, standard deviation 6.3 y), 1,020 strokes occurred. The age- and sex-adjusted combined PAR of prehypertension/hypertension, smoking, diabetes mellitus, atrial fibrillation, coronary disease, and overweight/obesity was 0.51 (95% CI 0.41-0.62) for any stroke; hypertension and smoking were the most important etiological factors. C-reactive protein, fruit and vegetable consumption, and carotid intima-media thickness in combination raised the total PAR by 0.06. The PAR was 0.55 (95% CI 0.41-0.68) for ischemic stroke and 0.70 (95% CI 0.45-0.87) for hemorrhagic stroke. The main limitations of our study are that our study population comprises almost exclusively Caucasians who live in a middle and high income area, and that risk factor awareness is higher in a study cohort than in the general population. About half of all strokes are attributable to established causal and modifiable factors. This finding encourages not only intervention on established etiological factors, but also further study of less well established factors. Please see later in the article for the Editors' Summary.

BackgroundModifiable factors affect cancer’s survival but literature did not differentiate prior to versus after cancer diagnosis. It is essential to provide references for the intervention prioritized at different stages.MethodsIn this prospective cohort study, we analyzed national data from the UK Biobank, including 121,399 participants, to assess the association of modifiable factors with cancer-specific survival (CSS) in two independent cohorts: a pre-cancer cohort (n = 78,027) and a post-cancer cohort (n = 43,372). Additionally, a weighted standardized score was derived to evaluate the joint effects across different domains. Interactions between the six domains and age at diagnosis, sex, and cancer site were evaluated using likelihood ratio tests. Subgroup analyses were then performed for factors showing significant effect modification. Population-attributable fractions (PAF) of different domains on 5-year cancer-specific death were calculated.ResultsOur study comprehensively presented the differential patterns of modifiable factors’ impact on CSS among pre-cancer and post-cancer cohorts, sexes and different cancer sites. In the pre-cancer cohort, CSS were predominantly attributable to smoking/alcohol consumption (PAF 9·2%) and daily activity (PAF 10·6%). Men exhibited a higher risk than women for dietary habits (HR:1·25 versus 1·18), daily activity (HR:1·50 versus 1·29) and living environment (HR:1·13 versus 1·03). The impact of modifiable factors, including daily activity, smoking/alcohol consumption, and physical measures, on CSS varied across different cancer sites. In the post-cancer cohort, 18·6% of 5-year cancer-specific deaths were attributable to unfavourable mental health. In subgroup analysis, the risk of CSS in the domain of smoking/alcohol consumption was higher in men than that in women (HR: 1·58 versus 1·34). The impact of modifiable factors, including smoking/alcohol consumption, mental health and physical measures, on CSS varied across different cancer sites.ConclusionsOur findings suggested that targeted prevention and early intervention strategies should be implemented to reduce the risk of cancer-related deaths.

Van Os is correct that the various categories of “psychotic” illness we find in ICD-10 (international classification of diseases, 10th revision) do not represent discrete diseases but rather describe clusters...