ABSTRACT
By September 2022, more than 600 million cases of SARS-CoV-2 infection have been reported globally, resulting in over 6.5 million deaths. COVID-19 mortality risk estimators are often, however, developed with small unrepresentative samples and with methodological limitations. It is highly important to develop predictive tools for pulmonary embolism (PE) in COVID-19 patients as one of the most severe preventable complications of COVID-19. Early recognition can help provide life-saving targeted anti-coagulation therapy right at admission. Using a dataset of more than 800,000 COVID-19 patients from an international cohort, we propose a cost-sensitive gradient-boosted machine learning model that predicts occurrence of PE and death at admission. Logistic regression, Cox proportional hazards models, and Shapley values were used to identify key predictors for PE and death. Our prediction model had a test AUROC of 75.9% and 74.2%, and sensitivities of 67.5% and 72.7% for PE and all-cause mortality respectively on a highly diverse and held-out test set. The PE prediction model was also evaluated on patients in UK and Spain separately with test results of 74.5% AUROC, 63.5% sensitivity and 78.9% AUROC, 95.7% sensitivity. Age, sex, region of admission, comorbidities (chronic cardiac and pulmonary disease, dementia, diabetes, hypertension, cancer, obesity, smoking), and symptoms (any, confusion, chest pain, fatigue, headache, fever, muscle or joint pain, shortness of breath) were the most important clinical predictors at admission. Age, overall presence of symptoms, shortness of breath, and hypertension were found to be key predictors for PE using our extreme gradient boosted model. This analysis based on the, until now, largest global dataset for this set of problems can inform hospital prioritisation policy and guide long term clinical research and decision-making for COVID-19 patients globally. Our machine learning model developed from an international cohort can serve to better regulate hospital risk prioritisation of at-risk patients.
Subject(s)
COVID-19 , Machine Learning , Pulmonary Embolism , Humans , COVID-19/mortality , COVID-19/complications , Pulmonary Embolism/mortality , Male , Female , Middle Aged , Aged , Hospitalization , SARS-CoV-2/isolation & purification , Cohort Studies , Spain/epidemiology , Adult , Aged, 80 and over , Risk Factors , United Kingdom/epidemiologyABSTRACT
Collaborative efforts in artificial intelligence (AI) are increasingly common between high-income countries (HICs) and low- to middle-income countries (LMICs). Given the resource limitations often encountered by LMICs, collaboration becomes crucial for pooling resources, expertise, and knowledge. Despite the apparent advantages, ensuring the fairness and equity of these collaborative models is essential, especially considering the distinct differences between LMIC and HIC hospitals. In this study, we show that collaborative AI approaches can lead to divergent performance outcomes across HIC and LMIC settings, particularly in the presence of data imbalances. Through a real-world COVID-19 screening case study, we demonstrate that implementing algorithmic-level bias mitigation methods significantly improves outcome fairness between HIC and LMIC sites while maintaining high diagnostic sensitivity. We compare our results against previous benchmarks, utilizing datasets from four independent United Kingdom Hospitals and one Vietnamese hospital, representing HIC and LMIC settings, respectively.
Subject(s)
COVID-19 , Developing Countries , Machine Learning , Humans , COVID-19/epidemiology , COVID-19/virology , Developed Countries , SARS-CoV-2/isolation & purification , United Kingdom , Bias , Vietnam , Income , AlgorithmsABSTRACT
Aims: Electrocardiogram (ECG) is widely considered the primary test for evaluating cardiovascular diseases. However, the use of artificial intelligence (AI) to advance these medical practices and learn new clinical insights from ECGs remains largely unexplored. We hypothesize that AI models with a specific design can provide fine-grained interpretation of ECGs to advance cardiovascular diagnosis, stratify mortality risks, and identify new clinically useful information. Methods and results: Utilizing a data set of 2 322 513 ECGs collected from 1 558 772 patients with 7 years follow-up, we developed a deep-learning model with state-of-the-art granularity for the interpretable diagnosis of cardiac abnormalities, gender identification, and hypertension screening solely from ECGs, which are then used to stratify the risk of mortality. The model achieved the area under the receiver operating characteristic curve (AUC) scores of 0.998 (95% confidence interval (CI), 0.995-0.999), 0.964 (95% CI, 0.963-0.965), and 0.839 (95% CI, 0.837-0.841) for the three diagnostic tasks separately. Using ECG-predicted results, we find high risks of mortality for subjects with sinus tachycardia (adjusted hazard ratio (HR) of 2.24, 1.96-2.57), and atrial fibrillation (adjusted HR of 2.22, 1.99-2.48). We further use salient morphologies produced by the deep-learning model to identify key ECG leads that achieved similar performance for the three diagnoses, and we find that the V1 ECG lead is important for hypertension screening and mortality risk stratification of hypertensive cohorts, with an AUC of 0.816 (0.814-0.818) and a univariate HR of 1.70 (1.61-1.79) for the two tasks separately. Conclusion: Using ECGs alone, our developed model showed cardiologist-level accuracy in interpretable cardiac diagnosis and the advancement in mortality risk stratification. In addition, it demonstrated the potential to facilitate clinical knowledge discovery for gender and hypertension detection which are not readily available.
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BACKGROUND: Previous studies have demonstrated that incorporating a polygenic risk score (PRS) to existing risk prediction models for breast cancer improves model fit, but to determine its clinical utility the impact on risk categorization needs to be established. We add a PRS to two well-established models and quantify the difference in classification using the net reclassification improvement (NRI). METHODS: We analyzed data from 126,490 post-menopausal women of "White British" ancestry, aged 40 to 69 years at baseline from the UK Biobank prospective cohort. The breast cancer outcome was derived from linked registry data and hospital records. We combined a PRS for breast cancer with 10-year risk scores from the Tyrer-Cuzick and Gail models, and compared these to the risk scores from the models using phenotypic variables alone. We report metrics of discrimination and classification, and consider the importance of the risk threshold selected. RESULTS: The Harrell's C statistic of the 10-year risk from the Tyrer-Cuzick and Gail models was 0.57 and 0.54, respectively, increasing to 0.67 when the PRS was included. Inclusion of the PRS gave a positive NRI for cases in both models [0.080 (95% confidence interval (CI), 0.053-0.104) and 0.051 (95% CI, 0.030-0.073), respectively], with negligible impact on controls. CONCLUSIONS: The addition of a PRS for breast cancer to the well-established Tyrer-Cuzick and Gail models provides a substantial improvement in the prediction accuracy and risk stratification. IMPACT: These findings could have important implications for the ongoing discussion about the value of PRS in risk prediction models and screening.
Subject(s)
Biological Specimen Banks , Breast Neoplasms , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/diagnosis , Middle Aged , United Kingdom/epidemiology , Aged , Adult , Risk Assessment/methods , Prospective Studies , Risk Factors , Multifactorial Inheritance , Genetic Predisposition to Disease , Genetic Risk Score , UK BiobankABSTRACT
AIMS: We evaluated whether incorporating information on ethnic background and polygenic risk enhanced the Leicester Risk Assessment (LRA) score for predicting 10-year risk of type 2 diabetes. METHODS: The sample included 202,529 UK Biobank participants aged 40-69 years. We computed the LRA score, and developed two new risk scores using training data (80% sample): LRArev, which incorporated additional information on ethnic background, and LRAprs, which incorporated polygenic risk for type 2 diabetes. We assessed discriminative and reclassification performance in a test set (20% sample). Type 2 diabetes was ascertained using primary care, hospital inpatient and death registry records. RESULTS: Over 10 years, 7,476 participants developed type 2 diabetes. The Harrell's C indexes were 0.796 (95% Confidence Interval [CI] 0.785, 0.806), 0.802 (95% CI 0.792, 0.813), and 0.829 (95% CI 0.820, 0.839) for the LRA, LRArev and LRAprs scores, respectively. The LRAprs score significantly improved the overall reclassification compared to the LRA (net reclassification index [NRI] = 0.033, 95% CI 0.015, 0.049) and LRArev (NRI = 0.040, 95% CI 0.024, 0.055) scores. CONCLUSIONS: Polygenic risk moderately improved the performance of the existing LRA score for 10-year risk prediction of type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/epidemiology , Middle Aged , Female , Male , Risk Assessment/methods , Adult , Aged , Follow-Up Studies , Risk Factors , Prognosis , Multifactorial Inheritance , Genetic Predisposition to DiseaseABSTRACT
The design of neural networks typically involves trial-and-error, a time-consuming process for obtaining an optimal architecture, even for experienced researchers. Additionally, it is widely accepted that loss functions of deep neural networks are generally non-convex with respect to the parameters to be optimised. We propose the Layer-wise Convex Theorem to ensure that the loss is convex with respect to the parameters of a given layer, achieved by constraining each layer to be an overdetermined system of non-linear equations. Based on this theorem, we developed an end-to-end algorithm (the AutoNet) to automatically generate layer-wise convex networks (LCNs) for any given training set. We then demonstrate the performance of the AutoNet-generated LCNs (AutoNet-LCNs) compared to state-of-the-art models on three electrocardiogram (ECG) classification benchmark datasets, with further validation on two non-ECG benchmark datasets for more general tasks. The AutoNet-LCN was able to find networks customised for each dataset without manual fine-tuning under 2 GPU-hours, and the resulting networks outperformed the state-of-the-art models with fewer than 5% parameters on all the above five benchmark datasets. The efficiency and robustness of the AutoNet-LCN markedly reduce model discovery costs and enable efficient training of deep learning models in resource-constrained settings.
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The UK Biobank has made general practitioner (GP) data (censoring date 2016-2017) available for approximately 45% of the cohort, whilst hospital inpatient and death registry (referred to as "HES/Death") data are available cohort-wide through 2018-2022 depending on whether the data comes from England, Wales or Scotland. We assessed the importance of case ascertainment via different data sources in UKB for three diseases that are usually first diagnosed in primary care: Parkinson's disease (PD), type 2 diabetes (T2D), and all-cause dementia. Including GP data at least doubled the number of incident cases in the subset of the cohort with primary care data (e.g. from 619 to 1390 for dementia). Among the 786 dementia cases that were only captured in the GP data before the GP censoring date, only 421 (54%) were subsequently recorded in HES. Therefore, estimates of the absolute incidence or risk-stratified incidence are misleadingly low when based only on the HES/Death data. For incident cases present in both HES/Death and GP data during the full follow-up period (i.e. until the HES censoring date), the median time difference between an incident diagnosis of dementia being recorded in GP and HES/Death was 2.25 years (i.e. recorded 2.25 years earlier in the GP records). Similar lag periods were also observed for PD (median 2.31 years earlier) and T2D (median 2.82 years earlier). For participants with an incident GP diagnosis, only 65.6% of dementia cases, 69.0% of PD cases, and 58.5% of T2D cases had their diagnosis recorded in HES/Death within 7 years since GP diagnosis. The effect estimates (hazard ratios, HR) of established risk factors for the three health outcomes mostly remain in the same direction and with a similar strength of association when cases are ascertained either using HES only or further adding GP data. The confidence intervals of the HR became narrower when adding GP data, due to the increased statistical power from the additional cases. In conclusion, it is desirable to extend both the coverage and follow-up period of GP data to allow researchers to maximise case ascertainment of chronic health conditions in the UK.
Subject(s)
Dementia , Diabetes Mellitus, Type 2 , Parkinson Disease , Humans , UK Biobank , Biological Specimen Banks , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Primary Health Care , Dementia/diagnosis , Dementia/epidemiologyABSTRACT
Deep neural networks have been integrated into the whole clinical decision procedure which can improve the efficiency of diagnosis and alleviate the heavy workload of physicians. Since most neural networks are supervised, their performance heavily depends on the volume and quality of available labels. However, few such labels exist for rare diseases (e.g., new pandemics). Here we report a medical multimodal large language model (Med-MLLM) for radiograph representation learning, which can learn broad medical knowledge (e.g., image understanding, text semantics, and clinical phenotypes) from unlabelled data. As a result, when encountering a rare disease, our Med-MLLM can be rapidly deployed and easily adapted to them with limited labels. Furthermore, our model supports medical data across visual modality (e.g., chest X-ray and CT) and textual modality (e.g., medical report and free-text clinical note); therefore, it can be used for clinical tasks that involve both visual and textual data. We demonstrate the effectiveness of our Med-MLLM by showing how it would perform using the COVID-19 pandemic "in replay". In the retrospective setting, we test the model on the early COVID-19 datasets; and in the prospective setting, we test the model on the new variant COVID-19-Omicron. The experiments are conducted on 1) three kinds of input data; 2) three kinds of downstream tasks, including disease reporting, diagnosis, and prognosis; 3) five COVID-19 datasets; and 4) three different languages, including English, Chinese, and Spanish. All experiments show that our model can make accurate and robust COVID-19 decision-support with little labelled data.
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BACKGROUND: Associations between kidney function and dementia risk are inconclusive. Chronic kidney disease (CKD) severity is determined by levels of both estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (ACR). However, whether there is a graded increase in dementia risk for worse eGFR in each ACR category is unclear. Also, whether genetic risk for dementia impacts the associations is unknown. The current study aims to investigate the associations between eGFR and albuminuria with dementia risk both individually and jointly, whether the associations vary by different follow-up periods, and whether genetic factors modified the associations. METHODS: In 202,702 participants aged ≥ 60 years from the UK Biobank, Cox proportional-hazards models were used to examine the associations between eGFR and urine albumin creatinine ratio (ACR) with risk of incident dementia. GFR was estimated based on serum creatinine, cystatin C, or both. The models were restricted to different follow-up periods (< 5 years, 5-10 years, and ≥ 10 years) to investigate potential reverse causation. RESULTS: Over 15 years of follow-up, 6,042 participants developed dementia. Decreased kidney function (eGFR < 60 ml/min/1.73m2) was associated with an increased risk of dementia (Hazard Ratio [HR] = 1.42, 95% Confidence Interval [CI] 1.28-1.58), compared to normal kidney function (≥ 90 ml/min/1.73m2). The strength of the association remained consistent when the models were restricted to different periods of follow-up. The HRs for incident dementia were 1.16 (95% CI 1.07-1.26) and 2.24 (95% CI 1.79-2.80) for moderate (3-30 mg/mmol) and severely increased ACR (≥ 30 mg/mmol) compared to normal ACR (< 3 mg/mmol). Dose-response associations were observed when combining eGFR and ACR, with those in the severest eGFR and ACR group having the greatest risk of dementia (HR = 4.70, 95% CI 2.34-9.43). APOE status significantly modified the association (p = 0.04), with stronger associations observed among participants with a lower genetic risk of dementia. There was no evidence of an interaction between kidney function and non-APOE polygenic risk of dementia with dementia risk (p = 0.42). CONCLUSIONS: Kidney dysfunction and albuminuria were individually and jointly associated with higher dementia risk. The associations were greater amongst participants with a lower genetic risk of dementia based on APOE, but not non-APOE polygenic risk.
Subject(s)
Albuminuria , Dementia , Humans , Albuminuria/epidemiology , Albuminuria/genetics , Biological Specimen Banks , Creatinine , Dementia/epidemiology , Dementia/genetics , Albumins , Kidney , United Kingdom/epidemiologyABSTRACT
OBJECTIVE: To externally evaluate the performance of QRISK3 for predicting 10 year risk of cardiovascular disease (CVD) in the UK Biobank cohort. METHODS: We used data from the UK Biobank, a large-scale prospective cohort study of 403 370 participants aged 40-69 years recruited between 2006 and 2010 in the UK. We included participants with no previous history of CVD or statin treatment and defined the outcome to be the first occurrence of coronary heart disease, ischaemic stroke or transient ischaemic attack, derived from linked hospital inpatient records and death registrations. RESULTS: Our study population included 233 233 women and 170 137 men, with 9295 and 13 028 incident CVD events, respectively. Overall, QRISK3 had moderate discrimination for UK Biobank participants (Harrell's C-statistic 0.722 in women and 0.697 in men) and discrimination declined by age (<0.62 in all participants aged 65 years or older). QRISK3 systematically overpredicted CVD risk in UK Biobank, particularly in older participants, by as much as 20%. CONCLUSIONS: QRISK3 had moderate overall discrimination in UK Biobank, which was best in younger participants. The observed CVD risk for UK Biobank participants was lower than that predicted by QRISK3, particularly for older participants. It may be necessary to recalibrate QRISK3 or use an alternate model in studies that require accurate CVD risk prediction in UK Biobank.
Subject(s)
Brain Ischemia , Cardiovascular Diseases , Stroke , Male , Humans , Female , Aged , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Risk Factors , Prospective Studies , Stroke/epidemiology , Biological Specimen Banks , United Kingdom/epidemiology , Risk AssessmentABSTRACT
We aimed to identify potential novel predictors for breast cancer among post-menopausal women, with pre-specified interest in the role of polygenic risk scores (PRS) for risk prediction. We utilised an analysis pipeline where machine learning was used for feature selection, prior to risk prediction by classical statistical models. An "extreme gradient boosting" (XGBoost) machine with Shapley feature-importance measures were used for feature selection among [Formula: see text] 1.7 k features in 104,313 post-menopausal women from the UK Biobank. We constructed and compared the "augmented" Cox model (incorporating the two PRS, known and novel predictors) with a "baseline" Cox model (incorporating the two PRS and known predictors) for risk prediction. Both of the two PRS were significant in the augmented Cox model ([Formula: see text]). XGBoost identified 10 novel features, among which five showed significant associations with post-menopausal breast cancer: plasma urea (HR = 0.95, 95% CI 0.92-0.98, [Formula: see text]), plasma phosphate (HR = 0.68, 95% CI 0.53-0.88, [Formula: see text]), basal metabolic rate (HR = 1.17, 95% CI 1.11-1.24, [Formula: see text]), red blood cell count (HR = 1.21, 95% CI 1.08-1.35, [Formula: see text]), and creatinine in urine (HR = 1.05, 95% CI 1.01-1.09, [Formula: see text]). Risk discrimination was maintained in the augmented Cox model, yielding C-index 0.673 vs 0.667 (baseline Cox model) with the training data and 0.665 vs 0.664 with the test data. We identified blood/urine biomarkers as potential novel predictors for post-menopausal breast cancer. Our findings provide new insights to breast cancer risk. Future research should validate novel predictors, investigate using multiple PRS and more precise anthropometry measures for better breast cancer risk prediction.
Subject(s)
Breast Neoplasms , Humans , Female , Proportional Hazards Models , Breast Neoplasms/diagnosis , Breast Neoplasms/epidemiology , Biological Specimen Banks , Postmenopause , Machine Learning , United Kingdom/epidemiologyABSTRACT
Context: Early diagnosis of type 2 diabetes is crucial to reduce severe comorbidities and complications. Current screening recommendations for type 2 diabetes include traditional risk factors, primarily body mass index (BMI) and family history, however genetics also plays a key role in type 2 diabetes risk. It is important to understand whether genetic predisposition to type 2 diabetes modifies the effect of these traditional factors on type 2 diabetes risk. Objective: This work aimed to investigate whether genetic risk of type 2 diabetes modifies associations between BMI and first-degree family history of diabetes with 1) prevalent prediabetes or undiagnosed diabetes; and 2) incident confirmed type 2 diabetes. Methods: We included 431 658 individuals aged 40 to 69 years at baseline of multiethnic ancestry from the UK Biobank. We used a multiethnic polygenic risk score for type 2 diabetes (PRST2D) developed by Genomics PLC. Prediabetes or undiagnosed diabetes was defined as baseline glycated hemoglobin greater than or equal to 42â mmol/mol (6.0%), and incident type 2 diabetes was derived from medical records. Results: At baseline, 43 472 participants had prediabetes or undiagnosed diabetes, and 17 259 developed type 2 diabetes over 15 years follow-up. Dose-response associations were observed for PRST2D with each outcome in each category of BMI or first-degree family history of diabetes. Those in the highest quintile of PRST2D with a normal BMI were at a similar risk as those in the middle quintile who were overweight. Participants who were in the highest quintile of PRST2D and did not have a first-degree family history of diabetes were at a similar risk as those with a family history who were in the middle category of PRST2D. Conclusion: Genetic risk of type 2 diabetes remains strongly associated with risk of prediabetes, undiagnosed diabetes, and future type 2 diabetes within categories of nongenetic risk factors. This could have important implications for identifying individuals at risk of type 2 diabetes for prevention and early diagnosis programs.
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INTRODUCTION: There is inconsistent evidence on whether genetic risk for dementia modifies the association between hypertension and dementia. METHODS: In 198,965 dementia-free participants aged ≥60 years, Cox proportional-hazards models were used to investigate the association between hypertension and incident dementia. A polygenic risk score (PRS) based on 38 non-apolipoprotein E (APOE) single nucleotide polymorphisms and APOE ε4 status were used to determine genetic risk for dementia. RESULTS: Over 15 years follow-up, 6270 participants developed dementia. Hypertension was associated with a 19% increased risk of dementia (hazard ratio = 1.19, 95% confidence interval 1.11-1.27). The associations remained similar when stratifying by genetic risk, with no evidence for multiplicative interaction by dementia PRS (P = 0.20) or APOE ε4 status (P = 0.16). However, the risk difference between those with and without hypertension was larger among those at higher genetic risk. DISCUSSION: Hypertension was associated with an increased risk of dementia regardless of genetic risk for dementia.
Subject(s)
Apolipoprotein E4 , Hypertension , Humans , Apolipoprotein E4/genetics , Genotype , Apolipoproteins E/genetics , Risk Factors , Hypertension/epidemiology , Hypertension/geneticsABSTRACT
Background: Current osteoporosis guidelines do not identify individuals with intellectual disabilities (ID) as at risk of fracture, potentially missing opportunities for prevention. We aimed to assess the incidence of fractures in people with ID over the life course. Methods: Descriptive analysis of open cohort study using anonymised electronic health records from the UK Clinical Practice Research Datalink, linked to the Hospital Episode Statistics database (Jan 1, 1998-Dec 31, 2017). All individuals with ID were matched on age and sex to five individuals without ID. We calculated the incidence rate (95% CI) per 10000 person-years (py) and incidence rate ratio (IRR, 95% CI) to compare fractures between individuals with and without ID (age 1-17 and ≥18 years) for any fracture, and in those aged 18-49 and ≥ 50 years for major osteoporotic fracture (vertebra, shoulder, wrist, hip), and for hip fracture. Findings: 43176 individuals with ID (15470 children aged 1-17 years; 27706 adults aged ≥ 18 years) were identified and included (40.4% females) along with 215733 matched control individuals. The median age at study entry was 24 (10th-90th centiles 3-54) years. Over a median (10th-90th centile) follow-up of 7.1 (0.9-17.6) and 6.5 (0.8-17.6) years, there were 5941 and 24363 incident fractures in the ID and non ID groups respectively. Incidence of any fracture was 143.5 (131.8-156.3) vs 120.7 (115.4-126.4)/10000 py (children), 174.2 (166.4-182.4)/10000 py vs 118.2 (115.3-121.2)/10000 py (adults) in females. In males it was 192.5 (182.4-203.2) vs 228.5 (223.0-234.1)/10000 py (children), 155.6 (149.3-162.1)/10000 py vs 128.4 (125.9-131.0)/10000 py (adults). IRR for major osteoporotic fracture was 1.81 (1.50-2.18) age 18-49 years, 1.69 (1.53-1.87) age ≥ 50 years in women. In men it was 1.56 (1.36-1.79) age 18-49 years, 2.45 (2.13-2.81) age ≥ 50 years. IRR for hip fracture was 7.79 (4.14-14.65) age 18-49 years, 2.28 (1.91-2.71) age ≥ 50 years in women. In men it was 6.04 (4.18-8.73) age 18-49 years, 3.91 (3.17-4.82) age ≥ 50 years. Comparable rates of major osteoporotic fracture and of hip fracture occurred approximately 15 and 20 years earlier respectively in women and 20 and 30 years earlier respectively in men with ID than without ID. Fracture distribution differed profoundly, hip fracture 9.9% vs 5.0% of any fracture in adults with ID vs without ID. Interpretation: The incidence, type, and distribution of fractures in people with intellectual disabilities suggest early onset osteoporosis. Prevention and management strategies are urgently required, particularly to reduce the incidence of hip fracture. Funding: National Institute for Health and Care Research.
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Polygenic risk scores (PRS) are proposed for use in clinical and research settings for risk stratification. However, there are limited investigations on how different PRS diverge from each other in risk prediction of individuals. We compared two recently published PRS for each of three conditions, breast cancer, hypertension and dementia, to assess the stability of using these algorithms for risk prediction in a single large population. We used imputed genotyping data from the UK Biobank prospective cohort, limited to the White British subset. We found that: (1) 20% or more of SNPs in the first PRS were not represented in the more recent PRS for all three diseases, by the same SNP or a surrogate with R2 > 0.8 by linkage disequilibrium (LD). (2) Although the difference in the area under the receiver operating characteristic curve (AUC) obtained using the two PRS is hardly appreciable for all three diseases, there were large differences in individual risk prediction between the two PRS. For instance, for each disease, of those classified in the top 5% of risk by the first PRS, over 60% were not so classified by the second PRS. We found substantial discordance between different PRS for the same disease, indicating that individuals could receive different medical advice depending on which PRS is used to assess their genetic susceptibility. It is desirable to resolve this uncertainty before using PRS for risk stratification in clinical settings.
Subject(s)
Genome-Wide Association Study , Multifactorial Inheritance , Biological Specimen Banks , Genetic Predisposition to Disease , Humans , Multifactorial Inheritance/genetics , Polymorphism, Single Nucleotide , Prospective Studies , Risk Factors , United KingdomABSTRACT
A polygenic risk score estimates the genetic risk of an individual for some disease or trait, calculated by aggregating the effect of many common variants associated with the condition. With the increasing availability of genetic data in large cohort studies such as the UK Biobank, inclusion of this genetic risk as a covariate in statistical analyses is becoming more widespread. Previously this required specialist knowledge, but as tooling and data availability have improved it has become more feasible for statisticians and epidemiologists to calculate existing scores themselves for use in analyses. While tutorial resources exist for conducting genome-wide association studies and generating of new polygenic risk scores, fewer guides exist for the simple calculation and application of existing genetic scores. This guide outlines the key steps of this process: selection of suitable polygenic risk scores from the literature, extraction of relevant genetic variants and verification of their quality, calculation of the risk score and key considerations of its inclusion in statistical models, using the UK Biobank imputed data as a model data set. Many of the techniques in this guide will generalize to other datasets, however we also focus on some of the specific techniques required for using data in the formats UK Biobank have selected. This includes some of the challenges faced when working with large numbers of variants, where the computation time required by some tools is impractical. While we have focused on only a couple of tools, which may not be the best ones for every given aspect of the process, one barrier to working with genetic data is the sheer volume of tools available, and the difficulty for a novice to assess their viability. By discussing in depth a couple of tools that are adequate for the calculation even at large scale, we hope to make polygenic risk scores more accessible to a wider range of researchers.
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AIMS: Many studies have investigated associations between polygenic risk scores (PRS) and the incidence of cardiovascular disease (CVD); few have examined whether risk factor-related PRS predict CVD outcomes among adults treated with risk-modifying therapies. We assessed whether PRS for systolic blood pressure (PRSSBP) and for low-density lipoprotein cholesterol (PRSLDL-C) were associated with achieving SBP and LDL-C-related targets, and with major adverse cardiovascular events (MACE: non-fatal stroke or myocardial infarction, CVD death, and revascularization procedures). METHODS AND RESULTS: Using observational data from the UK Biobank (UKB), we calculated PRSSBP and PRSLDL-C and constructed two sub-cohorts of unrelated adults of White British ancestry aged 40-69 years and with no history of CVD, who reported taking medications used in the treatment of hypertension or hypercholesterolaemia. Treatment effectiveness in achieving adequate risk factor control was ascertained using on-treatment blood pressure (BP) or LDL-C levels measured at enrolment (uncontrolled hypertension: BP ≥ 140/90 mmHg; uncontrolled hypercholesterolaemia: LDL-C ≥ 3 mmol/L). We conducted multivariable logistic and Cox regression modelling for incident events, adjusting for socioeconomic characteristics, and CVD risk factors. There were 55 439 participants using BP lowering therapies (51.0% male, mean age 61.0 years, median follow-up 11.5 years) and 33 787 using LDL-C lowering therapies (58.5% male, mean age 61.7 years, median follow-up 11.4 years). PRSSBP was associated with uncontrolled hypertension (odds ratio 1.70; 95% confidence interval: 1.60-1.80) top vs. bottom quintile, equivalent to a 5.4 mmHg difference in SBP, and with MACE [hazard ratio (HR) 1.13; 1.04-1.23]. PRSLDL-C was associated with uncontrolled hypercholesterolaemia (HR 2.78; 2.58-3.00) but was not associated with subsequent MACE. CONCLUSION: We extend previous findings in the UKB cohort to examine PRSSBP and PRSLDL-C with treatment effectiveness. Our results indicate that both PRSSBP and PRSLDL-C can help identify individuals who, despite being on treatment, have inadequately controlled SBP and LDL-C, and for SBP are at higher risk for CVD events. This extends the potential role of PRS in clinical practice from identifying patients who may need these interventions to identifying patients who may need more intensive intervention.
Subject(s)
Blood Pressure , Cardiovascular Diseases , Cholesterol, LDL , Hypercholesterolemia , Hypertension , Myocardial Infarction , Adult , Blood Pressure/genetics , Blood Pressure/physiology , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Cholesterol, LDL/genetics , Female , Humans , Hypercholesterolemia/diagnosis , Hypercholesterolemia/drug therapy , Hypercholesterolemia/epidemiology , Hypertension/diagnosis , Hypertension/drug therapy , Hypertension/epidemiology , Male , Middle Aged , Myocardial Infarction/complications , Risk Factors , Treatment OutcomeABSTRACT
INTRODUCTION: Little is known about the association between speech-in-noise (SiN) hearing impairment and dementia. METHODS: In 82,039 dementia-free participants aged ≥60 years were selected from the UK Biobank. Cox proportional-hazards models were used to investigate whether SiN hearing impairment is associated with an increased risk of incident dementia. RESULTS: Over 11 years of follow-up (median = 10.1), 1285 participants developed dementia. Insufficient and poor SiN hearing were associated with a 61% (hazard ratio [HR] = 1.61, 95% confidence [CI] 1.41-1.84) and 91% (HR = 1.91, 95% CI 1.55-2.36) increased risk of developing dementia, respectively, compared to normal SiN hearing. The association remained similar when restricting to follow-up intervals of ≤3, >3 to <6, >6 to <9, and >9 years. There was limited evidence for mediation through depressive symptoms and social isolation. DISCUSSION: SiN hearing impairment is independently associated with incident dementia, providing further evidence for hearing impairment as a potential modifiable dementia risk factor.
Subject(s)
Dementia , Hearing Loss , Biological Specimen Banks , Dementia/diagnosis , Hearing , Hearing Loss/complications , Hearing Loss/epidemiology , Humans , Risk Factors , Speech , United Kingdom/epidemiologyABSTRACT
OBJECTIVE: To identify factors associated with hypertension control among treated middle-aged UK adults. METHODS: A cross-sectional population-based study including 99 468 previously diagnosed, treated hypertensives enrolled in the UK Biobank. Hypertension control was defined as systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg. RESULTS: Median age was 62.3 years (IQR 57.3 to 66.0), 45.9% female, 92.0% white, 40.1% obese, 9.3% current smokers and 19.4% had prior cardiovascular disease. 38.1% (95% CI 37.8% to 38.4%) were controlled. In multivariable logistic regression, associations with lack of hypertension control included: older age (OR 0.61, 95% CI 0.58 to 0.64 for 60-69 years compared with age 40-50 years), higher alcohol use (OR 0.61, 95% CI 0.58 to 0.64, for consuming >30 units per week compared with none), black ethnicity (OR 0.73, 95% CI 0.65 to 0.82 compared with white), obesity (OR 0.73, 95% CI 0.71 to 0.76 compared with normal body mass index). The strongest positive association with control was having ≥3 comorbidities (OR 2.09, 95% CI 1.95 to 2.23). Comorbidities associated with control included cardiovascular disease (OR 2.11, 95% CI 2.04 to 2.19), migraines (OR 1.68, 95% CI 1.56 to 1.81), diabetes (OR 1.32, 95% CI 1.27 to 1.36) and depression (OR 1.27, 95% CI 1.20 to 1.34). CONCLUSIONS: In one of the largest population-based analyses of middle-aged adults with measured blood pressure, the majority of treated hypertensives were uncontrolled. Risk factors for hypertension were associated with a lower probability of control. Having a comorbidity was associated with higher probability of control, possibly due to more frequent interaction with the healthcare system and/or appropriate management of those at greater cardiovascular risk.
Subject(s)
Antihypertensive Agents/therapeutic use , Blood Pressure/physiology , Hypertension/epidemiology , Adult , Aged , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Hypertension/drug therapy , Hypertension/physiopathology , Male , Middle Aged , Prevalence , Prospective Studies , Risk Factors , United Kingdom/epidemiologyABSTRACT
INTRODUCTION: Hypertension is a leading risk factor for cardiovascular mortality and an emerging public health concern in sub-Saharan Africa. Few studies have examined performance on the management of hypertension in this region, where the context may be distinct from other developing regions. OBJECTIVES: We aimed to determine the prevalence and correlates of hypertension, awareness, treatment, and control among adults in Botswana, a middle-income African country undergoing rapid demographic transition and with high HIV burden. METHODS: In this 2014 cross-sectional survey of adults aged 15-69 years, information on sociodemographic characteristics, lifestyle behavior, and medical history was collected through in-person interviews and physical measurements (body mass index and triplicate blood pressure (BP)). Hypertension was defined as self-report of use of antihypertensives in the previous two weeks and/or having elevated BP (≥140/90 mmHg). Multivariable logistic regression was employed to explore factors associated with hypertension, awareness (report of previous diagnosis), treatment (antihypertensives), and control (BP < 140/90). RESULTS: Our analysis (N = 4,007) yielded an age-standardized hypertension prevalence of 30% (95% CI: 28%-32%, N = 1,393). Among hypertensives, 54% (50-58%) were unaware of their condition, 45% (40-50%) of those aware were untreated, and 63% (55-70%) of those on medications were suboptimally treated (BP ≥ 140/90 mmHg). A fifth of hypertensives who were diagnosed but not on medications had BP ≥ 180/110 mmHg. Diabetes was the strongest correlate of hypertension and awareness (aOR 4.00, 1.86-8.59; aOR 3.30, 1.44-7.55, respectively). Males were less likely to be aware (aOR 0.62, 0.41-0.94) or controlled (aOR 0.36, 0.16-0.83). Obese individuals were more likely to be treated (aOR 2.17, 1.12-4.22), yet less likely to be controlled (aOR 0.32, 0.15-0.66). CONCLUSIONS: We report the first nationally representative estimates of the hypertension care cascade performance in Botswana, which will support planning and future policy evaluations. Findings contribute to the relatively sparse evidence on this subject and may inform development of innovations that improve quality of hypertension management and adherence support in similar settings.