Genome-wide association studies have shown unequivocally that common complex disorders have a polygenic genetic architecture and have enabled researchers to identify genetic variants associated with diseases. These variants can be combined into a polygenic risk score that captures part of an individual’s susceptibility to diseases. Polygenic risk scores have been widely applied in research studies, confirming the association between the scores and disease status, but their clinical utility has yet to be established. Polygenic risk scores may be used to estimate an individual’s lifetime genetic risk of disease, but the current discriminative ability is low in the general population. Clinical implementation of polygenic risk score (PRS) may be useful in cohorts where there is a higher prior probability of disease, for example, in early stages of diseases to assist in diagnosis or to inform treatment choices. Important considerations are the weaker evidence base in application to non-European ancestry and the challenges in translating an individual’s PRS from a percentile of a normal distribution to a lifetime disease risk. In this review, we consider how PRS may be informative at different points in the disease trajectory giving examples of progress in the field and discussing obstacles that need to be addressed before clinical implementation.

/pdf/polygenic-risk-scores-from-research-tools-to-clinical-48mu53ya0e.pdf

Polygenic risk scores: from research tools to clinical instruments

Importance Genetic and lifestyle factors both contribute to the risk of developing cardiovascular disease, but whether poor health behaviors are associated with similar increases in risk among individuals with low, intermediate, or high genetic risk is unknown. Objective To investigate the association of combined health behaviors and factors within genetic risk groups with coronary artery disease, atrial fibrillation, stroke, hypertension, and type 2 diabetes as well as to investigate the interactions between genetic risk and lifestyle. Design, Setting, and Participants The UK Biobank cohort study includes more than 500 000 participants aged 40 to 70 years who were recruited from 22 assessment centers across the United Kingdom from 2006 to 2010. A total of 339 003 unrelated individuals of white British descent with available genotype and matching genetic data and reported sex were included in this study from the UK Biobank population-based sample. Individuals were included in the analyses of 1 or more new-onset diseases. Data were analyzed from April 2006 to March 2015. Main Outcomes and Measures Risks of new-onset cardiovascular disease and diabetes associated with genetic risk and combined health behaviors and factors. Genetic risk was categorized as low (quintile 1), intermediate (quintiles 2-4), or high (quintile 5). Within each genetic risk group, the risks of incident events associated with ideal, intermediate, or poor combined health behaviors and factors were investigated and compared with low genetic risk and ideal lifestyle. Results Of 339 003 individuals, 181 702 (53.6%) were female, and the mean (SD) age was 56.86 (7.99) years. During follow-up, 9771 of 325 133 participants (3.0%) developed coronary artery disease, 7095 of 333 637 (2.1%) developed atrial fibrillation, 3145 of 332 971 (0.9%) developed stroke, 11 358 of 234 651 (4.8%) developed hypertension, and 4379 of 322 014 (1.4%) developed diabetes. Genetic risk and lifestyle were independent predictors of incident events, and there were no interactions for any outcome. Compared with ideal lifestyle in the low genetic risk group, poor lifestyle was associated with a hazard ratio of up to 4.54 (95% CI, 3.72-5.54) for coronary artery disease, 5.41 (95% CI, 4.29-6.81) for atrial fibrillation, 4.68 (95% CI, 3.85-5.69) for hypertension, 2.26 (95% CI, 1.63-3.14) for stroke, and 15.46 (95% CI, 10.82-22.08) for diabetes in the high genetic risk group. Conclusions and Relevance In this large contemporary population, genetic composition and combined health behaviors and factors had a log-additive effect on the risk of developing cardiovascular disease. The relative effects of poor lifestyle were comparable between genetic risk groups. Behavioral lifestyle changes should be encouraged for all through comprehensive, multifactorial approaches, although high-risk individuals may be selected based on the genetic risk.

/pdf/associations-of-combined-genetic-and-lifestyle-risks-with-47g1y22y3q.pdf

Associations of Combined Genetic and Lifestyle Risks With Incident Cardiovascular Disease and Diabetes in the UK Biobank Study

Importance The incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain. Objective To examine whether a polygenic risk score for CAD improves risk prediction beyond pooled cohort equations. Design, Setting, and Participants Observational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency–matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD. Exposures Polygenic risk score for CAD, pooled cohort equations, and both combined. Main Outcomes and Measures CAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed. Results In the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women [58.2%]) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and −0.4% (95% CI, −0.5% to −0.4%) for noncases (overall net reclassification improvement, 4.0% [95% CI, 3.1% to 4.9%]). Conclusions and Relevance The addition of a polygenic risk score for CAD to pooled cohort equations was associated with a statistically significant, yet modest, improvement in the predictive accuracy for incident CAD and improved risk stratification for only a small proportion of individuals. The use of genetic information over the pooled cohort equations model warrants further investigation before clinical implementation.

/pdf/predictive-accuracy-of-a-polygenic-risk-score-enhanced-315dp6df4f.pdf

Predictive Accuracy of a Polygenic Risk Score-Enhanced Prediction Model vs a Clinical Risk Score for Coronary Artery Disease.

As penal power has been transformed in recent years, so too have relationships between prisoners and staff. This article discusses how these relationships are forged by the terms of ‘neo-paternalism’, focusing in particular on what is labelled ‘soft power’. It describes some of the impediments that hinder the development of closer relationships between prisoners and uniformed staff. It explores the implications of soft power for the prison’s interior legitimacy, and discusses soft power in relation to the culture of uniformed staff.

Soft power in prison: Implications for staff–prisoner relationships, liberty and legitimacy:

Empirical research on the moral quality of life in prison suggests that some prisons are more survivable than others. Prisoners describe stark differences in the moral and emotional climates of pri...

Moral performance, inhuman and degrading treatment and prison pain:

The Prison Officer

Objective To determine whether provision of web-based lifestyle advice and coronary heart disease risk information either based on phenotypic characteristics or phenotypic plus genetic characteristics affects changes in objectively measured health behaviours. Methods A parallel-group, open randomised trial including 956 male and female blood donors with no history of cardiovascular disease (mean [SD] age=56.7 [8.8] years) randomised to four study groups: control group (no information provided); web-based lifestyle advice only (lifestyle group); lifestyle advice plus information on estimated 10-year coronary heart disease risk based on phenotypic characteristics (phenotypic risk estimate) (phenotypic group) and lifestyle advice plus information on estimated 10-year coronary heart disease risk based on phenotypic (phenotypic risk estimate) and genetic characteristics (genetic risk estimate) (genetic group). The primary outcome was change in physical activity from baseline to 12 weeks assessed by wrist-worn accelerometer. Results 928 (97.1%) participants completed the trial. There was no evidence of intervention effects on physical activity (difference in adjusted mean change from baseline): lifestyle group vs control group 0.09 milligravity (mg) (95% CI −1.15 to 1.33); genetic group vs phenotypic group −0.33 mg (95% CI −1.55 to 0.90); phenotypic group and genetic group vs control group −0.52 mg (95% CI −1.59 to 0.55) and vs lifestyle group −0.61 mg (95% CI −1.67 to 0.46). There was no evidence of intervention effects on secondary biological, emotional and health-related behavioural outcomes except self-reported fruit and vegetable intake. Conclusions Provision of risk information, whether based on phenotypic or genotypic characteristics, alongside web-based lifestyle advice did not importantly affect objectively measured levels of physical activity, other health-related behaviours, biological risk factors or emotional well-being. Trial registration number ISRCTN17721237; Pre-results.

https://heart.bmj.com/content/heartjnl/105/13/982.full.pdf

Effect of communicating phenotypic and genetic risk of coronary heart disease alongside web-based lifestyle advice: the INFORM Randomised Controlled Trial

Objective To describe and explore perceptions, practices and motivations for active living in later life. Design Qualitative study with semistructured interviews and ‘semistructured’ participant observations of participant-selected activities, such as exercise classes, private or organised walks, shopping and gardening. Participants 27 participants (65–80 years) from the European Prospective Investigation into Cancer Norfolk study, purposefully selected by gender, age, occupational class, living status and residential location; 19 of the participants agreed to be accompanied for observed activities. Setting Participants’ homes, neighbourhoods, places of leisure activities and workplaces in Norfolk, England. Results All participants regarded a positive attitude as important for healthy ageing; this included staying active, both physically and mentally through sedentary activities such as reading and crosswords. ‘Getting out of the house’, being busy, or following a variety of interests were regarded as both important motivators and descriptions of their ‘activeness’. Purposeful activities formed an important part of this, for example, still being engaged in paid or voluntary work, having caring responsibilities, or smaller incidental activities such as helping neighbours or walking for transport. Many also reported adapting previous, often lifelong, activity preferences and habits to their ageing body, or replacing them altogether with lower impact activities such as walking. This included adapting to the physical limitations of partners and friends which dictated the intensity and frequency of shared activities. The social context of activities could thus form a barrier to active living, but could also encourage it through companionship, social responsibilities and social pressures. Conclusions Promoting and maintaining physical activity among older people may require more attention to activeness as an attitude and way of life as well as to its social context, and initiatives encouraging broader activity habits rather than discrete activities.

https://bmjopen.bmj.com/content/bmjopen/6/1/e009973.full.pdf

‘Keeping your body and mind active’: an ethnographic study of aspirations for healthy ageing

This article explores one interesting finding emerging from early findings of studies comparing private and public prisons in the UK: the relationship between prisoners and staff. These relationshi...

Prison privatization In search of a business-like atmosphere?

Individuals routinely receive information about their risk of coronary heart disease (CHD) based on traditional risk factors as part of their primary care. We are also able to calculate individual’s risk of CHD based on their genetic information and at present genetic testing for common diseases is available to the public. Due to the limitations in previous studies further understanding is needed about the impact of the risk information on individual’s well-being and health-behaviour. We aimed to explore the short term response to receiving different forms of CHD risk information and lifestyle advice for risk reduction. We conducted fourty-one face-to-face interviews and two focus groups across England with participants from the INFORM trial who received a combination of individualised phenotypic and genotypic CHD risk scores and web-based lifestyle advice. Risk scores were presented in different formats, e.g. absolute 10 year risk was presented as a thermometer and expressed as a percentage, natural frequency and ‘heart age’. Interviews and focus groups explored participants’ understanding and reaction to the risk scores and attempts to change lifestyle during the intervention. We tape-recorded and transcribed the interviews and focus groups and analysed them using thematic analysis. Three main themes were identified: limitations of risk scores to generate concern about CHD risk; the advantages of the ‘heart age’ format of risk score presentation in communicating a message of sub-optimal lifestyle; and intentions and attempts to make moderate lifestyle changes which were prompted by the web-based lifestyle advice. There are a number of limitations to the use of risk scores to communicate a message about the need for a lifestyle change. Of the formats used, the ‘heart age’, if noticed, appears to convey the most powerful message about how far from optimal risk an individual person is. An interactive, user friendly, goal setting based lifestyle website can act as a trigger to initiate moderate lifestyle changes, regardless of concerns about risk scores. Current Controlled Trials ISRCTN17721237
 . Registered 12 January 2015.

https://link.springer.com/content/pdf/10.1186%2Fs12889-016-3867-2.pdf

The response to receiving phenotypic and genetic coronary heart disease risk scores and lifestyle advice - a qualitative study.

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