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Dosing Discrimination: Regulating PDMP Risk Scores
In: 110 California Law Review 47 (2022)
SSRN
Association between polygenic risk score and risk of myopia
Yes ; Importance: Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. Objectives: To examine whether genetic information alone can identify children at risk of myopia development and whether including a child's genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. Design, Setting, and Participants: Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019. Main Outcomes and Measures: The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to −0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to −5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n = 95 619), age of onset of spectacle wear (n = 287 448), and educational attainment (n = 328 917). Results: A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P = .02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4–10.9) of high myopia. Conclusions and Relevance: A personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87). ; PhD studentship grant from the College of Optometrists (Drs Guggenheim and Williams; supporting Mr Mojarrad) entitled Genetic prediction of individuals at-risk for myopia development) and National Institute for Health Research (NIHR) Senior Research Fellowship award SRF-2015-08-005 (Dr Williams). The UK Medical Research Council and Wellcome grant 102215/2/13/2 and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children (ALSPAC). A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was conducted using the UK Biobank Resource (application 17351). The UK Biobank was established by the Wellcome Trust, the UK Medical Research Council, the Department for Health (London, England), the Scottish government (Edinburgh, Scotland), and the Northwest Regional Development Agency (Warrington, England). It also received funding from the Welsh Assembly Government (Cardiff, Wales), the British Heart Foundation, and Diabetes UK.
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Validating the Framingham Hypertension Risk Score: results from the Whitehall II study. ; Validating the Framingham Hypertension Risk Score: results from the Whitehall II study.: Validating the Framingham Hypertension Risk Score
International audience ; A promising hypertension risk prediction score using data from the US Framingham Offspring Study has been developed, but this score has not been tested in other cohorts. We examined the predictive performance of the Framingham hypertension risk score in a European population, the Whitehall II Study. Participants were 6704 London-based civil servants aged 35 to 68 years, 31% women, free from prevalent hypertension, diabetes mellitus, and coronary heart disease. Standard clinical examinations of blood pressure, weight and height, current cigarette smoking, and parental history of hypertension were undertaken every 5 years for a total of 4 times. We recorded a total of 2043 incident (new-onset) cases of hypertension in three 5-year baseline follow-up data cycles. Both discrimination (C statistic: 0.80) and calibration (Hosmer-Lemeshow chi(2): 11.5) of the Framingham hypertension risk score were good. Agreement between the predicted and observed hypertension incidences was excellent across the risk score distribution. The overall predicted:observed ratio was 1.08, slightly better among individuals >50 years of age (0.99 in men and 1.02 in women) than in younger participants (1.16 in men and 1.18 in women). Reclassification with a modified score on the basis of our study population did not improve the prediction (net reclassification improvement: -0.5%; 95% CI: -2.5% to 1.5%). These data suggest that the Framingham hypertension risk score provides a valid tool with which to estimate near-term risk of developing hypertension.
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Validating the Framingham Hypertension Risk Score: results from the Whitehall II study. ; Validating the Framingham Hypertension Risk Score: results from the Whitehall II study.: Validating the Framingham Hypertension Risk Score
International audience ; A promising hypertension risk prediction score using data from the US Framingham Offspring Study has been developed, but this score has not been tested in other cohorts. We examined the predictive performance of the Framingham hypertension risk score in a European population, the Whitehall II Study. Participants were 6704 London-based civil servants aged 35 to 68 years, 31% women, free from prevalent hypertension, diabetes mellitus, and coronary heart disease. Standard clinical examinations of blood pressure, weight and height, current cigarette smoking, and parental history of hypertension were undertaken every 5 years for a total of 4 times. We recorded a total of 2043 incident (new-onset) cases of hypertension in three 5-year baseline follow-up data cycles. Both discrimination (C statistic: 0.80) and calibration (Hosmer-Lemeshow chi(2): 11.5) of the Framingham hypertension risk score were good. Agreement between the predicted and observed hypertension incidences was excellent across the risk score distribution. The overall predicted:observed ratio was 1.08, slightly better among individuals >50 years of age (0.99 in men and 1.02 in women) than in younger participants (1.16 in men and 1.18 in women). Reclassification with a modified score on the basis of our study population did not improve the prediction (net reclassification improvement: -0.5%; 95% CI: -2.5% to 1.5%). These data suggest that the Framingham hypertension risk score provides a valid tool with which to estimate near-term risk of developing hypertension.
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Validating the Framingham Hypertension Risk Score: results from the Whitehall II study. ; Validating the Framingham Hypertension Risk Score: results from the Whitehall II study.: Validating the Framingham Hypertension Risk Score
International audience ; A promising hypertension risk prediction score using data from the US Framingham Offspring Study has been developed, but this score has not been tested in other cohorts. We examined the predictive performance of the Framingham hypertension risk score in a European population, the Whitehall II Study. Participants were 6704 London-based civil servants aged 35 to 68 years, 31% women, free from prevalent hypertension, diabetes mellitus, and coronary heart disease. Standard clinical examinations of blood pressure, weight and height, current cigarette smoking, and parental history of hypertension were undertaken every 5 years for a total of 4 times. We recorded a total of 2043 incident (new-onset) cases of hypertension in three 5-year baseline follow-up data cycles. Both discrimination (C statistic: 0.80) and calibration (Hosmer-Lemeshow chi(2): 11.5) of the Framingham hypertension risk score were good. Agreement between the predicted and observed hypertension incidences was excellent across the risk score distribution. The overall predicted:observed ratio was 1.08, slightly better among individuals >50 years of age (0.99 in men and 1.02 in women) than in younger participants (1.16 in men and 1.18 in women). Reclassification with a modified score on the basis of our study population did not improve the prediction (net reclassification improvement: -0.5%; 95% CI: -2.5% to 1.5%). These data suggest that the Framingham hypertension risk score provides a valid tool with which to estimate near-term risk of developing hypertension.
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Validating the Framingham Hypertension Risk Score: results from the Whitehall II study. ; Validating the Framingham Hypertension Risk Score: results from the Whitehall II study.: Validating the Framingham Hypertension Risk Score
International audience ; A promising hypertension risk prediction score using data from the US Framingham Offspring Study has been developed, but this score has not been tested in other cohorts. We examined the predictive performance of the Framingham hypertension risk score in a European population, the Whitehall II Study. Participants were 6704 London-based civil servants aged 35 to 68 years, 31% women, free from prevalent hypertension, diabetes mellitus, and coronary heart disease. Standard clinical examinations of blood pressure, weight and height, current cigarette smoking, and parental history of hypertension were undertaken every 5 years for a total of 4 times. We recorded a total of 2043 incident (new-onset) cases of hypertension in three 5-year baseline follow-up data cycles. Both discrimination (C statistic: 0.80) and calibration (Hosmer-Lemeshow chi(2): 11.5) of the Framingham hypertension risk score were good. Agreement between the predicted and observed hypertension incidences was excellent across the risk score distribution. The overall predicted:observed ratio was 1.08, slightly better among individuals >50 years of age (0.99 in men and 1.02 in women) than in younger participants (1.16 in men and 1.18 in women). Reclassification with a modified score on the basis of our study population did not improve the prediction (net reclassification improvement: -0.5%; 95% CI: -2.5% to 1.5%). These data suggest that the Framingham hypertension risk score provides a valid tool with which to estimate near-term risk of developing hypertension.
BASE
Validating the Framingham Hypertension Risk Score: results from the Whitehall II study. ; Validating the Framingham Hypertension Risk Score: results from the Whitehall II study.: Validating the Framingham Hypertension Risk Score
International audience ; A promising hypertension risk prediction score using data from the US Framingham Offspring Study has been developed, but this score has not been tested in other cohorts. We examined the predictive performance of the Framingham hypertension risk score in a European population, the Whitehall II Study. Participants were 6704 London-based civil servants aged 35 to 68 years, 31% women, free from prevalent hypertension, diabetes mellitus, and coronary heart disease. Standard clinical examinations of blood pressure, weight and height, current cigarette smoking, and parental history of hypertension were undertaken every 5 years for a total of 4 times. We recorded a total of 2043 incident (new-onset) cases of hypertension in three 5-year baseline follow-up data cycles. Both discrimination (C statistic: 0.80) and calibration (Hosmer-Lemeshow chi(2): 11.5) of the Framingham hypertension risk score were good. Agreement between the predicted and observed hypertension incidences was excellent across the risk score distribution. The overall predicted:observed ratio was 1.08, slightly better among individuals >50 years of age (0.99 in men and 1.02 in women) than in younger participants (1.16 in men and 1.18 in women). Reclassification with a modified score on the basis of our study population did not improve the prediction (net reclassification improvement: -0.5%; 95% CI: -2.5% to 1.5%). These data suggest that the Framingham hypertension risk score provides a valid tool with which to estimate near-term risk of developing hypertension.
BASE
Validating the Framingham Hypertension Risk Score: results from the Whitehall II study. ; Validating the Framingham Hypertension Risk Score: results from the Whitehall II study.: Validating the Framingham Hypertension Risk Score
International audience ; A promising hypertension risk prediction score using data from the US Framingham Offspring Study has been developed, but this score has not been tested in other cohorts. We examined the predictive performance of the Framingham hypertension risk score in a European population, the Whitehall II Study. Participants were 6704 London-based civil servants aged 35 to 68 years, 31% women, free from prevalent hypertension, diabetes mellitus, and coronary heart disease. Standard clinical examinations of blood pressure, weight and height, current cigarette smoking, and parental history of hypertension were undertaken every 5 years for a total of 4 times. We recorded a total of 2043 incident (new-onset) cases of hypertension in three 5-year baseline follow-up data cycles. Both discrimination (C statistic: 0.80) and calibration (Hosmer-Lemeshow chi(2): 11.5) of the Framingham hypertension risk score were good. Agreement between the predicted and observed hypertension incidences was excellent across the risk score distribution. The overall predicted:observed ratio was 1.08, slightly better among individuals >50 years of age (0.99 in men and 1.02 in women) than in younger participants (1.16 in men and 1.18 in women). Reclassification with a modified score on the basis of our study population did not improve the prediction (net reclassification improvement: -0.5%; 95% CI: -2.5% to 1.5%). These data suggest that the Framingham hypertension risk score provides a valid tool with which to estimate near-term risk of developing hypertension.
BASE
Validating the Framingham Hypertension Risk Score: results from the Whitehall II study. ; Validating the Framingham Hypertension Risk Score: results from the Whitehall II study.: Validating the Framingham Hypertension Risk Score
International audience ; A promising hypertension risk prediction score using data from the US Framingham Offspring Study has been developed, but this score has not been tested in other cohorts. We examined the predictive performance of the Framingham hypertension risk score in a European population, the Whitehall II Study. Participants were 6704 London-based civil servants aged 35 to 68 years, 31% women, free from prevalent hypertension, diabetes mellitus, and coronary heart disease. Standard clinical examinations of blood pressure, weight and height, current cigarette smoking, and parental history of hypertension were undertaken every 5 years for a total of 4 times. We recorded a total of 2043 incident (new-onset) cases of hypertension in three 5-year baseline follow-up data cycles. Both discrimination (C statistic: 0.80) and calibration (Hosmer-Lemeshow chi(2): 11.5) of the Framingham hypertension risk score were good. Agreement between the predicted and observed hypertension incidences was excellent across the risk score distribution. The overall predicted:observed ratio was 1.08, slightly better among individuals >50 years of age (0.99 in men and 1.02 in women) than in younger participants (1.16 in men and 1.18 in women). Reclassification with a modified score on the basis of our study population did not improve the prediction (net reclassification improvement: -0.5%; 95% CI: -2.5% to 1.5%). These data suggest that the Framingham hypertension risk score provides a valid tool with which to estimate near-term risk of developing hypertension.
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Beyond Statistics: The Economic Content of Risk Scores
In: NBER Working Paper No. w21304
SSRN
Plasma testosterone is associated with Framingham risk score
In: The aging male: the official journal of the International Society for the Study of the Aging Male, Band 15, Heft 3, S. 134-139
ISSN: 1473-0790
The Impact of ESG Risk Score on Holding Period Return
SSRN
Genomic Risk Score impact on susceptibility to systemic sclerosis
Objectives Genomic Risk Scores (GRS) successfully demonstrated the ability of genetics to identify those individuals at high risk for complex traits including immune-mediated inflammatory diseases (IMIDs). We aimed to test the performance of GRS in the prediction of risk for systemic sclerosis (SSc) for the first time. Methods Allelic effects were obtained from the largest SSc Genome-Wide Association Study (GWAS) to date (9 095 SSc and 17 584 healthy controls with European ancestry). The best-fitting GRS was identified under the additive model in an independent cohort that comprised 400 patients with SSc and 571 controls. Additionally, GRS for clinical subtypes (limited cutaneous SSc and diffuse cutaneous SSc) and serological subtypes (anti-topoisomerase positive (ATA+) and anti-centromere positive (ACA+)) were generated. We combined the estimated GRS with demographic and immunological parameters in a multivariate generalised linear model. Results The best-fitting SSc GRS included 33 single nucleotide polymorphisms (SNPs) and discriminated between patients with SSc and controls (area under the receiver operating characteristic (ROC) curve (AUC)=0.673). Moreover, the GRS differentiated between SSc and other IMIDs, such as rheumatoid arthritis and Sjögren's syndrome. Finally, the combination of GRS with age and immune cell counts significantly increased the performance of the model (AUC=0.787). While the SSc GRS was not able to discriminate between ATA+ and ACA+ patients (AUC<0.5), the serological subtype GRS, which was based on the allelic effects observed for the comparison between ACA+ and ATA+ patients, reached an AUC=0.693. Conclusions GRS was successfully implemented in SSc. The model discriminated between patients with SSc and controls or other IMIDs, confirming the potential of GRS to support early and differential diagnosis for SSc. ; Spanish Government RTI2018101332-B-100 ; Red de Investigación en Inflamación y Enfermedades Reumáticas (RIER) from Instituto de Salud Carlos III RD16/0012/0013 ; EU/EFPIA/Innovative Medicines Initiative Joint Undertaking PRECISESADS 115565 ; Spanish Ministry of Science and Innovation through the Juan de la Cierva incorporation program IJC2018-035131-I IJC2018-038026-I ; Spanish Ministry of Science and Innovation through the Ayudas para contratos predoctorales para la formación de doctores 2019 program RTI2018-101332-B-I00
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Common variants in Alzheimer's disease and risk stratification by polygenic risk scores
16 páginas, 5 figuras ; Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease. ; The present work has been performed as part of the doctoral program of I. de Rojas at the Universitat de Barcelona (Barcelona, Spain) supported by national grant from the Instituto de Salud Carlos III FI20/00215. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria "La Caixa", Fundació ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—"Una manera de hacer Europa"). Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW project number 733050814, 733050512) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND) and also funded by Inserm, Institut Pasteur de Lille, the Lille Métropole Communauté Urbaine, the French government's LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Genotyping of the German case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND (German Federal Ministry of Education and Research, BMBF: 01ED1619A). Full acknowledgments for the studies that contributed data can be found in the Supplementary Note. We thank the numerous participants, researchers, and staff from many studies who collected and contributed to the data. We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips was funded by the French National Foundation on AD and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer's Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIA/NHLBI grants AG049505, AG058589, HL105756 and AGES contract N01–AG–12100, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC–10–196728. This research has been conducted using the UK Biobank public resource obtained through the University of Edinburg Data Share (https://datashare.is.ed.ac.uk/handle/10283/3364). ; Peer reviewed
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