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Oliver Pain Alexandra C. Gillett Jehannine C. Austin Lasse Folkersen Cathryn M. Lewis 《European journal of human genetics : EJHG》2022,30(3):339
There is growing interest in the clinical application of polygenic scores as their predictive utility increases for a range of health-related phenotypes. However, providing polygenic score predictions on the absolute scale is an important step for their safe interpretation. We have developed a method to convert polygenic scores to the absolute scale for binary and normally distributed phenotypes. This method uses summary statistics, requiring only the area-under-the-ROC curve (AUC) or variance explained (R2) by the polygenic score, and the prevalence of binary phenotypes, or mean and standard deviation of normally distributed phenotypes. Polygenic scores are converted using normal distribution theory. We also evaluate methods for estimating polygenic score AUC/R2 from genome-wide association study (GWAS) summary statistics alone. We validate the absolute risk conversion and AUC/R2 estimation using data for eight binary and three continuous phenotypes in the UK Biobank sample. When the AUC/R2 of the polygenic score is known, the observed and estimated absolute values were highly concordant. Estimates of AUC/R2 from the lassosum pseudovalidation method were most similar to the observed AUC/R2 values, though estimated values deviated substantially from the observed for autoimmune disorders. This study enables accurate interpretation of polygenic scores using only summary statistics, providing a useful tool for educational and clinical purposes. Furthermore, we have created interactive webtools implementing the conversion to the absolute (https://opain.github.io/GenoPred/PRS_to_Abs_tool.html). Several further barriers must be addressed before clinical implementation of polygenic scores, such as ensuring target individuals are well represented by the GWAS sample.Subject terms: Personalized medicine, Medical genomics 相似文献
23.
Sarah E. Sheppard Laura Elizabeth Anderson Cathryn Sibbald Colleen Cotton Elizabeth Bhoj Marissa J. Perman Leslie Castelo‐Soccio 《Pediatric dermatology》2019,36(6):1007-1009
Epidermolysis bullosa simplex (EBS) is a skin fragility disorder resulting from mutations of structural proteins in the epidermis. We provide a brief report of long‐term survival and reproduction in a mother with EBS due to keratin 5 (KRT5) c.1429G > A (p.E477K) mutation, which causes a particularly severe form of the disease. 相似文献
24.
Cathryn Thomas John Rose 《Journal of Applied Research in Intellectual Disabilities》2010,23(2):167-178
Background The current study examines a model relating to the concept of reciprocity and burnout in staff, incorporating previous research findings based upon Weiner’s (1980, 1986) cognitive‐emotional model linking emotions, optimism and helping behaviour, with the aim of testing the model. Materials Staff working in community homes within the voluntary, private and public sector for people with intellectual disabilities within an urban borough completed a self‐report questionnaire including measures of reciprocity, burnout, emotion, optimism and helping behaviour. Results Support was found for an association between lack of reciprocity and levels of burnout. Burnout was found to be correlated with emotion, optimism and helping behaviour. Path analysis revealed significant associations between a lack of reciprocity with the organization and colleagues, burnout, positive affect, optimism and helping. Conclusions The findings provide support for the role of reciprocal relationships between care staff, the organization and work colleagues in burnout. Some support was found for the proposed model. The clinical implications of the study, methodological considerations and recommendations for future research are discussed. 相似文献
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Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis 总被引:6,自引:0,他引:6 下载免费PDF全文
Broderick C Hoek RM Forrester JV Liversidge J Sedgwick JD Dick AD 《The American journal of pathology》2002,161(5):1669-1677
Recent evidence supports the notion that tissue OX2 (CD200) constitutively provides down-regulatory signals to myeloid-lineage cells via CD200-receptor (CD200R). Thus, mice lacking CD200 (CD200(-/-)) show increased susceptibility to and accelerated onset of tissue-specific autoimmunity. In the retina there is extensive expression of CD200 on neurons and retinal vascular endothelium. We show here that retinal microglia in CD200(-/-) mice display normal morphology, but unlike microglia from wild-type CD200(+/+) mice are present in increased numbers and most significantly, express inducible nitric oxide synthase (NOS2), a macrophage activation marker. Onset and severity of uveitogenic peptide (1-20) of interphotoreceptor retinoid-binding protein-induced experimental autoimmune uveoretinitis is accelerated in CD200(-/-) mice and although tissue destruction appears no greater than seen in CD200(+/+) mice, there is continued increased ganglion and photoreceptor cell apoptosis. Myeloid cell infiltrate was increased in CD200(-/-) mice during experimental autoimmune uveoretinitis, although NOS2 expression was not heightened. The results indicate that the CD200:CD200R axis regulates retinal microglial activation. In CD200(-/-) mice the release of suppression of tonic macrophage activation, supported by increased NOS2 expression in the CD200(-/-) steady state accelerates disease onset but without any demonstration of increased target organ/tissue destruction. 相似文献
27.
Carl A. Anderson Jeffrey C. Barrett Mark Tremelling Rhian Gwilliam Elaine R. Nimmo Charlie W. Lees Catherine Hanson Radhi Ravindrarajah Dhiraj Varma Gregory Lewis Nick Watkins David Strachan Cathryn M. Lewis Jeremy Sanderson Panos Deloukas Christopher G. Mathew Miles Parkes 《Gastroenterology》2009,136(2):523-529
28.
Liebowitz MR DeMartinis NA Weihs K Londborg PD Smith WT Chung H Fayyad R Clary CM 《The Journal of clinical psychiatry》2003,64(7):785-792
BACKGROUND: Generalized social anxiety disorder is an early onset, highly chronic, frequently disabling disorder with a lifetime prevalence of approximately 13%. The goal of the current study was to evaluate the efficacy and tolerability of sertraline for the treatment of severe generalized social anxiety disorder in adults. METHOD: After a 1-week single-blind placebo lead-in period, patients with DSM-IV generalized social phobia were randomly assigned to 12 weeks of double-blind treatment with flexible doses of sertraline (50-200 mg/day) or placebo. Primary efficacy outcomes were the mean change in the Liebowitz Social Anxiety Scale (LSAS) total score and the responder rate for the Clinical Global Impressions-Improvement scale (CGI-I), defined as a CGI-I score = 2. Data were collected in 2000 and 2001. RESULTS: 211 patients were randomly assigned to sertraline (intent-to-treat [ITT] sample, 205), and 204 patients, to placebo (ITT sample, 196). At week 12, sertraline produced a significantly greater reduction in LSAS total score compared with placebo (mean last-observation-carried-forward [LOCF] change from baseline: -31.0 vs. -21.7; p =.001) and a greater proportion of responders (CGI-I score = 2: 55.6% vs. 29% among week 12 completers and 46.8% vs. 25.5% in the ITT-LOCF sample; p <.001 for both comparisons). Sertraline was well tolerated, with 7.6% of patients discontinuing due to adverse events versus 2.9% of placebo-treated patients. CONCLUSION: The results of the current study confirm the efficacy of sertraline in the treatment of severe social anxiety disorder. 相似文献
29.
Environmental enrichment slows disease progression in R6/2 Huntington's disease mice 总被引:10,自引:0,他引:10
Hockly E Cordery PM Woodman B Mahal A van Dellen A Blakemore C Lewis CM Hannan AJ Bates GP 《Annals of neurology》2002,51(2):235-242
Huntington's disease is a genetic disorder that causes motor dysfunction, personality changes, dementia, and premature death. There is currently no effective therapy. Several transgenic models of Huntington's disease are available, the most widely used of which is the R6/2 mouse, because of its rapid disease progression. Environmental enrichment alters gene expression in the normal mouse brain, and modulates the course of several neurological disorders. Environmentally enriched mice may actually mimic human disease more accurately. We found that even limited environmental enrichment slows decline in RotaRod performance in R6/2 mice, despite rapid disease progression, whereas in normal littermates, maximal enrichment was required to induce a marked improvement in behavioral tests. Enrichment also delayed the loss of peristriatal cerebral volume in R6/2 brains. These results could provide the basis for a rational approach to ameliorate the effects of Huntington's disease. 相似文献
30.
Pollack MH Rapaport MH Fayyad R Otto MW Nierenberg AA Clary CM 《Journal of psychiatric research》2002,36(4):229-236
The early identification of likely remitters and non-remitters to pharmacotherapy for panic disorder may have important implications for clinical treatment decisions. To address this question, combined data from two fixed-dose and two flexible dose placebo-controlled studies of sertraline treatment of panic disorder were examined. Patients (N=544) diagnosed with panic disorder, with or without agoraphobia, were treated with 50 mg of sertraline, 100 mg of sertraline, flexible dosages of sertraline, or placebo. Measures of early improvement included panic attack frequency (full + limited symptom attacks), anticipatory anxiety, the Hamilton Anxiety Rating Scale (HAM-A), and the Clinical Global Impression Improvement (CGI-I) Scale. Improvement as reflected in CGI-I ratings and change from baseline in the HAM-A at weeks 1, 2, and 3 significantly (P<0.0001) predicted endpoint clinical remission (defined at endpoint as no full panic attacks and a CGI-Severity rating of 1 or 2). Improvements in panic attack frequency and anticipatory anxiety were not consistent predictors in multivariate predictive models. Receiver-Operator Curve analyses revealed good specificity (0.83) for change in CGI-I at week 2, and good sensitivity (0.82) for change in HAM-A at week 3. Predictive success for HAM-A and CGI-I was not significantly different for fixed vs. flexible dose sertraline treatment, nor for sertraline vs. placebo treatment. The use of ROC analyses for examination of early response as a predictor of final remission holds promise for aiding clinicians in decision making regarding the need for alternative or supplemental treatment approaches during the course of pharmacotherapy for panic disorder. 相似文献