Alexander Thompson

BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain. METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies. RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths. CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

CONTEXT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. OBJECTIVE: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. DESIGN, SETTING, AND PARTICIPANTS: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). MAIN OUTCOME MEASURES: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk. RESULTS: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. CONCLUSION: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.  

BACKGROUND: Evidence is sparse about the genetic determinants of major lipids in Pakistanis. METHODS AND RESULTS: Variants (n=45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans. Pakistani genetic architecture was distinct from that of several ethnic groups represented in international reference samples. Forty-one variants at 14 loci were significantly associated with levels of HDL-C, triglyceride, or LDL-C. The most significant lipid-related variants identified among Pakistanis corresponded to genes previously shown to be relevant to Europeans, such as CETP associated with HDL-C levels (rs711752; P<10(-13)), APOA5/ZNF259 (rs651821; P<10(-13)) and GCKR (rs1260326; P<10(-13)) with triglyceride levels; and CELSR2 variants with LDL-C levels (rs646776; P<10(-9)). For Pakistanis, these 41 variants explained 6.2%, 7.1%, and 0.9% of the variation in HDL-C, triglyceride, and LDL-C, respectively. Compared with Europeans, the allele frequency of rs662799 in APOA5 among Pakistanis was higher and its impact on triglyceride concentration was greater (P-value for difference <10(-4)). CONCLUSIONS: Several lipid-related genetic variants are common to Pakistanis and Europeans, though they explain only a modest proportion of population variation in lipid concentration. Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans.

There is significant variation in the reported estimates of Huntington's disease (HD) prevalence in different settings. This systematic review was undertaken to describe and assess the sources of heterogeneity in estimated prevalence values, and to consider the role of quantitative synthesis in the context of such heterogeneity. Observational studies from which a prevalence estimate (point or period) or cumulative incidence of HD could be calculated between 1993 and 2024 were sought from Medline and Embase databases. The study features are described and the sources of heterogeneity are discussed. A meta-regression was conducted including predictor variables: continent, median age of population, number of years since 1993, case ascertainment method, and Healthcare Access and Quality Index score. 43 studies met the inclusion criteria. Significant clinical and methodological heterogeneity between studies is described, including differences in case definitions and ascertainment methods, and in the estimates of disease burden calculated. There were differences in the estimated point prevalence between regions and populations within regions, while the estimated point prevalence was shown to be increasing since 1993. Wide prediction intervals in the overall pooled point prevalence (95% prediction interval: 0.32-37.55 cases per 100,000), and the European pooled point prevalence (95% prediction interval: 1.64-19.18 cases per 100,000), indicate the scale of heterogeneity between studies and settings. While such heterogeneity currently limits the validity and utility of quantitative synthesis, developing an accepted consensus on the minimum standards and reporting requirements for HD prevalence studies could reduce the methodological heterogeneity between future studies, enabling more valid and meaningful quantitative synthesis in future.

BACKGROUND: Birth prevalence estimates for Wolf-Hirschhorn syndrome (WHS) are frequently quoted as either one in 50 000 or one in 20 000 to one in 50 000. OBJECTIVE: To estimate the total birth and live birth prevalences of WHS in England between 2015 and 2020, and compare the results with previously published reports and data for common trisomies. METHODS: Data on total births and live births were obtained from the English National Congenital Anomaly and Rare Disease Registration Service. Total births were live births plus stillbirths, miscarriages after 20 weeks, and termination of pregnancy. RESULTS: There were 56 total births, resulting in 30 live births. Total birth prevalence was 2.16 per 100 000 [95% confidence interval (CI): 1.63-2.80 per 100 000], equivalent to one in 46 303 (95% CI: one in 35 656-one in 61 297). The live birth prevalence was 1.16 per 100 000 (95% CI: 0.78-1.66 per 100 000), equivalent to one in 86 092 (95% CI: one in 60 307-one in 127 601), consistent with an earlier UK study. CONCLUSION: We believe the frequently quoted WHS birth prevalence figures are an overestimate and recommend that birth prevalence figures are based on empirical data, with the nature of the numerator and denominator stated clearly.