Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this ...trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
IMPORTANCE: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. OBJECTIVE: To identify the genetic ...variants associated with juvenile ALS. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. MAIN OUTCOMES AND MEASURES: De novo variants present only in the index case and not in unaffected family members. RESULTS: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. CONCLUSIONS AND RELEVANCE: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
Coronary Heart Disease Risk Equivalence in Diabetes Depends on Concomitant Risk Factors
Barbara V. Howard , PHD 1 ,
Lyle G. Best , MD 2 ,
James M. Galloway , MD 3 ,
William James Howard , MD 4 ,
...Kristina Jones , MPH 1 ,
Elisa T. Lee , PHD 5 ,
Robert E. Ratner , MD 1 ,
Helaine E. Resnick , MPH, PHD 1 and
Richard B. Devereux , MD 6
1 MedStar Research Institute, Washington, DC
2 Department of Family Practice Medicine, University of North Dakota, Grand Forks, North Dakota
3 Native American Cardiology Program, University of Arizona, Tucson, Arizona
4 Washington Hospital Center, Washington, DC
5 University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
6 Weill Medical College, Cornell University School of Medicine, Ithaca, New York
Address correspondence to Barbara V. Howard, PhD, MedStar Research Institute, 6495 New Hampshire Ave., Suite 201, Hyattsville,
MD 20783. E-mail: barbara.v.howard{at}medstar.net
Abstract
OBJECTIVE —Diabetes has been defined as a coronary heart disease (CHD) risk equivalent, and more aggressive treatment goals have been
proposed for diabetic patients.
RESEARCH DESIGN AND METHODS —We studied the influence of single and multiple risk factors on the 10-year cumulative incidence of fatal and nonfatal CHD
and cardiovascular disease (CVD) in diabetic and nondiabetic men and women, with and without baseline CHD or CVD, in a population
( n = 4,549) with a high prevalence of diabetes.
RESULTS —In both sexes, diabetes increased the risk for CHD (hazard ratio 1.99 and 2.93 for men and women, respectively). Diabetic
men and women had a 10-year cumulative incidence of CHD of 25.9 and 19.1%, respectively, compared with 57.4 and 58.4% for
nondiabetic men and women with previous CHD. The pattern was similar when only fatal events were considered. Diabetic individuals
with one or two risk factors had a 10-year cumulative incidence of CHD that was only 1.4 times higher than that of nondiabetic
individuals (14%). However, the 10-year incidence of CHD in diabetic subjects with multiple risk factors was >40%, and the
incidence of fatal CHD was higher in these subjects than in nondiabetic subjects with previous CHD. Data for CVD showed similar
patterns, as did separate analyses by sex.
CONCLUSIONS —Our results and comparisons with other available data show wide variation in the rate of CHD in diabetes, depending on the
population and existing risk factors. Most individuals had a 10-year cumulative incidence >20%, but only those with multiple
risk factors had a 10-year cumulative incidence that was equivalent to that of patients with CHD. Until more data are available,
it may be prudent to consider targets based on the entire risk factor profile rather than just the presence of diabetes.
ATP III, Adult Treatment Panel III
CABG, coronary artery bypass graft
CHD, coronary heart disease
CVD, cardiovascular disease
IFG, impaired fasting glucose
MI, myocardial infarction
PTCA, percutaneous transluminal coronary angioplasty
SHS, Strong Heart Study
Footnotes
The views expressed in this report are those of the authors and do not necessarily reflect those of the Indian Health Service.
B.V.H. has received consulting fees from Merck, the Egg Nutrition Council, General Mills, and Schering-Plough and grant/research
support from Pfizer, Merck, and Schering-Plough. W.J.H has received consulting fees from Merck, Pfizer, AstraZeneca, Schering-Plough,
Abbott, and Reliant and grant/research support from Merck, Schering-Plough, Pfizer, and AstraZeneca.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
See accompanying editorial, p. 457.
Accepted November 6, 2005.
Received July 12, 2005.
DIABETES CARE
IntroductionRandomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. ...Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions.Methods and analysisThe INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare.Ethics and disseminationThe University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.
This research examines the development of confidence and accuracy over time in the context of forecasting. Although overconfidence has been studied in many contexts, little research examines its ...progression over long periods of time or in consequential policy domains. This study employs a unique data set from a geopolitical forecasting tournament spanning three years in which thousands of forecasters predicted the outcomes of hundreds of events. We sought to apply insights from research to structure the questions, interactions, and elicitations to improve forecasts. Indeed, forecasters’ confidence roughly matched their accuracy. As information came in, accuracy increased. Confidence increased at approximately the same rate as accuracy, and good calibration persisted. Nevertheless, there was evidence of a small amount of overconfidence (3%), especially on the most confident forecasts. Training helped reduce overconfidence, and team collaboration improved forecast accuracy. Together, teams and training reduced overconfidence to 1%. Our results provide reason for tempered optimism regarding confidence calibration and its development over time in consequential field contexts.
This paper was accepted by Yuval Rottenstreich, judgment and decision making
.
Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association ...studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the
locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
American Indian (AI) communities experience persistent diabetes-related disparities, yet few nutrition interventions are designed for AI with type 2 diabetes or address socio-contextual barriers to ...healthy eating. We describe our process of adapting the evidence-based Cooking Matters® program for use by AI adults with type 2 diabetes in a rural and resource-limited setting in the North-Central United States. We conducted three focus groups with AI adults with diabetes to (i) identify Cooking Matters® adaptations and (ii) gather feedback on appropriateness of the adapted intervention using Barrera and Castro's cultural adaptation framework. Transcripts were coded using an inductive, constant comparison approach. Queries of codes were reviewed to identify themes. Contextual considerations included limited access to grocery stores and transportation barriers, reliance on government food assistance and the intergenerational burden of diabetes. Adaptations to content and delivery included incorporating traditional and locally available foods; appealing to children or others in multigenerational households and prioritizing visual over written content. Our use of Barrera and Castro's framework adds rigor and structure to the cultural adaptation process and increases the likelihood of future intervention success. Other researchers may benefit from using this framework to guide the adaptation of evidence-based interventions in AI communities.
There are few data about the impact of the recently-defined category of prehypertension (systolic blood pressure 120 to 139 mm Hg or diastolic blood pressure 80 to 89 mm Hg) on cardiovascular disease ...incidence. It is also unknown whether this association differs between individuals with or without diabetes. A total of 2629 Strong Heart Study participants free from hypertension and cardiovascular disease at baseline examination were followed for 12 years to observe incident cardiovascular disease. Approximately 42% of the 2629 participants had diabetes. We assessed the prevalence of prehypertension and the hazard ratios of incident cardiovascular disease associated with prehypertension. Prehypertension was more prevalent in diabetic than nondiabetic participants (59.4% versus 48.2%, P<0.001 adjusted for age). Compared with nondiabetic participants with normal blood pressure, the hazard ratios of cardiovascular disease were 3.70 (95% confidence interval2.66, 5.15) for those with both prehypertension and diabetes, 1.80 (1.28, 2.54) for those with prehypertension alone and 2.90 (2.03, 4.16) for those with diabetes alone. Impaired glucose tolerance or impaired fasting glucose also greatly increased the cardiovascular disease risk in prehypertensive people. Clinical investigation of more aggressive interventions, such as drug treatment for blood pressure control for prehypertensive individuals with impaired fasting glucose, impaired glucose tolerance, or diabetes is warranted.
Short leukocyte telomere length (LTL) has been associated with atherosclerosis in cross-sectional studies, but the prospective relationship between telomere shortening and risk of developing carotid ...atherosclerosis has not been well-established. This study examines whether LTL at baseline predicts incidence and progression of carotid atherosclerosis in American Indians in the Strong Heart Study. The analysis included 2,819 participants who were free of overt cardiovascular disease at baseline (2001-2003) and were followed through the end of 2006-2009 (average 5.5-yr follow-up). Discrete atherosclerotic plaque was defined as focal protrusion with an arterial wall thickness ≥50% the surrounding wall. Carotid progression was defined as having a higher plaque score at the end of study follow-up compared to baseline. Associations of LTL with incidence and progression of carotid plaque were examined using Cox proportional hazard regression, adjusting for standard coronary risk factors. Compared to participants in the highest LTL tertile, those in the lowest tertile had significantly elevated risk for both incident plaque (HR, 1.49; 95% CI, 1.09-2.03) and plaque progression (HR, 1.61; 95% CI, 1.26-2.07). Our results provide initial evidence for a potential prognostic utility of LTL in risk prediction for atherosclerosis.
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