18 research outputs found
Statistical power considerations in genotype-based recall randomized controlled trials
Randomized controlled trials (RCT) are often underpowered for validating gene-treatment interactions. Using published data from the Diabetes Prevention Program (DPP), we examined power in conventional and genotype-based recall (GBR) trials. We calculated sample size and statistical power for genemetformin interactions (vs. placebo) using incidence rates, gene-drug interaction effect estimates and allele frequencies reported in the DPP for the rs8065082 SLC47A1 variant, a metformin transported encoding locus. We then calculated statistical power for interactions between genetic risk scores (GRS), metformin treatment and intensive lifestyle intervention (ILI) given a range of sampling frames, clinical trial sample sizes, interaction effect estimates, and allele frequencies; outcomes were type 2 diabetes incidence (time-to-event) and change in small LDL particles (continuous outcome). Thereafter, we compared two recruitment frameworks: GBR (participants recruited from the extremes of a GRS distribution) and conventional sampling (participants recruited without explicit emphasis on genetic characteristics). We further examined the influence of outcome measurement error on statistical power. Under most simulated scenarios, GBR trials have substantially higher power to observe gene-drug and gene-lifestyle interactions than same-sized conventional RCTs. GBR trials are becoming popular for validation of gene-treatment interactions; our analyses illustrate the strengths and weaknesses of this design
Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci
Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: Rs13422522 (NYAP2; P = 8.87 × 10-11), rs12454712 (BCL2; P = 2.7 × 10-8), and rs10506418 (FAM19A2; P = 1.9 × 10-8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci
Evaluation of appendicitis risk prediction models in adults with suspected appendicitis
Background
Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis.
Methods
A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis).
Results
Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent).
Conclusion
Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified
Expression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non-Small Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell Analysis
Purpose: To determine the tumor tissue/cell distribution, functional
associations, and clinical significance of PD-1, LAG3, and TIM-3 protein
expression in human non-small cell lung cancer (NSCLC).
Experimental Design: Using multiplexed quantitative immunofluorescence,
we performed localized measurements of CD3, PD-1, LAG-3, and TIM-3
protein in > 800 clinically annotated NSCLCs from three independent
cohorts represented in tissue microarrays. Associations between the
marker’s expression and major genomic alterations were studied in The
Cancer Genome Atlas NSCLC dataset. Using mass cytometry (CyTOF) analysis
of leukocytes collected from 20 resected NSCLCs, we determined the
levels, coexpression, and functional profile of PD-1, LAG-3, and TIM-3
expressing immune cells. Finally, we measured the markers in baseline
samples from 90 patients with advanced NSCLC treated with PD-1 axis
blockers and known response to treatment.
Results: PD-1, LAG-3, and TIM-3 were detected in tumorinfiltrating
lymphocytes (TIL) from 55%, 41.5%, and 25.3% of NSCLC cases,
respectively. These markers showed a prominent association with each
other and limited association with major clinicopathologic variables and
survival in patients not receiv-ing immunotherapy. Expression of the
markers was lower in EGFR-mutated adenocarcinomas and displayed limited
association with tumor mutational burden. In single-cell CyTOF analysis,
PD-1 and LAG-3 were predominantly localized on T-cell subsets/NKT cells,
whereas TIM-3 expression was higher in NK cells and macrophages.
Coexpression of PD-1, LAG-3, and TIM-3 was associated with prominent
T-cell activation (CD69/CD137), effector function (Granzyme-B), and
proliferation (Ki-67), but also with elevated levels of proapoptotic
markers (FAS/BIM). LAG-3 and TIM-3 were present in TIL subsets lacking
PD-1 expression and showed a distinct functional profile. In baseline
samples from 90 patients with advanced NSCLC treated with PD-1 axis
blockers, elevated LAG-3 was significantly associated with shorter
progressionfree survival.
Conclusions: PD-1, LAG-3, and TIM-3 have distinct tissue/cell
distribution, functional implications, and genomic correlates in human
NSCLC. Expression of these immune inhibitory receptors in TILs is
associated with prominent activation, but also with a proapoptotic
T-cell phenotype. Elevated LAG-3 expression is associated with
insensitivity to PD-1 axis blockade, suggesting independence of these
immune evasion pathways