In this short note, we derive a new bias adjusted maximum likelihood estimate for the shape parameter of the Weibull distribution with complete data and type I censored data. The proposed estimate of ...the shape parameter is significantly less biased and more efficient than the corresponding maximum likelihood estimate, while being simple to compute using existing maximum likelihood software procedures.
Data with censoring is common in many areas of science and the associated statistical models are generally estimated with the method of maximum likelihood combined with a model selection criterion ...such as Akaike’s information criterion. This manuscript demonstrates how the information theoretic minimum message length principle can be used to estimate statistical models in the presence of type I random and fixed censoring data. The exponential distribution with fixed and random censoring is used as an example to demonstrate the process where we observe that the minimum message length estimate of mean survival time has some advantages over the standard maximum likelihood estimate.
The association between aging and cancer is complex. Recent studies have developed measures of biological aging based on DNA methylation and called them “age acceleration.” We aimed to assess the ...associations of age acceleration with risk of and survival from seven common cancers. Seven case–control studies of DNA methylation and colorectal, gastric, kidney, lung, prostate and urothelial cancer and B‐cell lymphoma nested in the Melbourne Collaborative Cohort Study were conducted. Cancer cases, vital status and cause of death were ascertained through linkage with cancer and death registries. Conditional logistic regression and Cox models were used to estimate odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals (CI) for associations of five age acceleration measures derived from the Human Methylation 450 K Beadchip assay with cancer risk (N = 3,216 cases) and survival (N = 1,726 deaths), respectively. Epigenetic aging was associated with increased cancer risk, ranging from 4% to 9% per five‐year age acceleration for the 5 measures considered. Heterogeneity by study was observed, with stronger associations for risk of kidney cancer and B‐cell lymphoma. An associated increased risk of death following cancer diagnosis ranged from 2% to 6% per five‐year age acceleration, with no evidence of heterogeneity by cancer site. Cancer risk and mortality were increased by 15–30% for the fourth versus first quartile of age acceleration. DNA methylation‐based measures of biological aging are associated with increased cancer risk and shorter cancer survival, independently of major health risk factors.
What's new?
Aging is associated with profound changes in DNA methylation levels. These can be used to build accurate age predictors (“epigenetic clocks”) that deviate from chronological age by only a few years, a phenomenon named “age acceleration”. In this study of seven types of cancer, the authors found that age acceleration was associated with both increased cancer risk and decreased cancer survival, independently of major health risk factors. These results support the usefulness of methylation markers of biological aging as a tool to predict health outcomes and may provide valuable insight into the relationship between aging and cancer.
Polygenic risk scores (PRSs) are a promising approach to accurately predict an individual's risk of developing disease. The area under the receiver operating characteristic curve (AUC) of PRSs in ...their population are often only reported for models that are adjusted for age and sex, which are known risk factors for the disease of interest and confound the association between the PRS and the disease. This makes comparison of PRS between studies difficult because the genetic effects cannot be disentangled from effects of age and sex (which have a high AUC without the PRS). In this study, we used data from the UK Biobank and applied the stacked clumping and thresholding method and a variation called maximum clumping and thresholding method to develop PRSs to predict coronary artery disease, hypertension, atrial fibrillation, stroke and type 2 diabetes. We created case-control training datasets in which age and sex were controlled by design. We also excluded prevalent cases to prevent biased estimation of disease risks. The maximum clumping and thresholding PRSs required many fewer single-nucleotide polymorphisms to achieve almost the same discriminatory ability as the stacked clumping and thresholding PRSs. Using the testing datasets, the AUCs for the maximum clumping and thresholding PRSs were 0.599 (95% confidence interval CI: 0.585, 0.613) for atrial fibrillation, 0.572 (95% CI: 0.560, 0.584) for coronary artery disease, 0.585 (95% CI: 0.564, 0.605) for type 2 diabetes, 0.559 (95% CI: 0.550, 0.569) for hypertension and 0.514 (95% CI: 0.494, 0.535) for stroke. By developing a PRS using a dataset in which age and sex are controlled by design, we have obtained true estimates of the discriminatory ability of the PRSs alone rather than estimates that include the effects of age and sex.
Polygenic risk scores (PRSs) are a promising approach to accurately predict an individual's risk of developing disease. The area under the receiver operating characteristic curve (AUC) of PRSs in ...their population are often only reported for models that are adjusted for age and sex, which are known risk factors for the disease of interest and confound the association between the PRS and the disease. This makes comparison of PRS between studies difficult because the genetic effects cannot be disentangled from effects of age and sex (which have a high AUC without the PRS). In this study, we used data from the UK Biobank and applied the stacked clumping and thresholding method and a variation called maximum clumping and thresholding method to develop PRSs to predict coronary artery disease, hypertension, atrial fibrillation, stroke and type 2 diabetes. We created case-control training datasets in which age and sex were controlled by design. We also excluded prevalent cases to prevent biased estimation of disease risks. The maximum clumping and thresholding PRSs required many fewer single-nucleotide polymorphisms to achieve almost the same discriminatory ability as the stacked clumping and thresholding PRSs. Using the testing datasets, the AUCs for the maximum clumping and thresholding PRSs were 0.599 (95% confidence interval CI: 0.585, 0.613) for atrial fibrillation, 0.572 (95% CI: 0.560, 0.584) for coronary artery disease, 0.585 (95% CI: 0.564, 0.605) for type 2 diabetes, 0.559 (95% CI: 0.550, 0.569) for hypertension and 0.514 (95% CI: 0.494, 0.535) for stroke. By developing a PRS using a dataset in which age and sex are controlled by design, we have obtained true estimates of the discriminatory ability of the PRSs alone rather than estimates that include the effects of age and sex.
To determine the association of genetic variants of the VEGFA gene with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (AMD).
A ...prospective cohort study.
We included 201 consecutive patients receiving anti-VEGF injections for neovascular AMD.
Patients were followed over 12 months. They were treated with 3 initial monthly ranibizumab or bevacizumab injections. Thereafter, the decision to retreat was made by clinicians at each follow-up visit on the basis of retreatment criteria. Seven tagged single nucleotide polymorphisms (tSNPs) in the VEGFA gene were selected and examined. Multivariate data analysis was used to determine the role of each tSNP in treatment outcome.
The influence of selected VEGFA tSNPs on visual acuity (VA) outcome at 6 months.
Mean baseline VA was 51±17 Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores. Overall, the mean change in VA from baseline was +6.5±12, +4.4±13.4, and +2.3±14.6 letters at 3, 6, and 12 months, respectively. The tSNP rs3025000 was the only SNP significantly associated (P<1 × 10(-4)) with visual outcome at 6 months with multiple correction. The presence of the T allele (TC or TT genotypes) at this tSNP predicted a better outcome of +7 letters at 6 months compared with the CC genotype. In a subgroup analysis, presence of the T allele predicted a significantly higher chance of the patients belonging to the responder group (gain of ≥5 letters from baseline) after 3, 6, and 12 months treatment (odds ratio, 2.7, 3.5, and 2.4; 95% confidence interval, 1.46-5.07, 1.82-6.71, and 1.27-4.57, respectively) than any other outcome group.
Pharmacogenetic association with anti-VEGF treatments may influence the visual outcomes in neovascular AMD. In patients with the T allele in tSNP rs3025000, there was a significantly better visual outcome at 6 months and a greater chance of the patients belonging to the responder group with anti-VEGF treatment at 3, 6, and 12 months. The VA outcomes of patients harboring the T allele at SNP rs3025000 were comparable with those of the pivotal clinical trials but with fewer injections, making the treatment perhaps more cost effective in certain subgroups of patients.
The authors have no proprietary or commercial interest in any of the materials discussed in this article.
We conducted a genome-wide association study of blood DNA methylation and smoking, attempted replication of previously discovered associations, and assessed the reversibility of smoking-associated ...methylation changes. DNA methylation was measured in baseline peripheral blood samples for 5,044 participants in the Melbourne Collaborative Cohort Study. For 1,032 participants, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. A cross-sectional analysis of the association between smoking and DNA methylation and a longitudinal analysis of changes in smoking status and changes in DNA methylation were conducted. We used our cross-sectional analysis to replicate previously reported associations for current (N = 3,327) and former (N = 172) smoking. A comprehensive smoking index accounting for the biological half-life of smoking compounds and several aspects of smoking history was constructed to assess the reversibility of smoking-induced methylation changes. This measure of lifetime exposure to smoking allowed us to detect more associations than comparing current with never smokers. We identified 4,496 cross-sectional associations at P < 10
−7
, including 3,296 annotated to 1,326 genes that were not previously implicated in smoking-associated DNA methylation changes at this significance threshold. We replicated the majority of previously reported associations (P < 10
−7
) for current and former smokers. In our data, we observed for former smokers a substantial degree of return to the methylation levels of never smokers, compared with current smokers (median: 74%, IQR = 63-86%), corresponding to small values (median: 2.75, IQR = 1.5-5.25) for the half-life parameter of the comprehensive smoking index. Longitudinal analyses identified 368 sites at which methylation changed upon smoking cessation. Our study demonstrates the usefulness of the comprehensive smoking index to detect associations between smoking and DNA methylation at CpGs across the genome, replicates the vast majority of previously reported associations, and quantifies the reversibility of smoking-induced methylation changes.
Lipid dyshomeostasis is associated with the most common form of dementia, Alzheimer's disease (AD). Substantial progress has been made in identifying positron emission tomography and cerebrospinal ...fluid biomarkers for AD, but they have limited use as front‐line diagnostic tools.
Extracellular vesicles (EVs) are released by all cells and contain a subset of their parental cell composition, including lipids. EVs are released from the brain into the periphery, providing a potential source of tissue and disease specific lipid biomarkers. However, the EV lipidome of the central nervous system is currently unknown and the potential of brain‐derived EVs (BDEVs) to inform on lipid dyshomeostasis in AD remains unclear.
The aim of this study was to reveal the lipid composition of BDEVs in human frontal cortex, and to determine whether BDEVs have an altered lipid profile in AD. Using semi‐quantitative mass spectrometry, we describe the BDEV lipidome, covering four lipid categories, 17 lipid classes and 692 lipid molecules. BDEVs were enriched in glycerophosphoserine (PS) lipids, a characteristic of small EVs. Here we further report that BDEVs are enriched in ether‐containing PS lipids, a finding that further establishes ether lipids as a feature of EVs.
BDEVs in the AD frontal cortex offered improved detection of dysregulated lipids in AD over global lipid profiling of this brain region. AD BDEVs had significantly altered glycerophospholipid and sphingolipid levels, specifically increased plasmalogen glycerophosphoethanolamine and decreased polyunsaturated fatty acyl containing lipids, and altered amide‐linked acyl chain content in sphingomyelin and ceramide lipids relative to CTL. The most prominent alteration was a two‐fold decrease in lipid species containing anti‐inflammatory/pro‐resolving docosahexaenoic acid.
The in‐depth lipidome analysis provided in this study highlights the advantage of EVs over more complex tissues for improved detection of dysregulated lipids that may serve as potential biomarkers in the periphery.
Abstract
Background
Mammogram risk scores based on texture and density defined by different brightness thresholds are associated with breast cancer risk differently and could reveal distinct ...information about breast cancer risk. We aimed to investigate causal relationships between these intercorrelated mammogram risk scores to determine their relevance to breast cancer aetiology.
Methods
We used digitised mammograms for 371 monozygotic twin pairs, aged 40–70 years without a prior diagnosis of breast cancer at the time of mammography, from the Australian Mammographic Density Twins and Sisters Study. We generated normalised, age-adjusted, and standardised risk scores based on textures using the Cirrus algorithm and on three spatially independent dense areas defined by increasing brightness threshold: light areas, bright areas, and brightest areas. Causal inference was made using the Inference about Causation from Examination of FAmilial CONfounding (ICE FALCON) method.
Results
The mammogram risk scores were correlated within twin pairs and with each other (
r
= 0.22–0.81; all
P
< 0.005). We estimated that 28–92% of the associations between the risk scores could be attributed to causal relationships between the scores, with the rest attributed to familial confounders shared by the scores. There was consistent evidence for positive causal effects: of Cirrus, light areas, and bright areas on the brightest areas (accounting for 34%, 55%, and 85% of the associations, respectively); and of light areas and bright areas on Cirrus (accounting for 37% and 28%, respectively).
Conclusions
In a mammogram, the lighter (less dense) areas have a causal effect on the brightest (highly dense) areas, including through a causal pathway via textural features. These causal relationships help us gain insight into the relative aetiological importance of different mammographic features in breast cancer. For example our findings are consistent with the brightest areas being more aetiologically important than lighter areas for screen-detected breast cancer; conversely, light areas being more aetiologically important for interval breast cancer. Additionally, specific textural features capture aetiologically independent breast cancer risk information from dense areas. These findings highlight the utility of ICE FALCON and family data in decomposing the associations between intercorrelated disease biomarkers into distinct biological pathways.
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