Project description:Searching for genetic determinants of human longevity has been challenged by the rarity of data sets with large numbers of individuals who have reached extreme old age, inconsistent definitions of the phenotype, and the difficulty of defining appropriate controls. Meta-analysis - a statistical method to summarize results from different studies - has become a common tool in genetic epidemiology to accrue large sample sizes for powerful genetic association studies. In conducting a meta-analysis of studies of human longevity however, particular attention must be made to the definition of cases and controls (including their health status) and on the effect of possible confounders such as sex and ethnicity upon the genetic effect to be estimated. We will show examples of how a meta-analysis can inflate the false negative rates of genetic association studies or it can bias estimates of the association between a genetic variant and extreme longevity.
Project description:Testosterone replacement therapy has been approved in the United States since the 1950s for men with "classical" hypogonadism. These men have specific and well-recognized hypothalamic, pituitary, or testicular conditions leading to deficient or absent endogenous testosterone. A more controversial treatment population is aging men, many with comorbidities, who have low serum testosterone concentrations compared with young healthy men and who do not have the well-recognized medical conditions that cause "classical" hypogonadism. Testosterone continues to be widely used in these men with "age-related hypogonadism" even though the benefits of testosterone for this use are uncertain and there are important risks, including a potential risk of major adverse cardiac events for the testosterone class, and two testosterone products with increases in blood pressure that can increase the risk of myocardial infarction and stroke. Given the uncertain clinical benefit of testosterone in men with "age-related hypogonadism" in the face of known and potential adverse outcomes, none of the testosterone products is FDA approved for such use.
Project description:ObjectiveTo estimate the relative risks of death, myocardial infarction, stroke, and renal failure or dysfunction between antifibrinolytics and no treatment following the suspension of aprotinin from the market in 2008 for safety reasons and its recent reintroduction in Europe and Canada.DesignSystematic review and network meta-analysis.Data sourcesA Cochrane review of antifibrinolytic treatments was chosen as the starting point for this systematic review. Medline, Embase, and the Cochrane register of trials were searched with no date restrictions for observational evidence.Study selectionPropensity matched or adjusted observational studies with two or more of the interventions of interest (aprotinin, tranexamic acid, epsilon-aminocaproic acid, and no treatment) that were carried out in patients undergoing cardiac surgery.Data analysisNetwork meta-analysis was used to compare treatments, and odds ratios with 95% credible intervals were estimated. Meta-analyses were carried out for randomised controlled trials alone and for randomised controlled trials with observational studies.Results106 randomised controlled trials and 11 observational studies (43,270 patients) were included. Based on the results from analysis of randomised controlled trials, tranexamic acid was associated on average with a reduced risk of death compared with aprotinin (odds ratio 0.64, 95% credible interval 0.41 to 0.99). When observational data were incorporated, comparisons showed an increased risk of mortality with aprotinin on average relative to tranexamic acid (odds ratio 0.71, 95% credible interval 0.50 to 0.98) and epsilon-aminocaproic acid (0.60, 0.43 to 0.87), and an increased risk of renal failure or dysfunction on average relative to all comparators: odds ratio 0.66 (95% credible interval 0.45 to 0.88) compared with no treatment, 0.66 (0.48 to 0.91) versus tranexamic acid, and 0.65 (0.45 to 0.88) versus epsilon-aminocaproic acid.ConclusionAlthough meta-analyses of randomised controlled trials were largely inconclusive, inclusion of observational data suggest concerns remain about the safety of aprotinin. Tranexamic and epsilon-aminocaproic acid are effective alternatives that may be safer for patients.
Project description:Dietary DNA metabarcoding enables researchers to identify and characterize trophic interactions with a high degree of taxonomic precision. It is also sensitive to sources of bias and contamination in the field and laboratory. One of the earliest and most common strategies for dealing with such sensitivities has been to remove all low-abundance sequences and conduct ecological analyses based on the presence or absence of food taxa. Although this step is now often perceived to be necessary, evidence of its sufficiency is lacking and more attention to the risk of introducing other errors is needed. Using computer simulations, we demonstrate that common strategies to remove low-abundance sequences can erroneously eliminate true dietary sequences in ways that impact downstream inferences. Using real data from well-studied wildlife populations in Yellowstone National Park, we further show how these strategies can markedly alter the composition of dietary profiles in ways that scale-up to obscure ecological interpretations about dietary generalism, specialism, and composition. Although the practice of removing low-abundance sequences may continue to be a useful strategy to address research questions that focus on a subset of relatively abundant foods, its continued widespread use risks generating misleading perceptions about the structure of trophic networks. Researchers working with dietary DNA metabarcoding data-or similar data such as environmental DNA, microbiomes, or pathobiomes-should be aware of drawbacks and consider alternative bioinformatic, experimental, and statistical solutions.
Project description:BackgroundErythropoiesis-stimulating agents are used to treat anemia in patients with cancer. However, their safety and effectiveness is controversial. We did a systematic review of the clinical efficacy and harms of these agents in adults with anemia related to cancer or chemotherapy.MethodsWe conducted a systematic review of published and unpublished randomized controlled trials (RCTs) using accepted methods for literature searches, article selection, data extraction and quality assessment. We included RCTs involving anemic adults with cancer. We compared the use of erythropoiesis-stimulating agents with nonuse and assessed clinical outcomes (all-cause mortality, cardiovascular events and hypertension, health-related quality of life, blood transfusions and tumour response) and harms (serious adverse events) between groups.ResultsWe identified 52 trials (n = 12 006) that met our selection criteria. The pooled all-cause mortality during treatment was significantly higher in the group receiving erythropoiesis-stimulating therapy than in the control group (relative risk [RR] 1.15, 95% confidence interval [CI] 1.03 to 1.29). Compared with no treatment, use of erythropoiesis-stimulating agents led to clinically detectable improvements in disease-specific measures of quality of life. It also reduced the use of blood transfusions (RR 0.64, 95% CI 0.56 to 0.73). However, it led to an increased risk of thrombotic events (RR 1.69, 95% CI 1.27 to 2.24) and serious adverse events (RR 1.16, 95% CI 1.08 to 1.25).InterpretationUse of erythropoiesis-stimulating agents in patients with cancer-related anemia improved some disease-specific measures of quality of life and decreased the use of blood transfusions. However, it increased the risk of death and serious adverse events. Our findings suggest that such therapy not be used routinely as an alternative to blood transfusion in patients with anemia related to cancer.
Project description:BackgroundA hallmark of unregulated drug markets is their unpredictability and constant evolution with newly introduced substances. People who use drugs and the public health workforce are often unaware of the appearance of new drugs on the unregulated market and their type, safe dosage, and potential adverse effects. This increases risks to people who use drugs, including the risk of unknown consumption and unintentional drug poisoning. Early warning systems (EWSs) can help monitor the landscape of emerging drugs in a given community by collecting and tracking up-to-date information and determining trends. However, there are currently few ways to systematically monitor the appearance and harms of new drugs on the unregulated market in Canada.ObjectiveThe goal of this work is to examine how artificial intelligence can assist in identifying patterns of drug-related risks and harms, by monitoring the social media activity of public health and law enforcement groups. This information is beneficial in the form of an EWS as it can be used to identify new and emerging drug trends in various communities.MethodsTo collect data for this study, 145 relevant Twitter accounts throughout Quebec (n=33), Ontario (n=78), and British Columbia (n=34) were manually identified. Tweets posted between August 23 and December 21, 2021, were collected via the application programming interface developed by Twitter for a total of 40,393 tweets. Next, subject matter experts (1) developed keyword filters that reduced the data set to 3746 tweets and (2) manually identified relevant tweets for monitoring and early warning efforts for a total of 464 tweets. Using this information, a zero-shot classifier was applied to tweets from step 1 with a set of keep (drug arrest, drug discovery, and drug report) and not-keep (drug addiction support, public safety report, and others) labels to see how accurately it could extract the tweets identified in step 2.ResultsWhen looking at the accuracy in identifying relevant posts, the system extracted a total of 584 tweets and had an overlap of 392 out of 477 (specificity of ~84.5%) with the subject matter experts. Conversely, the system identified a total of 3162 irrelevant tweets and had an overlap of 3090 (sensitivity of ~94.1%) with the subject matter experts.ConclusionsThis study demonstrates the benefits of using artificial intelligence to assist in finding relevant tweets for an EWS. The results showed that it can be quite accurate in filtering out irrelevant information, which greatly reduces the amount of manual work required. Although the accuracy in retaining relevant information was observed to be lower, an analysis showed that the label definitions can impact the results significantly and would therefore be suitable for future work to refine. Nonetheless, the performance is promising and demonstrates the usefulness of artificial intelligence in this domain.
Project description:The synchronization of nonlinear systems connected over large-scale networks has gained popularity in a variety of applications, such as power grids, sensor networks, and biology. Stochastic uncertainty in the interconnections is a ubiquitous phenomenon observed in these physical and biological networks. We provide a size-independent network sufficient condition for the synchronization of scalar nonlinear systems with stochastic linear interactions over large-scale networks. This sufficient condition, expressed in terms of nonlinear dynamics, the Laplacian eigenvalues of the nominal interconnections, and the variance and location of the stochastic uncertainty, allows us to define a synchronization margin. We provide an analytical characterization of important trade-offs between the internal nonlinear dynamics, network topology, and uncertainty in synchronization. For nearest neighbour networks, the existence of an optimal number of neighbours with a maximum synchronization margin is demonstrated. An analytical formula for the optimal gain that produces the maximum synchronization margin allows us to compare the synchronization properties of various complex network topologies.