Diagnosis of cancer as an emergency: a critical review of current evidence

Many patients with cancer are diagnosed through an emergency presentation, which is associated with inferior clinical and patient-reported outcomes compared with those of patients who are diagnosed electively or through screening. Reducing the proportion of patients with cancer who are diagnosed as emergencies is, therefore, desirable; however, the optimal means of achieving this aim are uncertain owing to the involvement of different tumour, patient and health-care factors, often in combination. Most relevant evidence relates to patients with colorectal or lung cancer in a few economically developed countries, and defines emergency presentations contextually (that is, whether patients presented to emergency health-care services and/or received emergency treatment shortly before their diagnosis) as opposed to clinically (whether patients presented with life-threatening manifestations of their cancer). Consistent inequalities in the risk of emergency presentations by patient characteristics and cancer type have been described, but limited evidence is available on whether, and how, such presentations can be prevented. Evidence on patients' symptoms and health-care use before presentation as an emergency is sparse. In this Review, we describe the extent, causes and implications of a diagnosis of cancer following an emergency presentation, and provide recommendations for public health and health-care interventions, and research efforts aimed at addressing this under-researched aspect of cancer diagnosis

A complex pattern of post‐divergence expansion, contraction, introgression and asynchronous responses to Pleistocene climate changes in two Dipelta sister species from western China

The well-known vicariance and dispersal models dominate in understanding the allopatric pattern for related species and presume the simultaneous occurrence of speciation and biogeographic events. However, the formation of allopatry may postdate the species divergence. We examined this hypothesis using DNA sequence data from 3 chloroplast fragments and 5 nuclear loci of Dipelta floribunda and D. yunnanensis, two shrub species with the circum Sichuan Basin distribution, combining the climatic niche modeling approach. The best-fit model supported by the approximate Bayesian computation (ABC) analysis indicated that, D. floribunda and D. yunnanensis diverged during the mid-Pleistocene period, consistent with the largest glacial period in the Qinghai-Tibet Plateau (QTP). The historically inter-specific gene flow was identified but seemed to have ceased after the last interglacial period (LIG), when the range of D. floribunda moved northward from the south of the Sichuan Basin. Further, populations of D. floribunda had expanded obviously in the north of the Sichuan Basin after the last glacial maximum (LGM). Relatively, the range of D. yunnanensis expanded before the LGM, reduced during the post-LGM especially in the north of the Sichuan Basin, reflecting the asynchronous responses of related species to the contemporary climate changes. Our results suggested that complex topography should be considered in understanding the distributional patterns even for closely related species and their demographic responses

Accounting for Population Stratification in Practice: A Comparison of the Main Strategies Dedicated to Genome-Wide Association Studies

Genome-Wide Association Studies are powerful tools to detect genetic variants associated with diseases. Their results have, however, been questioned, in part because of the bias induced by population stratification. This is a consequence of systematic differences in allele frequencies due to the difference in sample ancestries that can lead to both false positive or false negative findings. Many strategies are available to account for stratification but their performances differ, for instance according to the type of population structure, the disease susceptibility locus minor allele frequency, the degree of sampling imbalanced, or the sample size. We focus on the type of population structure and propose a comparison of the most commonly used methods to deal with stratification that are the Genomic Control, Principal Component based methods such as implemented in Eigenstrat, adjusted Regressions and Meta-Analyses strategies. Our assessment of the methods is based on a large simulation study, involving several scenarios corresponding to many types of population structures. We focused on both false positive rate and power to determine which methods perform the best. Our analysis showed that if there is no population structure, none of the tests led to a bias nor decreased the power except for the Meta-Analyses. When the population is stratified, adjusted Logistic Regressions and Eigenstrat are the best solutions to account for stratification even though only the Logistic Regressions are able to constantly maintain correct false positive rates. This study provides more details about these methods. Their advantages and limitations in different stratification scenarios are highlighted in order to propose practical guidelines to account for population stratification in Genome-Wide Association Studies

Genomic signatures of population decline in the malaria mosquito Anopheles gambiae

Population genomic features such as nucleotide diversity and linkage disequilibrium are expected to be strongly shaped by changes in population size, and might therefore be useful for monitoring the success of a control campaign. In the Kilifi district of Kenya, there has been a marked decline in the abundance of the malaria vector Anopheles gambiae subsequent to the rollout of insecticide-treated bed nets. To investigate whether this decline left a detectable population genomic signature, simulations were performed to compare the effect of population crashes on nucleotide diversity, Tajima's D, and linkage disequilibrium (as measured by the population recombination parameter ρ). Linkage disequilibrium and ρ were estimated for An. gambiae from Kilifi, and compared them to values for Anopheles arabiensis and Anopheles merus at the same location, and for An. gambiae in a location 200 km from Kilifi. In the first simulations ρ changed more rapidly after a population crash than the other statistics, and therefore is a more sensitive indicator of recent population decline. In the empirical data, linkage disequilibrium extends 100-1000 times further, and ρ is 100-1000 times smaller, for the Kilifi population of An. gambiae than for any of the other populations. There were also significant runs of homozygosity in many of the individual An. gambiae mosquitoes from Kilifi. These results support the hypothesis that the recent decline in An. gambiae was driven by the rollout of bed nets. Measuring population genomic parameters in a small sample of individuals before, during and after vector or pest control may be a valuable method of tracking the effectiveness of interventions

The evolution of strong reproductive isolation between sympatric intertidal snails

The evolution of strong reproductive isolation (RI) is fundamental to the origins and maintenance of biological diversity, especially in situations where geographical distributions of taxa broadly overlap. But what is the history behind strong barriers currently acting in sympatry? Using whole-genome sequencing and single nucleotide polymorphism genotyping, we inferred (i) the evolutionary relationships, (ii) the strength of RI, and (iii) the demographic history of divergence between two broadly sympatric taxa of intertidal snail. Despite being cryptic, based on external morphology, Littorina arcana and Littorina saxatilis differ in their mode of female reproduction (egg-laying versus brooding), which may generate a strong post-zygotic barrier. We show that egg-laying and brooding snails are closely related, but genetically distinct. Genotyping of 3092 snails from three locations failed to recover any recent hybrid or backcrossed individuals, confirming that RI is strong. There was, however, evidence for a very low level of asymmetrical introgression, suggesting that isolation remains incomplete. The presence of strong, asymmetrical RI was further supported by demographic analysis of these populations. Although the taxa are currently broadly sympatric, demographic modelling suggests that they initially diverged during a short period of geographical separation involving very low gene flow. Our study suggests that some geographical separation may kick-start the evolution of strong RI, facilitating subsequent coexistence of taxa in sympatry. The strength of RI needed to achieve sympatry and the subsequent effect of sympatry on RI remain open questions. This article is part of the theme issue ‘Towards the completion of speciation: the evolution of reproductive isolation beyond the first barriers'

Discovery of Rare Variants via Sequencing: Implications for the Design of Complex Trait Association Studies

There is strong evidence that rare variants are involved in complex disease etiology. The first step in implicating rare variants in disease etiology is their identification through sequencing in both randomly ascertained samples (e.g., the 1,000 Genomes Project) and samples ascertained according to disease status. We investigated to what extent rare variants will be observed across the genome and in candidate genes in randomly ascertained samples, the magnitude of variant enrichment in diseased individuals, and biases that can occur due to how variants are discovered. Although sequencing cases can enrich for casual variants, when a gene or genes are not involved in disease etiology, limiting variant discovery to cases can lead to association studies with dramatically inflated false positive rates

Evidence for Pervasive Adaptive Protein Evolution in Wild Mice

The relative contributions of neutral and adaptive substitutions to molecular evolution has been one of the most controversial issues in evolutionary biology for more than 40 years. The analysis of within-species nucleotide polymorphism and between-species divergence data supports a widespread role for adaptive protein evolution in certain taxa. For example, estimates of the proportion of adaptive amino acid substitutions (alpha) are 50% or more in enteric bacteria and Drosophila. In contrast, recent estimates of alpha for hominids have been at most 13%. Here, we estimate alpha for protein sequences of murid rodents based on nucleotide polymorphism data from multiple genes in a population of the house mouse subspecies Mus musculus castaneus, which inhabits the ancestral range of the Mus species complex and nucleotide divergence between M. m. castaneus and M. famulus or the rat. We estimate that 57% of amino acid substitutions in murids have been driven by positive selection. Hominids, therefore, are exceptional in having low apparent levels of adaptive protein evolution. The high frequency of adaptive amino acid substitutions in wild mice is consistent with their large effective population size, leading to effective natural selection at the molecular level. Effective natural selection also manifests itself as a paucity of effectively neutral nonsynonymous mutations in M. m. castaneus compared to humans

An increased fraction of circulating miR-363 and miR-16 is particle bound in patients with chronic lymphocytic leukaemia as compared to normal subjects.

In vitro culture studies have shown that miR-363 is enriched in extracellular vesicles from chronic lymphocytic leukaemia cells. We wondered whether miR-363 was detectable in plasma, which is an essential precondition for further studies to assess its usefulness as a biomarker. Using samples from two clinical trials: one enrolling patients with advanced disease and the other asymptomatic patients with early stage disease, we determined plasma miR-363 levels and secondly investigated the distribution of this miRNA between plasma and particle bound fractions in patients and normal subjects.Advanced disease (n = 95) was associated with higher levels of miR-363 than early stage disease (n = 45) or normal subjects (n = 11) but there was no association with markers of prognosis. The distribution of specific miRNA between particle bound and plasma protein fractions was investigated using size exclusion chromatography on plasma from patients (n = 4) and normal subjects (n = 3). ~ 20% of total miR-16 and miR-363 is particle bound in patients while there was no detectable particle bound material in normal subjects. Our work demonstrates that miR-363 levels are raised in chronic lymphocytic leukaemia patients and raises the possibility that distribution of circulating miRNA between plasma fractions differs in health and disease

Joint Analysis for Genome-Wide Association Studies in Family-Based Designs

In family-based data, association information can be partitioned into the between-family information and the within-family information. Based on this observation, Steen et al. (Nature Genetics. 2005, 683–691) proposed an interesting two-stage test for genome-wide association (GWA) studies under family-based designs which performs genomic screening and replication using the same data set. In the first stage, a screening test based on the between-family information is used to select markers. In the second stage, an association test based on the within-family information is used to test association at the selected markers. However, we learn from the results of case-control studies (Skol et al. Nature Genetics. 2006, 209–213) that this two-stage approach may be not optimal. In this article, we propose a novel two-stage joint analysis for GWA studies under family-based designs. For this joint analysis, we first propose a new screening test that is based on the between-family information and is robust to population stratification. This new screening test is used in the first stage to select markers. Then, a joint test that combines the between-family information and within-family information is used in the second stage to test association at the selected markers. By extensive simulation studies, we demonstrate that the joint analysis always results in increased power to detect genetic association and is robust to population stratification