196 research outputs found
Two-Locus Likelihoods under Variable Population Size and Fine-Scale Recombination Rate Estimation
Two-locus sampling probabilities have played a central role in devising an
efficient composite likelihood method for estimating fine-scale recombination
rates. Due to mathematical and computational challenges, these sampling
probabilities are typically computed under the unrealistic assumption of a
constant population size, and simulation studies have shown that resulting
recombination rate estimates can be severely biased in certain cases of
historical population size changes. To alleviate this problem, we develop here
new methods to compute the sampling probability for variable population size
functions that are piecewise constant. Our main theoretical result, implemented
in a new software package called LDpop, is a novel formula for the sampling
probability that can be evaluated by numerically exponentiating a large but
sparse matrix. This formula can handle moderate sample sizes () and
demographic size histories with a large number of epochs (). In addition, LDpop implements an approximate formula for the sampling
probability that is reasonably accurate and scales to hundreds in sample size
(). Finally, LDpop includes an importance sampler for the posterior
distribution of two-locus genealogies, based on a new result for the optimal
proposal distribution in the variable-size setting. Using our methods, we study
how a sharp population bottleneck followed by rapid growth affects the
correlation between partially linked sites. Then, through an extensive
simulation study, we show that accounting for population size changes under
such a demographic model leads to substantial improvements in fine-scale
recombination rate estimation. LDpop is freely available for download at
https://github.com/popgenmethods/ldpopComment: 32 pages, 13 figure
Inference of Population History using Coalescent HMMs: Review and Outlook
Studying how diverse human populations are related is of historical and
anthropological interest, in addition to providing a realistic null model for
testing for signatures of natural selection or disease associations.
Furthermore, understanding the demographic histories of other species is
playing an increasingly important role in conservation genetics. A number of
statistical methods have been developed to infer population demographic
histories using whole-genome sequence data, with recent advances focusing on
allowing for more flexible modeling choices, scaling to larger data sets, and
increasing statistical power. Here we review coalescent hidden Markov models, a
powerful class of population genetic inference methods that can effectively
utilize linkage disequilibrium information. We highlight recent advances, give
advice for practitioners, point out potential pitfalls, and present possible
future research directions.Comment: 12 pages, 2 figure
A Likelihood-Free Inference Framework for Population Genetic Data using Exchangeable Neural Networks
An explosion of high-throughput DNA sequencing in the past decade has led to
a surge of interest in population-scale inference with whole-genome data.
Recent work in population genetics has centered on designing inference methods
for relatively simple model classes, and few scalable general-purpose inference
techniques exist for more realistic, complex models. To achieve this, two
inferential challenges need to be addressed: (1) population data are
exchangeable, calling for methods that efficiently exploit the symmetries of
the data, and (2) computing likelihoods is intractable as it requires
integrating over a set of correlated, extremely high-dimensional latent
variables. These challenges are traditionally tackled by likelihood-free
methods that use scientific simulators to generate datasets and reduce them to
hand-designed, permutation-invariant summary statistics, often leading to
inaccurate inference. In this work, we develop an exchangeable neural network
that performs summary statistic-free, likelihood-free inference. Our framework
can be applied in a black-box fashion across a variety of simulation-based
tasks, both within and outside biology. We demonstrate the power of our
approach on the recombination hotspot testing problem, outperforming the
state-of-the-art.Comment: 9 pages, 8 figure
Flexible non-parametric tests of sample exchangeability and feature independence
In scientific studies involving analyses of multivariate data, two questions
often arise for the researcher. First, is the sample exchangeable, meaning that
the joint distribution of the sample is invariant to the ordering of the units?
Second, are the features independent of one another, or can the features be
grouped so that the groups are mutually independent? We propose a
non-parametric approach that addresses these two questions. Our approach is
conceptually simple, yet fast and flexible. It controls the Type I error across
realistic scenarios, and handles data of arbitrary dimensions by leveraging
large-sample asymptotics. In the exchangeability detection setting, through
extensive simulations and a comparison against unsupervised tests of
stratification based on random matrix theory, we find that our approach
compares favorably in various scenarios of interest. We apply our method to
problems in population and statistical genetics, including stratification
detection and linkage disequilibrium splitting. We also consider other
application domains, applying our approach to post-clustering single-cell
chromatin accessibility data and World Values Survey data, where we show how
users can partition features into independent groups, which helps generate new
scientific hypotheses about the features.Comment: Main Text: 25 pages Supplementary Material: 39 page
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Downregulation of Protein 4.1R impairs centrosome function,bipolar spindle organization and anaphase
Centrosomes nucleate and organize interphase MTs and areinstrumental in the assembly of the mitotic bipolar spindle. Here wereport that two members of the multifunctional protein 4.1 family havedistinct distributions at centrosomes. Protein 4.1R localizes to maturecentrioles whereas 4.1G is a component of the pericentriolar matrixsurrounding centrioles. To selectively probe 4.1R function, we used RNAinterference-mediated depletion of 4.1R without decreasing 4.1Gexpression. 4.1R downregulation reduces MT anchoring and organization atinterphase and impairs centrosome separation during prometaphase.Metaphase chromosomes fail to properly condense/align and spindleorganization is aberrant. Notably 4.1R depletion causes mislocalizationof its binding partner NuMA (Nuclear Mitotic Apparatus Protein),essential for spindle pole focusing, and disrupts ninein. Duringanaphase/telophase, 4.1R-depleted cells have lagging chromosomes andaberrant MT bridges. Our data provide functional evidence that 4.1R makescrucial contributions to centrosome integrity and to mitotic spindlestructure enabling mitosis and anaphase to proceed with the coordinatedprecision required to avoid pathological events
Cognitive Training and Transcranial Direct Current Stimulation in Mild Cognitive Impairment: A Randomized Pilot Trial
BackgroundTranscranial direct current stimulation (tDCS), a non-invasive stimulation, represents a potential intervention to enhance cognition across clinical populations including Alzheimer’s disease and mild cognitive impairment (MCI). This randomized clinical trial in MCI investigated the effects of anodal tDCS (a-tDCS) delivered to left inferior frontal gyrus (IFG) combined with gist-reasoning training (SMART) versus sham tDCS (s-tDCS) plus SMART on measures of cognitive and neural changes in resting cerebral blood flow (rCBF). We were also interested in SMART effects on cognitive performance regardless of the tDCS group.MethodsTwenty-two MCI participants, who completed the baseline cognitive assessment (T1), were randomized into one of two groups: a-tDCS + SMART and s-tDCS + SMART. Of which, 20 participants completed resting pCASL MRI scan to measure rCBF. Eight SMART sessions were administered over 4 weeks with a-tDCS or s-tDCS stimulation for 20 min before each session. Participants were assessed immediately (T2) and 3-months after training (T3).ResultsSignificant group × time interactions showed cognitive gains at T2 in executive function (EF) measure of inhibition [DKEFS- Color word (p = 0.047)], innovation [TOSL (p = 0.01)] and on episodic memory [TOSL (p = 0.048)] in s-tDCS + SMART but not in a-tDCS + SMART group. Nonetheless, the gains did not persist for 3 months (T3) after the training. A voxel-based analysis showed significant increase in regional rCBF in the right middle frontal cortex (MFC) (cluster-wise p = 0.05, k = 1,168 mm3) in a-tDCS + SMART compared to s-tDCS + SMART. No significant relationship was observed between the increased CBF with cognition. Irrespective of group, the combined MCI showed gains at T2 in EF of conceptual reasoning [DKEFS card sort (p = 0.033)] and category fluency [COWAT (p = 0.055)], along with gains at T3 in EF of verbal fluency [COWAT (p = 0.009)].ConclusionOne intriguing finding is a-tDCS to left IFG plus SMART increased blood flow to right MFC, however, the stimulation seemingly blocked cognitive benefits of SMART on EF (inhibition and innovation) and episodic memory compared to s-tDCS + SMART group. Although the sample size is small, this paper contributes to growing evidence that cognitive training provides a way to significantly enhance cognitive performance in adults showing memory loss, where the role of a-tDCS in augmenting these effects need further study
Ethical Considerations for the Clinical Oncologist in an Era of Oncology Drug Shortages
Shortages of injectable drugs affect many cancer patients and providers in the U.S. today. Scholars and policymakers have recently begun to devote increased attention to these issues, but only a few tangible resources exist to guide clinical oncologists in developing strategies for dealing with drug shortages on a recurring basis. This article discusses existing information from the scholarly literature, policy analyses, and other relevant sources and seeks to provide practical ethical guidance to the broad audience of oncology professionals who are increasingly confronted with such cases in their practice. We begin by providing a brief overview of the history, causes, and regulatory context of oncology drug shortages in the U.S., followed by a discussion of ethical frameworks that have been proposed in this setting. We conclude with practical recommendations for ethical professional behavior in these increasingly common and challenging situations
Expanding the stdpopsim species catalog, and lessons learned for realistic genome simulations
Simulation is a key tool in population genetics for both methods development and empirical research, but producing simulations that recapitulate the main features of genomic datasets remains a major obstacle. Today, more realistic simulations are possible thanks to large increases in the quantity and quality of available genetic data, and the sophistication of inference and simulation software. However, implementing these simulations still requires substantial time and specialized knowledge. These challenges are especially pronounced for simulating genomes for species that are not well-studied, since it is not always clear what information is required to produce simulations with a level of realism sufficient to confidently answer a given question. The community-developed framework stdpopsim seeks to lower this barrier by facilitating the simulation of complex population genetic models using up-to-date information. The initial version of stdpopsim focused on establishing this framework using six well-characterized model species (Adrion et al., 2020). Here, we report on major improvements made in the new release of stdpopsim (version 0.2), which includes a significant expansion of the species catalog and substantial additions to simulation capabilities. Features added to improve the realism of the simulated genomes include non-crossover recombination and provision of species-specific genomic annotations. Through community-driven efforts, we expanded the number of species in the catalog more than threefold and broadened coverage across the tree of life. During the process of expanding the catalog, we have identified common sticking points and developed the best practices for setting up genome-scale simulations. We describe the input data required for generating a realistic simulation, suggest good practices for obtaining the relevant information from the literature, and discuss common pitfalls and major considerations. These improvements to stdpopsim aim to further promote the use of realistic whole-genome population genetic simulations, especially in non-model organisms, making them available, transparent, and accessible to everyone
The ENCODE Imputation Challenge: a critical assessment of methods for cross-cell type imputation of epigenomic profiles
A promising alternative to comprehensively performing genomics experiments is to, instead, perform a subset of experiments and use computational methods to impute the remainder. However, identifying the best imputation methods and what measures meaningfully evaluate performance are open questions. We address these questions by comprehensively analyzing 23 methods from the ENCODE Imputation Challenge. We find that imputation evaluations are challenging and confounded by distributional shifts from differences in data collection and processing over time, the amount of available data, and redundancy among performance measures. Our analyses suggest simple steps for overcoming these issues and promising directions for more robust research
The ENCODE Imputation Challenge: a critical assessment of methods for cross-cell type imputation of epigenomic profiles
A promising alternative to comprehensively performing genomics experiments is to, instead, perform a subset of experiments and use computational methods to impute the remainder. However, identifying the best imputation methods and what measures meaningfully evaluate performance are open questions. We address these questions by comprehensively analyzing 23 methods from the ENCODE Imputation Challenge. We find that imputation evaluations are challenging and confounded by distributional shifts from differences in data collection and processing over time, the amount of available data, and redundancy among performance measures. Our analyses suggest simple steps for overcoming these issues and promising directions for more robust research
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