Molecular recording of mammalian embryogenesis, bioRxiv, 2018-08-03

Understanding the emergence of complex multicellular organisms from single totipotent cells, or ontogenesis, represents a foundational question in biology. The study of mammalian development is particularly challenging due to the difficulty of monitoring embryos in utero, the variability of progenitor field sizes, and the indeterminate relationship between the generation of uncommitted progenitors and their progression to subsequent stages. Here, we present a flexible, high information, multi-channel molecular recorder with a single cell (sc) readout and apply it as an evolving lineage tracer to define a mouse cell fate map from fertilization through gastrulation. By combining lineage information with scRNA-seq profiles, we recapitulate canonical developmental relationships between different tissue types and reveal an unexpected transcriptional convergence of endodermal cells from extra-embryonic and embryonic origins, illustrating how lineage information complements scRNA-seq to define cell types. Finally, we apply our cell fate map to estimate the number of embryonic progenitor cells and the degree of asymmetric partitioning within the pluripotent epiblast during specification. Our approach enables massively parallel, high-resolution recording of lineage and other information in mammalian systems to facilitate a quantitative framework for describing developmental processes.

biorxiv developmental-biology 0-100-users 2018

Reaction times and other skewed distributions problems with the mean and the median, bioRxiv, 2018-08-03

ABSTRACTTo summarise skewed (asymmetric) distributions, such as reaction times, typically the mean or the median are used as measures of central tendency. Using the mean might seem surprising, given that it provides a poor measure of central tendency for skewed distributions, whereas the median provides a better indication of the location of the bulk of the observations. However, the sample median is biased with small sample sizes, it tends to overestimate the population median. This is not the case for the mean. Based on this observation, Miller (1988) concluded that “sample medians must not be used to compare reaction times across experimental conditions when there are unequal numbers of trials in the conditions.” Here we replicate and extend Miller (1988), and demonstrate that his conclusion was ill-advised for several reasons. First, the median’s bias can be corrected using a percentile bootstrap bias correction. Second, a careful examination of the sampling distributions reveals that the sample median is median unbiased, whereas the mean is median biased when dealing with skewed distributions. That is, on average the sample mean estimates the population mean, but typically this is not the case. In addition, simulations of false and true positives in various situations show that no method dominates. Crucially, neither the mean nor the median are sufficient or even necessary to compare skewed distributions. Different questions require different methods and it would be unwise to use the mean or the median in all situations. Better tools are available to get a deeper understanding of how distributions differ we illustrate a powerful alternative that relies on quantile estimation. All the code and data to reproduce the figures and analyses in the article are available online.

biorxiv neuroscience 100-200-users 2018

Moving beyond P values Everyday data analysis with estimation plots, bioRxiv, 2018-07-26

Over the past 75 years, a number of statisticians have advised that the data-analysis method known as null-hypothesis significance testing (NHST) should be deprecated (Berkson, 1942; Halsey et al., 2015; Wasserstein et al., 2019). The limitations of NHST have been extensively discussed, with a broad consensus that current statistical practice in the biological sciences needs reform. However, there is less agreement on reform’s specific nature, with vigorous debate surrounding what would constitute a suitable alternative (Altman et al., 2000; Benjamin et al., 2017; Cumming and Calin-Jageman, 2016). An emerging view is that a more complete analytic technique would use statistical graphics to estimate effect sizes and evaluate their uncertainty (Cohen, 1994; Cumming and Calin-Jageman, 2016). As these estimation methods require only minimal statistical retraining, they have great potential to shift the current data-analysis culture away from dichotomous thinking towards quantitative reasoning (Claridge-Chang and Assam, 2016). The evolution of statistics has been inextricably linked to the development of quantitative displays that support complex visual reasoning (Tufte, 2001). We consider that the graphic we describe here as estimation plot is the most intuitive way to display the complete statistical information about experimental data sets. However, a major obstacle to adopting estimation plots is accessibility to suitable software. To lower this hurdle, we have developed free software that makes high-quality estimation plotting available to all. Here, we explain the rationale for estimation plots by contrasting them with conventional charts used to display data with NHST results, and describe how the use of these graphs affords five major analytical advantages.

biorxiv bioinformatics 500+-users 2018

 

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