Meta-learners for Estimating Heterogeneous Treatment Effects using Machine Learning

There is growing interest in estimating and analyzing heterogeneous treatment effects in experimental and observational studies. We describe a number of meta-algorithms that can take advantage of any supervised learning or regression method in machine learning and statistics to estimate the Conditional Average Treatment Effect (CATE) function. Meta-algorithms build on base algorithms---such as Random Forests (RF), Bayesian Additive Regression Trees (BART) or neural networks---to estimate the CATE, a function that the base algorithms are not designed to estimate directly. We introduce a new meta-algorithm, the X-learner, that is provably efficient when the number of units in one treatment group is much larger than in the other, and can exploit structural properties of the CATE function. For example, if the CATE function is linear and the response functions in treatment and control are Lipschitz continuous, the X-learner can still achieve the parametric rate under regularity conditions. We then introduce versions of the X-learner that use RF and BART as base learners. In extensive simulation studies, the X-learner performs favorably, although none of the meta-learners is uniformly the best. In two persuasion field experiments from political science, we demonstrate how our new X-learner can be used to target treatment regimes and to shed light on underlying mechanisms. A software package is provided that implements our methods

Dietary history contributes to enterotype-like clustering and functional metagenomic content in the intestinal microbiome of wild mice

Understanding the origins of gut microbial community structure is critical for the identification and interpretation of potential fitnessrelated traits for the host. The presence of community clusters characterized by differences in the abundance of signature taxa, referred to as enterotypes, is a debated concept first reported in humans and later extended to other mammalian hosts. In this study, we provide a thorough assessment of their existence in wild house mice using a panel of evaluation criteria.We identify support for two clusters that are compositionally similar to clusters identified in humans, chimpanzees, and laboratory mice, characterized by differences in Bacteroides, Robinsoniella, and unclassified genera belonging to the family Lachnospiraceae. To further evaluate these clusters, we (i) monitored community changes associated with moving mice from the natural to a laboratory environment, (ii) performed functional metagenomic sequencing, and (iii) subjected wild-caught samples to stable isotope analysis to reconstruct dietary patterns. This process reveals differences in the proportions of genes involved in carbohydrate versus protein metabolism in the functional metagenome, as well as differences in plant- versus meat-derived food sources between clusters. In conjunction with wild-caught mice quickly changing their enterotype classification upon transfer to a standard laboratory chow diet, these results provide strong evidence that dietary history contributes to the presence of enterotype-like clustering in wild mice

A de novo evolved gene in the house mouse regulates female pregnancy cycles

The de novo emergence of new genes has been well documented through genomic analyses. However, a functional analysis, especially of very young protein-coding genes, is still largely lacking. Here, we identify a set of house mouse-specific protein-coding genes and assess their translation by ribosome profiling and mass spectrometry data. We functionally analyze one of them, ̑extitGm13030}, which is specifically expressed in females in the oviduct. The interruption of the reading frame affects the transcriptional network in the oviducts at a specific stage of the estrous cycle. This includes the upregulation of ̑extit{Dcpp} genes, which are known to stimulate the growth of preimplantation embryos. As a consequence, knockout females have their second litters after shorter times and have a higher infanticide rate. Given that ̑extit{Gm13030 shows no signs of positive selection, our findings support the hypothesis that a de novo evolved gene can directly adopt a function without much sequence adaptation

Analysis of coupled heat and moisture transfer in masonry structures

Evaluation of effective or macroscopic coefficients of thermal conductivity under coupled heat and moisture transfer is presented. The paper first gives a detailed summary on the solution of a simple steady state heat conduction problem with an emphasis on various types of boundary conditions applied to the representative volume element -- a periodic unit cell. Since the results essentially suggest no superiority of any type of boundary conditions, the paper proceeds with the coupled nonlinear heat and moisture problem subjecting the selected representative volume element to the prescribed macroscopically uniform heat flux. This allows for a direct use of the academic or commercially available codes. Here, the presented results are derived with the help of the SIFEL (SIimple Finite Elements) system.Comment: 23 pages, 11 figure

Inositol Pyrophosphate-Controlled Kinetochore Architecture and Mitotic Entry in S. pombe

Inositol pyrophosphates (IPPs) comprise a specific class of signaling molecules that regulate central biological processes in eukaryotes. The conserved Vip1/PPIP5K family controls intracellular IP8 levels, the highest phosphorylated form of IPPs present in yeasts, as it has both inositol kinase and pyrophosphatase activities. Previous studies have shown that the fission yeast S. pombe Vip1/PPIP5K family member Asp1 impacts chromosome transmission fidelity via the modulation of spindle function. We now demonstrate that an IP8 analogue is targeted by endogenous Asp1 and that cellular IP8 is subject to cell cycle control. Mitotic entry requires Asp1 kinase function and IP8 levels are increased at the G2/M transition. In addition, the kinetochore, the conductor of chromosome segregation that is assembled on chromosomes is modulated by IP8. Members of the yeast CCAN kinetochore-subcomplex such as Mal2/CENP-O localize to the kinetochore depending on the intracellular IP8-level: higher than wild-type IP8 levels reduce Mal2 kinetochore targeting, while a reduction in IP8 has the opposite effect. As our perturbations of the inositol polyphosphate and IPP pathways demonstrate that kinetochore architecture depends solely on IP8 and not on other IPPs, we conclude that chromosome transmission fidelity is controlled by IP8 via an interplay between entry into mitosis, kinetochore architecture, and spindle dynamics.Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)Medical Research Council (MRC)Peer Reviewe

Dedicated transcriptomics combined with power analysis lead to functional understanding of genes with weak phenotypic changes in knockout lines

Author summary Knockout mice benefit the understanding of gene functions in mammals. However, it has proven difficult for many genes to identify clear phenotypes, related due to lack of sufficient assays. As Lewis Wolpert put it in a famous quote “But did you take them to the opera?”, thus metaphorically alluding to the need to extend phenotyping efforts. This insight led to the establishment of phenotyping pipelines that are nowadays routinely used to characterize knock-out lines. However, transcriptomic approaches based on RNA-Seq have been much less explored for such deep-level studies. We conducted here both, a theoretical power analysis and practical RNA-Seq experiments on two knockout lines with small phenotypic effects to investigate the parameters including sample size, sequencing depth, fold change, and dispersion. Our dedicated RNA-Seq studies discovered thousands of genes with small transcriptional changes and enriched in specific functions in both knockout lines. We find that it is more important to increase the number of samples than to increase the sequencing depth. Our work shows that a deep RNA-Seq study on knockouts is powerful for understanding gene functions in cases of weak phenotypic effects, and provides a guideline for the experimental design of such studies

Molecular diet analysis in mussels and other metazoan filter feeders and an assessment of their utility as natural eDNA samplers

Molecular gut content analysis is a popular tool to study food web interactions and has recently been suggested as an alternative source for DNA-based biomonitoring. However, the overabundant consumer's DNA often outcompetes that of its diet during PCR. Lineage-specific primers are an efficient means to reduce consumer amplification while retaining broad specificity for dietary taxa. Here, we designed an amplicon sequencing assay to monitor the eukaryotic diet of mussels and other metazoan filter feeders and explore the utility of mussels as natural eDNA samplers to monitor planktonic communities. We designed several lineage-specific rDNA primers with broad taxonomic suitability for eukaryotes. The primers were tested using DNA extracts of different limnic and marine mussel species and the results compared to eDNA water samples collected next to the mussel colonies. In addition, we analysed several 25-year time series samples of mussels from German rivers. Our primer sets efficiently prevent the amplification of mussels and other metazoans. The recovered DNA reflects a broad dietary preference across the eukaryotic tree of life and considerable taxonomic overlap with filtered water samples. We also show the utility of a reversed version of our primers, which prevents amplification of nonmetazoan taxa from complex eukaryote community samples, by enriching fauna associated with the marine brown algae Fucus vesiculosus. Our protocol will enable large-scale dietary analysis in metazoan filter feeders, facilitate aquatic food web analysis and allow surveying of aquacultures for pathogens. Moreover, we show that mussels and other aquatic filter feeders can serve as complementary DNA source for biomonitoring

Diversity and substrate-specificity of green algae and other micro-eukaryotes colonizing amphibian clutches in Germany, revealed by DNA metabarcoding

Amphibian clutches are colonized by diverse but poorly studied communities of micro-organisms. One of the most noted ones is the unicellular green alga, Oophila amblystomatis, but the occurrence and role of other micro-organisms in the capsular chamber surrounding amphibian clutches have remained largely unstudied. Here, we undertook a multi-marker DNA metabarcoding study to characterize the community of algae and other micro-eukaryotes associated with agile frog (Rana dalmatina) clutches. Samplings were performed at three small ponds in Germany, from four substrates: water, sediment, tree leaves from the bottom of the pond, and R. dalmatina clutches. Sampling substrate strongly determined the community compositions of algae and other micro-eukaryotes. Therefore, as expected, the frog clutch-associated communities formed clearly distinct clusters. Clutch-associated communities in our study were structured by a plethora of not only green algae, but also diatoms and other ochrophytes. The most abundant operational taxonomic units (OTUs) in clutch samples were taxa from Chlamydomonas, Oophila, but also from Nitzschia and other ochrophytes. Sequences of Oophila “Clade B” were found exclusively in clutches. Based on additional phylogenetic analyses of 18S rDNA and of a matrix of 18 nuclear genes derived from transcriptomes, we confirmed in our samples the existence of two distinct clades of green algae assigned to Oophila in past studies. We hypothesize that “Clade B” algae correspond to the true Oophila, whereas “Clade A” algae are a series of Chlorococcum species that, along with other green algae, ochrophytes and protists, colonize amphibian clutches opportunistically and are often cultured from clutch samples due to their robust growth performance. The clutch-associated communities were subject to filtering by sampling location, suggesting that the taxa colonizing amphibian clutches can drastically differ depending on environmental conditions