Automated calibration of consensus weighted distance-based clustering approaches using sharp.

MOTIVATION: In consensus clustering, a clustering algorithm is used in combination with a subsampling procedure to detect stable clusters. Previous studies on both simulated and real data suggest that consensus clustering outperforms native algorithms. RESULTS: We extend here consensus clustering to allow for attribute weighting in the calculation of pairwise distances using existing regularized approaches. We propose a procedure for the calibration of the number of clusters (and regularization parameter) by maximizing the sharp score, a novel stability score calculated directly from consensus clustering outputs, making it extremely computationally competitive. Our simulation study shows better clustering performances of (i) approaches calibrated by maximizing the sharp score compared to existing calibration scores and (ii) weighted compared to unweighted approaches in the presence of features that do not contribute to cluster definition. Application on real gene expression data measured in lung tissue reveals clear clusters corresponding to different lung cancer subtypes. AVAILABILITY AND IMPLEMENTATION: The R package sharp (version ≥1.4.3) is available on CRAN at https://CRAN.R-project.org/package=sharp.

Variational Bayes for high-dimensional proportional hazards models with applications within gene expression.

MOTIVATION: Few Bayesian methods for analyzing high-dimensional sparse survival data provide scalable variable selection, effect estimation and uncertainty quantification. Such methods often either sacrifice uncertainty quantification by computing maximum a posteriori estimates, or quantify the uncertainty at high (unscalable) computational expense. RESULTS: We bridge this gap and develop an interpretable and scalable Bayesian proportional hazards model for prediction and variable selection, referred to as sparse variational Bayes. Our method, based on a mean-field variational approximation, overcomes the high computational cost of Markov chain Monte Carlo, whilst retaining useful features, providing a posterior distribution for the parameters and offering a natural mechanism for variable selection via posterior inclusion probabilities. The performance of our proposed method is assessed via extensive simulations and compared against other state-of-the-art Bayesian variable selection methods, demonstrating comparable or better performance. Finally, we demonstrate how the proposed method can be used for variable selection on two transcriptomic datasets with censored survival outcomes, and how the uncertainty quantification offered by our method can be used to provide an interpretable assessment of patient risk. AVAILABILITY AND IMPLEMENTATION: our method has been implemented as a freely available R package survival.svb (https://github.com/mkomod/survival.svb). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Atopic dermatitis or eczema? Consequences of ambiguity in disease name for biomedical literature mining.

BACKGROUND: Biomedical research increasingly relies on computational approaches to extract relevant information from large corpora of publications. OBJECTIVE: To investigate the consequence of the ambiguity between the use of terms "Eczema" and "Atopic Dermatitis" (AD) from the Information Retrieval perspective, and its impact on meta-analyses, systematic reviews and text mining. METHODS: Articles were retrieved by querying the PubMed using terms 'eczema' (D003876) and "dermatitis, atopic" (D004485). We used machine learning to investigate the differences between the contexts in which each term is used. We used a decision tree approach and trained model to predict if an article would be indexed with eczema or AD tags. We used text-mining tools to extract biological entities associated with eczema and AD, and investigated the discrepancy regarding the retrieval of key findings according to the terminology used. RESULTS: Atopic dermatitis query yielded more articles related to veterinary science, biochemistry, cellular and molecular biology; the eczema query linked to public health, infectious disease and respiratory system. Medical Subject Headings terms associated with "AD" or "Eczema" differed, with an agreement between the top 40 lists of 52%. The presence of terms related to cellular mechanisms, especially allergies and inflammation, characterized AD literature. The metabolites mentioned more frequently than expected in articles with AD tag differed from those indexed with eczema. Fewer enriched genes were retrieved when using eczema compared to AD query. CONCLUSIONS AND CLINICAL RELEVANCE: There is a considerable discrepancy when using text mining to extract bio-entities related to eczema or AD. Our results suggest that any systematic approach (particularly when looking for metabolites or genes related to the condition) should be performed using both terms jointly. We propose to use decision tree learning as a tool to spot and characterize ambiguity, and provide the source code for disambiguation at https://github.com/cfrainay/ResearchCodeBase.

Connectivity patterns between multiple allergen specific IgE antibodies and their association with severe asthma.

BACKGROUND: Allergic sensitization is associated with severe asthma, but assessment of sensitization is not recommended by most guidelines. OBJECTIVE: We hypothesized that patterns of IgE responses to multiple allergenic proteins differ between sensitized participants with mild/moderate and severe asthma. METHODS: IgE to 112 allergenic molecules (components, c-sIgE) was measured using multiplex array among 509 adults and 140 school-age and 131 preschool children with asthma/wheeze from the Unbiased BIOmarkers for the PREDiction of respiratory diseases outcomes cohort, of whom 595 had severe disease. We applied clustering methods to identify co-occurrence patterns of components (component clusters) and patterns of sensitization among participants (sensitization clusters). Network analysis techniques explored the connectivity structure of c-sIgE, and differential network analysis looked for differences in c-sIgE interactions between severe and mild/moderate asthma. RESULTS: Four sensitization clusters were identified, but with no difference between disease severity groups. Similarly, component clusters were not associated with asthma severity. None of the c-sIgE were identified as associates of severe asthma. The key difference between school children and adults with mild/moderate compared with those with severe asthma was in the network of connections between c-sIgE. Participants with severe asthma had higher connectivity among components, but these connections were weaker. The mild/moderate network had fewer connections, but the connections were stronger. Connectivity between components with no structural homology tended to co-occur among participants with severe asthma. Results were independent from the different sample sizes of mild/moderate and severe groups. CONCLUSIONS: The patterns of interactions between IgE to multiple allergenic proteins are predictors of asthma severity among school children and adults with allergic asthma.

PEITH(Θ): perfecting experiments with information theory in Python with GPU support.

Motivation: Different experiments provide differing levels of information about a biological system. This makes it difficult, a priori, to select one of them beyond mere speculation and/or belief, especially when resources are limited. With the increasing diversity of experimental approaches and general advances in quantitative systems biology, methods that inform us about the information content that a given experiment carries about the question we want to answer, become crucial. Results: PEITH(Θ) is a general purpose, Python framework for experimental design in systems biology. PEITH(Θ) uses Bayesian inference and information theory in order to derive which experiments are most informative in order to estimate all model parameters and/or perform model predictions. Availability and implementation: https://github.com/MichaelPHStumpf/Peitho. Contact: m.stumpf@imperial.ac.uk or juliane.liepe@mpibpc.mpg.de.

Nanog Fluctuations in Embryonic Stem Cells Highlight the Problem of Measurement in Cell Biology.

A number of important pluripotency regulators, including the transcription factor Nanog, are observed to fluctuate stochastically in individual embryonic stem cells. By transiently priming cells for commitment to different lineages, these fluctuations are thought to be important to the maintenance of, and exit from, pluripotency. However, because temporal changes in intracellular protein abundances cannot be measured directly in live cells, fluctuations are typically assessed using genetically engineered reporter cell lines that produce a fluorescent signal as a proxy for protein expression. Here, using a combination of mathematical modeling and experiment, we show that there are unforeseen ways in which widely used reporter strategies can systematically disturb the dynamics they are intended to monitor, sometimes giving profoundly misleading results. In the case of Nanog, we show how genetic reporters can compromise the behavior of important pluripotency-sustaining positive feedback loops, and induce a bifurcation in the underlying dynamics that gives rise to heterogeneous Nanog expression patterns in reporter cell lines that are not representative of the wild-type. These findings help explain the range of published observations of Nanog variability and highlight the problem of measurement in live cells.

The nature and nurture of cell heterogeneity: accounting for macrophage gene-environment interactions with single-cell RNA-Seq.

BACKGROUND: Single-cell RNA-Seq can be a valuable and unbiased tool to dissect cellular heterogeneity, despite the transcriptome's limitations in describing higher functional phenotypes and protein events. Perhaps the most important shortfall with transcriptomic 'snapshots' of cell populations is that they risk being descriptive, only cataloging heterogeneity at one point in time, and without microenvironmental context. Studying the genetic ('nature') and environmental ('nurture') modifiers of heterogeneity, and how cell population dynamics unfold over time in response to these modifiers is key when studying highly plastic cells such as macrophages. RESULTS: We introduce the programmable Polaris™ microfluidic lab-on-chip for single-cell sequencing, which performs live-cell imaging while controlling for the culture microenvironment of each cell. Using gene-edited macrophages we demonstrate how previously unappreciated knockout effects of SAMHD1, such as an altered oxidative stress response, have a large paracrine signaling component. Furthermore, we demonstrate single-cell pathway enrichments for cell cycle arrest and APOBEC3G degradation, both associated with the oxidative stress response and altered proteostasis. Interestingly, SAMHD1 and APOBEC3G are both HIV-1 inhibitors ('restriction factors'), with no known co-regulation. CONCLUSION: As single-cell methods continue to mature, so will the ability to move beyond simple 'snapshots' of cell populations towards studying the determinants of population dynamics. By combining single-cell culture, live-cell imaging, and single-cell sequencing, we have demonstrated the ability to study cell phenotypes and microenvironmental influences. It's these microenvironmental components - ignored by standard single-cell workflows - that likely determine how macrophages, for example, react to inflammation and form treatment resistant HIV reservoirs.

Stem and progenitor cell dysfunction in human trisomies.

Trisomy 21, the commonest constitutional aneuploidy in humans, causes profound perturbation of stem and progenitor cell growth, which is both cell context dependent and developmental stage specific and mediated by complex genetic mechanisms beyond increased Hsa21 gene dosage. While proliferation of fetal hematopoietic and testicular stem/progenitors is increased and may underlie increased susceptibility to childhood leukemia and testicular cancer, fetal stem/progenitor proliferation in other tissues is markedly impaired leading to the characteristic craniofacial, neurocognitive and cardiac features in individuals with Down syndrome. After birth, trisomy 21-mediated premature aging of stem/progenitor cells may contribute to the progressive multi-system deterioration, including development of Alzheimer's disease.

The ecology in the hematopoietic stem cell niche determines the clinical outcome in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a blood disease that disrupts normal function of the hematopoietic system. Despite the great progress made in terms of molecular therapies for CML, there remain large gaps in our understanding. By comparing mathematical models that describe CML progression and etiology we sought to identify those models that provide the best description of disease dynamics and their underlying mechanisms. Data for two clinical outcomes--disease remission or relapse--are considered, and we investigate these using Bayesian inference techniques throughout. We find that it is not possible to choose between the models based on fits to the data alone; however, by studying model predictions we can discard models that fail to take niche effects into account. More detailed analysis of the remaining models reveals mechanistic differences: for one model, leukemia stem cell dynamics determine the disease outcome; and for the other model disease progression is determined at the stage of progenitor cells, in particular by differences in progenitor death rates. This analysis also reveals distinct transient dynamics that will be experimentally accessible, but are currently at the limits of what is possible to measure. To resolve these differences we need to be able to probe the hematopoietic stem cell niche directly. Our analysis highlights the importance of further mapping of the bone marrow hematopoietic niche microenvironment as the "ecological" interactions between cells in this niche appear to be intricately linked to disease outcome.

Information theory and signal transduction systems: from molecular information processing to network inference.

Sensing and responding to the environment are two essential functions that all biological organisms need to master for survival and successful reproduction. Developmental processes are marshalled by a diverse set of signalling and control systems, ranging from systems with simple chemical inputs and outputs to complex molecular and cellular networks with non-linear dynamics. Information theory provides a powerful and convenient framework in which such systems can be studied; but it also provides the means to reconstruct the structure and dynamics of molecular interaction networks underlying physiological and developmental processes. Here we supply a brief description of its basic concepts and introduce some useful tools for systems and developmental biologists. Along with a brief but thorough theoretical primer, we demonstrate the wide applicability and biological application-specific nuances by way of different illustrative vignettes. In particular, we focus on the characterisation of biological information processing efficiency, examining cell-fate decision making processes, gene regulatory network reconstruction, and efficient signal transduction experimental design.

Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21.

The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid-primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo- and lymphopoiesis.

Maximizing the information content of experiments in systems biology.

Our understanding of most biological systems is in its infancy. Learning their structure and intricacies is fraught with challenges, and often side-stepped in favour of studying the function of different gene products in isolation from their physiological context. Constructing and inferring global mathematical models from experimental data is, however, central to systems biology. Different experimental setups provide different insights into such systems. Here we show how we can combine concepts from Bayesian inference and information theory in order to identify experiments that maximize the information content of the resulting data. This approach allows us to incorporate preliminary information; it is global and not constrained to some local neighbourhood in parameter space and it readily yields information on parameter robustness and confidence. Here we develop the theoretical framework and apply it to a range of exemplary problems that highlight how we can improve experimental investigations into the structure and dynamics of biological systems and their behavior.

Optimizing threshold-schedules for sequential approximate Bayesian computation: applications to molecular systems.

The likelihood-free sequential Approximate Bayesian Computation (ABC) algorithms are increasingly popular inference tools for complex biological models. Such algorithms proceed by constructing a succession of probability distributions over the parameter space conditional upon the simulated data lying in an ε-ball around the observed data, for decreasing values of the threshold ε. While in theory, the distributions (starting from a suitably defined prior) will converge towards the unknown posterior as ε tends to zero, the exact sequence of thresholds can impact upon the computational efficiency and success of a particular application. In particular, we show here that the current preferred method of choosing thresholds as a pre-determined quantile of the distances between simulated and observed data from the previous population, can lead to the inferred posterior distribution being very different to the true posterior. Threshold selection thus remains an important challenge. Here we propose that the threshold-acceptance rate curve may be used to determine threshold schedules that avoid local optima, while balancing the need to minimise the threshold with computational efficiency. Furthermore, we provide an algorithm based upon the unscented transform, that enables the threshold-acceptance rate curve to be efficiently predicted in the case of deterministic and stochastic state space models.

On optimality of kernels for approximate Bayesian computation using sequential Monte Carlo.

Approximate Bayesian computation (ABC) has gained popularity over the past few years for the analysis of complex models arising in population genetics, epidemiology and system biology. Sequential Monte Carlo (SMC) approaches have become work-horses in ABC. Here we discuss how to construct the perturbation kernels that are required in ABC SMC approaches, in order to construct a sequence of distributions that start out from a suitably defined prior and converge towards the unknown posterior. We derive optimality criteria for different kernels, which are based on the Kullback-Leibler divergence between a distribution and the distribution of the perturbed particles. We will show that for many complicated posterior distributions, locally adapted kernels tend to show the best performance. We find that the added moderate cost of adapting kernel functions is easily regained in terms of the higher acceptance rate. We demonstrate the computational efficiency gains in a range of toy examples which illustrate some of the challenges faced in real-world applications of ABC, before turning to two demanding parameter inference problems in molecular biology, which highlight the huge increases in efficiency that can be gained from choice of optimal kernels. We conclude with a general discussion of the rational choice of perturbation kernels in ABC SMC settings.

Genomic attributes of airway commensal bacteria and mucosa.

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.

Automated calibration for stability selection in penalised regression and graphical models.

Stability selection represents an attractive approach to identify sparse sets of features jointly associated with an outcome in high-dimensional contexts. We introduce an automated calibration procedure via maximisation of an in-house stability score and accommodating a priori-known block structure (e.g. multi-OMIC) data. It applies to [Least Absolute Shrinkage Selection Operator (LASSO)] penalised regression and graphical models. Simulations show our approach outperforms non-stability-based and stability selection approaches using the original calibration. Application to multi-block graphical LASSO on real (epigenetic and transcriptomic) data from the Norwegian Women and Cancer study reveals a central/credible and novel cross-OMIC role of LRRN3 in the biological response to smoking. Proposed approaches were implemented in the R package sharp.

Cardiometabolic and renal phenotypes and transitions in the United States population.

Cardiovascular and renal conditions have both shared and distinct determinants. In this study, we applied unsupervised clustering to multiple rounds of the National Health and Nutrition Examination Survey from 1988 to 2018, and identified 10 cardiometabolic and renal phenotypes. These included a 'low risk' phenotype; two groups with average risk factor levels but different heights; one group with low body-mass index and high levels of high-density lipoprotein cholesterol; five phenotypes with high levels of one or two related risk factors ('high heart rate', 'high cholesterol', 'high blood pressure', 'severe obesity' and 'severe hyperglycemia'); and one phenotype with low diastolic blood pressure (DBP) and low estimated glomerular filtration rate (eGFR). Prevalence of the 'high blood pressure' and 'high cholesterol' phenotypes decreased over time, contrasted by a rise in the 'severe obesity' and 'low DBP, low eGFR' phenotypes. The cardiometabolic and renal traits of the US population have shifted from phenotypes with high blood pressure and cholesterol toward poor kidney function, hyperglycemia and severe obesity.

Emulator-based Bayesian optimization for efficient multi-objective calibration of an individual-based model of malaria.

Individual-based models have become important tools in the global battle against infectious diseases, yet model complexity can make calibration to biological and epidemiological data challenging. We propose using a Bayesian optimization framework employing Gaussian process or machine learning emulator functions to calibrate a complex malaria transmission simulator. We demonstrate our approach by optimizing over a high-dimensional parameter space with respect to a portfolio of multiple fitting objectives built from datasets capturing the natural history of malaria transmission and disease progression. Our approach quickly outperforms previous calibrations, yielding an improved final goodness of fit. Per-objective parameter importance and sensitivity diagnostics provided by our approach offer epidemiological insights and enhance trust in predictions through greater interpretability.

Age groups that sustain resurging COVID-19 epidemics in the United States.

After initial declines, in mid-2020 a resurgence in transmission of novel coronavirus disease (COVID-19) occurred in the United States and Europe. As efforts to control COVID-19 disease are reintensified, understanding the age demographics driving transmission and how these affect the loosening of interventions is crucial. We analyze aggregated, age-specific mobility trends from more than 10 million individuals in the United States and link these mechanistically to age-specific COVID-19 mortality data. We estimate that as of October 2020, individuals aged 20 to 49 are the only age groups sustaining resurgent SARS-CoV-2 transmission with reproduction numbers well above one and that at least 65 of 100 COVID-19 infections originate from individuals aged 20 to 49 in the United States. Targeting interventions-including transmission-blocking vaccines-to adults aged 20 to 49 is an important consideration in halting resurgent epidemics and preventing COVID-19-attributable deaths.

Accelerated MRI-predicted brain ageing and its associations with cardiometabolic and brain disorders.

Brain structure in later life reflects both influences of intrinsic aging and those of lifestyle, environment and disease. We developed a deep neural network model trained on brain MRI scans of healthy people to predict "healthy" brain age. Brain regions most informative for the prediction included the cerebellum, hippocampus, amygdala and insular cortex. We then applied this model to data from an independent group of people not stratified for health. A phenome-wide association analysis of over 1,410 traits in the UK Biobank with differences between the predicted and chronological ages for the second group identified significant associations with over 40 traits including diseases (e.g., type I and type II diabetes), disease risk factors (e.g., increased diastolic blood pressure and body mass index), and poorer cognitive function. These observations highlight relationships between brain and systemic health and have implications for understanding contributions of the latter to late life dementia risk.