CBA: cluster-guided batch alignment for single cell RNA-seq

The power of single-cell RNA sequencing (scRNA-seq) in detecting cell heterogeneity or developmental process is becoming more and more evident every day. The granularity of this knowledge is further propelled when combining two batches of scRNA-seq into a single large dataset. This strategy is however hampered by technical differences between these batches. Typically, these batch effects are resolved by matching similar cells across the different batches. Current approaches, however, do not take into account that we can constrain this matching further as cells can also be matched on their cell type identity. We use an auto-encoder to embed two batches in the same space such that cells are matched. To accomplish this, we use a loss function that preserves: (1) cell-cell distances within each of the two batches, as well as (2) cell-cell distances between two batches when the cells are of the same cell-type. The cell-type guidance is unsupervised, i.e., a cell-type is defined as a cluster in the original batch. We evaluated the performance of our cluster-guided batch alignment (CBA) using pancreas and mouse cell atlas datasets, against six state-of-the-art single cell alignment methods: Seurat v3, BBKNN, Scanorama, Harmony, LIGER, and BERMUDA. Compared to other approaches, CBA preserves the cluster separation in the original datasets while still being able to align the two datasets. We confirm that this separation is biologically meaningful by identifying relevant differential expression of genes for these preserved clusters.Molecular Technology and Informatics for Personalised Medicine and Healt

Personalization of tagging systems

Social media systems have encouraged end user participation in the Internet, for the purpose of storing and distributing Internet content, sharing opinions and maintaining relationships. Collaborative tagging allows users to annotate the resulting user-generated content, and enables effective retrieval of otherwise uncategorised data. However, compared to professional web content production, collaborative tagging systems face the challenge that end-users assign tags in an uncontrolled manner, resulting in unsystematic and inconsistent metadata. This paper introduces a framework for the personalization of social media systems. We pinpoint three tasks that would benefit from personalization: collaborative tagging, collaborative browsing and collaborative s

A structural equation model for imaging genetics using spatial transcriptomics.

Imaging genetics deals with relationships between genetic variation and imaging variables, often in a disease context. The complex relationships between brain volumes and genetic variants have been explored with both dimension reduction methods and model-based approaches. However, these models usually do not make use of the extensive knowledge of the spatio-anatomical patterns of gene activity. We present a method for integrating genetic markers (single nucleotide polymorphisms) and imaging features, which is based on a causal model and, at the same time, uses the power of dimension reduction. We use structural equation models to find latent variables that explain brain volume changes in a disease context, and which are in turn affected by genetic variants. We make use of publicly available spatial transcriptome data from the Allen Human Brain Atlas to specify the model structure, which reduces noise and improves interpretability. The model is tested in a simulation setting and applied on a case study of the Alzheimer’s Disease Neuroimaging Initiative.FSW – Publicaties zonder aanstelling Universiteit Leide

Scale-invariant segmentation of dynamic contrast-enhanced perfusion MR-images with inherent scale selection

Selection of the best set of scales is problematic when developing signaldriven approaches for pixel-based image segmentation. Often, different possibly conflicting criteria need to be fulfilled in order to obtain the best tradeoff between uncertainty (variance) and location accuracy. The optimal set of scales depends on several factors: the noise level present in the image material, the prior distribution of the different types of segments, the class-conditional distributions associated with each type of segment as well as the actual size of the (connected) segments. We analyse, theoretically and through experiments, the possibility of using the overall and class-conditional error rates as criteria for selecting the optimal sampling of the linear and morphological scale spaces. It is shown that the overall error rate is optimised by taking the prior class distribution in the image material into account. However, a uniform (ignorant) prior distribution ensures constant class-conditional error rates. Consequently, we advocate for a uniform prior class distribution when an uncommitted, scaleinvariant segmentation approach is desired. Experiments with a neural net classifier developed for segmentation of dynamic MR images, acquired with a paramagnetic tracer, support the theoretical results. Furthermore, the experiments show that the addition of spatial features to the classifier, extracted from the linear or morphological scale spaces, improves the segmentation result compared to a signal-driven approach based solely on the dynamic MR signal. The segmentation results obtained from the two types of features are compared using two novel quality measures that characterise spatial properties of labelled images

Unsupervised protein embeddings outperform hand-crafted sequence and structure features at predicting molecular function

Motivation: Protein function prediction is a difficult bioinformatics problem. Many recent methods use deep neural networks to learn complex sequence representations and predict function from these. Deep supervised models require a lot of labeled training data which are not available for this task. However, a very large amount of protein sequences without functional labels is available.Results: We applied an existing deep sequence model that had been pretrained in an unsupervised setting on the supervised task of protein molecular function prediction. We found that this complex feature representation is effective for this task, outperforming hand-crafted features such as one-hot encoding of amino acids, k-mer counts, secondary structure and backbone angles. Also, it partly negates the need for complex prediction models, as a two-layer perceptron was enough to achieve competitive performance in the third Critical Assessment of Functional Annotation benchmark. We also show that combining this sequence representation with protein 3D structure information does not lead to performance improvement, hinting that 3D structure is also potentially learned during the unsupervised pretraining

Reply to the Commentary on population matched (pm) germline allelic variants of immunoglobulin (IG) loci: relevance in infectious diseases and vaccination studies in human populations

Molecular Epidemiolog

Population matched (pm) germline allelic variants of immunoglobulin (IG) loci: relevance in infectious diseases and vaccination studies in human populations

Immunoglobulin (IG) loci harbor inter-individual allelic variants in many different germline IG variable, diversity and joining genes of the IG heavy (IGH), kappa (IGK) and lambda (IGL) loci, which together form the genetic basis of the highly diverse antigen-specific B-cell receptors. These allelic variants can be shared between or be specific to human populations. The current immunogenetics resources gather the germline alleles, however, lack the population specificity of the alleles which poses limitations for disease-association studies related to immune responses in different human populations. Therefore, we systematically identified germline alleles from 26 different human populations around the world, profiled by "1000 Genomes" data. We identified 409 IGHV, 179 IGKV, and 199 IGLV germline alleles supported by at least seven haplotypes. The diversity of germline alleles is the highest in Africans. Remarkably, the variants in the identified novel alleles show strikingly conserved patterns, the same as found in other IG databases, suggesting over-time evolutionary selection processes. We could relate the genetic variants to population-specific immune responses, e.g. IGHV1-69 for flu in Africans. The population matched IG (pmIG) resource will enhance our understanding of the SHM-related B-cell receptor selection processes in (infectious) diseases and vaccination within and between different human populations.Molecular Epidemiolog

Transcriptomic signatures associated with regional cortical thickness changes in Parkinson's disease

Cortical atrophy is a common manifestation in Parkinson's disease (PD), particularly in advanced stages of the disease. To elucidate the molecular underpinnings of cortical thickness changes in PD, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and patterns of cortical thickness based on T1-weighted anatomical MRI data of 149 PD patients and 369 controls. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of PD. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in PD are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in PD and possibly influence motor and cognitive functions.Neuro Imaging Researc