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

Machine learning-based somatic variant calling in cell-free DNA of metastatic breast cancer patients using large NGS panels

Abstract Next generation sequencing of cell-free DNA (cfDNA) is a promising method for treatment monitoring and therapy selection in metastatic breast cancer (MBC). However, distinguishing tumor-specific variants from sequencing artefacts and germline variation with low false discovery rate is challenging when using large targeted sequencing panels covering many tumor suppressor genes. To address this, we built a machine learning model to remove false positive variant calls and augmented it with additional filters to ensure selection of tumor-derived variants. We used cfDNA of 70 MBC patients profiled with both the small targeted Oncomine breast panel (Thermofisher) and the much larger Qiaseq Human Breast Cancer Panel (Qiagen). The model was trained on the panels’ common regions using Oncomine hotspot mutations as ground truth. Applied to Qiaseq data, it achieved 35% sensitivity and 36% precision, outperforming basic filtering. For 20 patients we used germline DNA to filter for somatic variants and obtained 245 variants in total, while our model found seven variants, of which six were also detected using the germline strategy. In ten tumor-free individuals, our method detected in total one (potentially germline) variant, in contrast to 521 variants detected without our model. These results indicate that our model largely detects somatic variants

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

This work was supported by Keygene N.V., a crop innovation company in the Netherlands and by the Spanish MINECO/FEDER Project TEC201680141-P with the associated FPI grant BES-2017-079792.The authors thank Dr. Elvin Isufi and Chirag Raman for their valuable comments and feedback.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.Keygene N.V., a crop innovation company in the NetherlandsSpanish MINECO/FEDER TEC201680141-PFPI grant BES-2017-07979

An in-depth comparison of linear and non-linear joint embedding methods for bulk and single-cell multi-omics

Multi-omic analyses are necessary to understand the complex biological processes taking place at the tissue and cell level, but also to make reliable predictions about, for example, disease outcome. Several linear methods exist that create a joint embedding using paired information per sample, but recently there has been a rise in the popularity of neural architectures that embed paired -omics into the same non-linear manifold. This work describes a head-to-head comparison of linear and non-linear joint embedding methods using both bulk and single-cell multi-modal datasets. We found that non-linear methods have a clear advantage with respect to linear ones for missing modality imputation. Performance comparisons in the downstream tasks of survival analysis for bulk tumor data and cell type classification for single-cell data lead to the following insights: First, concatenating the principal components of each modality is a competitive baseline and hard to beat if all modalities are available at test time. However, if we only have one modality available at test time, training a predictive model on the joint space of that modality can lead to performance improvements with respect to just using the unimodal principal components. Second, -omic profiles imputed by neural joint embedding methods are realistic enough to be used by a classifier trained on real data with limited performance drops. Taken together, our comparisons give hints to which joint embedding to use for which downstream task. Overall, product-of-experts performed well in most tasks and was reasonably fast, while early integration (concatenation) of modalities did quite poorly.</p

Hematopoiesis of a Healthy Supercentenarian is Dominated by One Myeloid-Biased Stem Cell Clone for at least 9 Years

Electrical Engineering, Mathematics and Computer ScienceIntelligent SystemsPattern Recognition and Bioinformatic

Protein function prediction using pre-trained ELMO embeddings

This dataset includes the data for training the protein function prediction models at github.com/stamakro/GCN-for-Structure-and-Function. For each protein, a pickle file is provided, containing its sequence, ELMo embedding and labels. It also includes the weights of the trained models that can be applied directly. README file at github.com/stamakro/GCN-for-Structure-and-Functio

What does that gene do?: Gene function prediction by machine learning with applications to plants

Billions of people world-wide rely on plant-based food for their daily energy intake. As global warming and the spread of diseases (such as the banana Panama disease) is substantially hindering the cultivation of plants, the need to develop temperature- and/or disease-resistant varieties is getting more and more pressing. The field of plant breeding has been revolutionized by the use of molecular biology methods, such as DNA and RNA sequencing, which substantially accelerated the finding of genes that are likely to influence a trait of interest. The outcome of such experiments is typically a long list of candidate genes whose involvement in the trait needs to be experimentally validated. Prioritizing these experiments, i.e. testing the most promising genes first, can save a lot of time, effort and money, but is often hindered by the fact that the cellular roles (functions) of plant genes and the corresponding proteins is often unknown. Experimentally discovering the functions of genes is equally time-consuming and costly, so it is crucial to have computer algorithms that can automatically predict gene or protein functionswith high accuracy. After decades of research on this field, considerable progress has been made, but we are still far from a widely-acceptable and accurate solution to the problem.This thesis explores different research directions to improve protein function prediction, by developing new machine learning algorithms. These directions include new ways to represent proteins, exploiting semantic relationships among functions, and function-specific feature selection. The thesis also deals with the problem of missing protein interaction data for non-model species and quantifies its effect on protein function prediction. All in all, it provides novel insights to the problem that future work can build upon to lead to new breakthroughs.Pattern Recognition and Bioinformatic