Interpretable and Predictive Deep Neural Network Modeling of the SARS-CoV-2 Spike Protein Sequence to Predict COVID-19 Disease Severity.

Through the COVID-19 pandemic, SARS-CoV-2 has gained and lost multiple mutations in novel or unexpected combinations. Predicting how complex mutations affect COVID-19 disease severity is critical in planning public health responses as the virus continues to evolve. This paper presents a novel computational framework to complement conventional lineage classification and applies it to predict the severe disease potential of viral genetic variation. The transformer-based neural network model architecture has additional layers that provide sample embeddings and sequence-wide attention for interpretation and visualization. First, training a model to predict SARS-CoV-2 taxonomy validates the architecture's interpretability. Second, an interpretable predictive model of disease severity is trained on spike protein sequence and patient metadata from GISAID. Confounding effects of changing patient demographics, increasing vaccination rates, and improving treatment over time are addressed by including demographics and case date as independent input to the neural network model. The resulting model can be interpreted to identify potentially significant virus mutations and proves to be a robust predctive tool. Although trained on sequence data obtained entirely before the availability of empirical data for Omicron, the model can predict the Omicron's reduced risk of severe disease, in accord with epidemiological and experimental data.

Predicting COVID-19 disease severity from SARS-CoV-2 spike protein sequence by mixed effects machine learning.

Epidemiological studies show that COVID-19 variants-of-concern, like Delta and Omicron, pose different risks for severe disease, but they typically lack sequence-level information for the virus. Studies which do obtain viral genome sequences are generally limited in time, location, and population scope. Retrospective meta-analyses require time-consuming data extraction from heterogeneous formats and are limited to publicly available reports. Fortuitously, a subset of GISAID, the global SARS-CoV-2 sequence repository, includes "patient status" metadata that can indicate whether a sequence record is associated with mild or severe disease. While GISAID lacks data on comorbidities relevant to severity, such as obesity and chronic disease, it does include metadata for age and sex to use as additional attributes in modeling. With these caveats, previous efforts have demonstrated that genotype-patient status models can be fit to GISAID data, particularly when country-of-origin is used as an additional feature. But are these models robust and biologically meaningful? This paper shows that, in fact, temporal and geographic biases in sequences submitted to GISAID, as well as the evolving pandemic response, particularly reduction in severe disease due to vaccination, create complex issues for model development and interpretation. This paper poses a potential solution: efficient mixed effects machine learning using GPBoost, treating country as a random effect group. Training and validation using temporally split GISAID data and emerging Omicron variants demonstrates that GPBoost models are more predictive of the impact of spike protein mutations on patient outcomes than fixed effect XGBoost, LightGBM, random forests, and elastic net logistic regression models.

Mapping Data to Deep Understanding: Making the Most of the Deluge of SARS-CoV-2 Genome Sequences.

Next-generation sequencing has been essential to the global response to the COVID-19 pandemic. As of January 2022, nearly 7 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences are available to researchers in public databases. Sequence databases are an abundant resource from which to extract biologically relevant and clinically actionable information. As the pandemic has gone on, SARS-CoV-2 has rapidly evolved, involving complex genomic changes that challenge current approaches to classifying SARS-CoV-2 variants. Deep sequence learning could be a potentially powerful way to build complex sequence-to-phenotype models. Unfortunately, while they can be predictive, deep learning typically produces "black box" models that cannot directly provide biological and clinical insight. Researchers should therefore consider implementing emerging methods for visualizing and interpreting deep sequence models. Finally, researchers should address important data limitations, including (i) global sequencing disparities, (ii) insufficient sequence metadata, and (iii) screening artifacts due to poor sequence quality control.

Genetic grouping of SARS-CoV-2 coronavirus sequences using informative subtype markers for pandemic spread visualization.

We propose an efficient framework for genetic subtyping of SARS-CoV-2, the novel coronavirus that causes the COVID-19 pandemic. Efficient viral subtyping enables visualization and modeling of the geographic distribution and temporal dynamics of disease spread. Subtyping thereby advances the development of effective containment strategies and, potentially, therapeutic and vaccine strategies. However, identifying viral subtypes in real-time is challenging: SARS-CoV-2 is a novel virus, and the pandemic is rapidly expanding. Viral subtypes may be difficult to detect due to rapid evolution; founder effects are more significant than selection pressure; and the clustering threshold for subtyping is not standardized. We propose to identify mutational signatures of available SARS-CoV-2 sequences using a population-based approach: an entropy measure followed by frequency analysis. These signatures, Informative Subtype Markers (ISMs), define a compact set of nucleotide sites that characterize the most variable (and thus most informative) positions in the viral genomes sequenced from different individuals. Through ISM compression, we find that certain distant nucleotide variants covary, including non-coding and ORF1ab sites covarying with the D614G spike protein mutation which has become increasingly prevalent as the pandemic has spread. ISMs are also useful for downstream analyses, such as spatiotemporal visualization of viral dynamics. By analyzing sequence data available in the GISAID database, we validate the utility of ISM-based subtyping by comparing spatiotemporal analyses using ISMs to epidemiological studies of viral transmission in Asia, Europe, and the United States. In addition, we show the relationship of ISMs to phylogenetic reconstructions of SARS-CoV-2 evolution, and therefore, ISMs can play an important complementary role to phylogenetic tree-based analysis, such as is done in the Nextstrain project. The developed pipeline dynamically generates ISMs for newly added SARS-CoV-2 sequences and updates the visualization of pandemic spatiotemporal dynamics, and is available on Github at https://github.com/EESI/ISM (Jupyter notebook), https://github.com/EESI/ncov_ism (command line tool) and via an interactive website at https://covid19-ism.coe.drexel.edu/.