Identifying Protein Features and Pathways Responsible for Toxicity Using Machine Learning and Tox21: Implications for Predictive Toxicology.

Humans are exposed to numerous compounds daily, some of which have adverse effects on health. Computational approaches for modeling toxicological data in conjunction with machine learning algorithms have gained popularity over the last few years. Machine learning approaches have been used to predict toxicity-related biological activities using chemical structure descriptors. However, toxicity-related proteomic features have not been fully investigated. In this study, we construct a computational pipeline using machine learning models for predicting the most important protein features responsible for the toxicity of compounds taken from the Tox21 dataset that is implemented within the multiscale Computational Analysis of Novel Drug Opportunities (CANDO) therapeutic discovery platform. Tox21 is a highly imbalanced dataset consisting of twelve in vitro assays, seven from the nuclear receptor (NR) signaling pathway and five from the stress response (SR) pathway, for more than 10,000 compounds. For the machine learning model, we employed a random forest with the combination of Synthetic Minority Oversampling Technique (SMOTE) and the Edited Nearest Neighbor (ENN) method (SMOTE+ENN), which is a resampling method to balance the activity class distribution. Within the NR and SR pathways, the activity of the aryl hydrocarbon receptor (NR-AhR) and the mitochondrial membrane potential (SR-MMP) were two of the top-performing twelve toxicity endpoints with AUCROCs of 0.90 and 0.92, respectively. The top extracted features for evaluating compound toxicity were analyzed for enrichment to highlight the implicated biological pathways and proteins. We validated our enrichment results for the activity of the AhR using a thorough literature search. Our case study showed that the selected enriched pathways and proteins from our computational pipeline are not only correlated with AhR toxicity but also form a cascading upstream/downstream arrangement. Our work elucidates significant relationships between protein and compound interactions computed using CANDO and the associated biological pathways to which the proteins belong for twelve toxicity endpoints. This novel study uses machine learning not only to predict and understand toxicity but also elucidates therapeutic mechanisms at a proteomic level for a variety of toxicity endpoints.

A multimodal framework for extraction and fusion of satellite images and public health data.

In low- and middle-income countries, the substantial costs associated with traditional data collection pose an obstacle to facilitating decision-making in the field of public health. Satellite imagery offers a potential solution, but the image extraction and analysis can be costly and requires specialized expertise. We introduce SatelliteBench, a scalable framework for satellite image extraction and vector embeddings generation. We also propose a novel multimodal fusion pipeline that utilizes a series of satellite imagery and metadata. The framework was evaluated generating a dataset with a collection of 12,636 images and embeddings accompanied by comprehensive metadata, from 81 municipalities in Colombia between 2016 and 2018. The dataset was then evaluated in 3 tasks: including dengue case prediction, poverty assessment, and access to education. The performance showcases the versatility and practicality of SatelliteBench, offering a reproducible, accessible and open tool to enhance decision-making in public health.

Integrated platform for multiscale molecular imaging and phenotyping of the human brain.

Understanding cellular architectures and their connectivity is essential for interrogating system function and dysfunction. However, we lack technologies for mapping the multiscale details of individual cells and their connectivity in the human organ-scale system. We developed a platform that simultaneously extracts spatial, molecular, morphological, and connectivity information of individual cells from the same human brain. The platform includes three core elements: a vibrating microtome for ultraprecision slicing of large-scale tissues without losing cellular connectivity (MEGAtome), a polymer hydrogel-based tissue processing technology for multiplexed multiscale imaging of human organ-scale tissues (mELAST), and a computational pipeline for reconstructing three-dimensional connectivity across multiple brain slabs (UNSLICE). We applied this platform for analyzing human Alzheimer's disease pathology at multiple scales and demonstrating scalable neural connectivity mapping in the human brain.

Emulating Target Trials Comparing Early and Delayed Intubation Strategies.

BACKGROUND: Whether intubation should be initiated early in the clinical course of critically ill patients remains a matter of debate. Results from prior observational studies are difficult to interpret because of avoidable flaws including immortal time bias, inappropriate eligibility criteria, and unrealistic treatment strategies. RESEARCH QUESTION: Do treatment strategies that intubate patients early in the critical care admission improve 30-day survival compared with strategies that delay intubation? STUDY DESIGN AND METHODS: We estimated the effect of strategies that require early intubation of critically ill patients compared with those that delay intubation. With data extracted from the Medical Information Mart for Intensive Care-IV database, we emulated three target trials, varying the flexibility of the treatment strategies and the baseline eligibility criteria. RESULTS: Under unrealistically strict treatment strategies with broad eligibility criteria, the 30-day mortality risk was 7.1 percentage points higher for intubating early compared with delaying intubation (95% CI, 6.2-7.9). Risk differences were 0.4 (95% CI, -0.1 to 0.9) and -0.9 (95% CI, -2.5 to 0.7) percentage points in subsequent target trial emulations that included more realistic treatment strategies and eligibility criteria. INTERPRETATION: When realistic treatment strategies and eligibility criteria are used, strategies that delay intubation result in similar 30-day mortality risks compared with those that intubate early. Delaying intubation ultimately avoids intubation in most patients.

Telehealth and digital health innovations: A mixed landscape of access.

In the wake of emergent natural and anthropogenic disasters, telehealth presents opportunities to improve access to healthcare when physical access is not possible. Yet, since the beginning of the COVID pandemic, lessons learned reveal that various populations in the United States do not or cannot adopt telehealth due to inequitable access. We explored the Digital Determinants of Health (DDoHs) for telehealth, characterizing the role of accessibility, broadband connectivity and electrical grids, and patient intersectionality. In addition to its role as an existing Social Determinant of Health, Policies and Laws directly and indirectly affect these DDoHs, making access more complex for marginalized populations. Digital systems lack the flexibility, accessibility, and usability to inclusively provide the essential services patients need in telehealth. We propose the following recommendations: (1) design technology and systems using accessibility and value sensitive design principles; (2) support a range of technologies and settings; (3) support multiple and diverse users; and (4) support clear paths for repair when technical systems fail to meet users' needs. Addressing these requires change not only from providers but also from the institutions providing these systems.

Enabling chronic obstructive pulmonary disease diagnosis through chest X-rays: A multi-site and multi-modality study.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is one of the most common chronic illnesses in the world. Unfortunately, COPD is often difficult to diagnose early when interventions can alter the disease course, and it is underdiagnosed or only diagnosed too late for effective treatment. Currently, spirometry is the gold standard for diagnosing COPD but it can be challenging to obtain, especially in resource-poor countries. Chest X-rays (CXRs), however, are readily available and may have the potential as a screening tool to identify patients with COPD who should undergo further testing or intervention. In this study, we used three CXR datasets alongside their respective electronic health records (EHR) to develop and externally validate our models. METHOD: To leverage the performance of convolutional neural network models, we proposed two fusion schemes: (1) model-level fusion, using Bootstrap aggregating to aggregate predictions from two models, (2) data-level fusion, using CXR image data from different institutions or multi-modal data, CXR image data, and EHR data for model training. Fairness analysis was then performed to evaluate the models across different demographic groups. RESULTS: Our results demonstrate that DL models can detect COPD using CXRs with an area under the curve of over 0.75, which could facilitate patient screening for COPD, especially in low-resource regions where CXRs are more accessible than spirometry. CONCLUSIONS: By using a ubiquitous test, future research could build on this work to detect COPD in patients early who would not otherwise have been diagnosed or treated, altering the course of this highly morbid disease.

Strategies and solutions to address Digital Determinants of Health (DDOH) across underinvested communities.

Healthcare has long struggled to improve services through technology without further widening health disparities. With the significant expansion of digital health, a group of healthcare professionals and scholars from across the globe are proposing the official usage of the term "Digital Determinants of Health" (DDOH) to explicitly call out the relationship between technology, healthcare, and equity. This is the final paper in a series published in PLOS Digital Health that seeks to understand and summarize current knowledge of the strategies and solutions that help to mitigate the negative effects of DDOH for underinvested communities. Through a search of English-language Medline, Scopus, and Google Scholar articles published since 2010, 345 articles were identified that discussed the application of digital health technology among underinvested communities. A group of 8 reviewers assessed 132 articles selected at random for the mention of solutions that minimize differences in DDOH. Solutions were then organized by categories of policy; design and development; implementation and adoption; and evaluation and ongoing monitoring. The data were then assessed by category and the findings summarized. The reviewers also looked for common themes across the solutions and evidence of effectiveness. From this limited scoping review, the authors found numerous solutions mentioned across the papers for addressing DDOH and many common themes emerged regardless of the specific community or digital health technology under review. There was notably less information on solutions regarding ongoing evaluation and monitoring which corresponded with a lack of research evidence regarding effectiveness. The findings directionally suggest that universal strategies and solutions can be developed to address DDOH independent of the specific community under focus. With the need for the further development of DDOH measures, we also provide a framework for DDOH assessment.

The impact of commercial health datasets on medical research and health-care algorithms.

As the health-care industry emerges into a new era of digital health driven by cloud data storage, distributed computing, and machine learning, health-care data have become a premium commodity with value for private and public entities. Current frameworks of health data collection and distribution, whether from industry, academia, or government institutions, are imperfect and do not allow researchers to leverage the full potential of downstream analytical efforts. In this Health Policy paper, we review the current landscape of commercial health data vendors, with special emphasis on the sources of their data, challenges associated with data reproducibility and generalisability, and ethical considerations for data vending. We argue for sustainable approaches to curating open-source health data to enable global populations to be included in the biomedical research community. However, to fully implement these approaches, key stakeholders should come together to make health-care datasets increasingly accessible, inclusive, and representative, while balancing the privacy and rights of individuals whose data are being collected.

Bias in artificial intelligence algorithms and recommendations for mitigation.

The adoption of artificial intelligence (AI) algorithms is rapidly increasing in healthcare. Such algorithms may be shaped by various factors such as social determinants of health that can influence health outcomes. While AI algorithms have been proposed as a tool to expand the reach of quality healthcare to underserved communities and improve health equity, recent literature has raised concerns about the propagation of biases and healthcare disparities through implementation of these algorithms. Thus, it is critical to understand the sources of bias inherent in AI-based algorithms. This review aims to highlight the potential sources of bias within each step of developing AI algorithms in healthcare, starting from framing the problem, data collection, preprocessing, development, and validation, as well as their full implementation. For each of these steps, we also discuss strategies to mitigate the bias and disparities. A checklist was developed with recommendations for reducing bias during the development and implementation stages. It is important for developers and users of AI-based algorithms to keep these important considerations in mind to advance health equity for all populations.

Few-Shot Learning Geometric Ensemble for Multi-label Classification of Chest X-Rays.

This paper aims to identify uncommon cardiothoracic diseases and patterns on chest X-ray images. Training a machine learning model to classify rare diseases with multi-label indications is challenging without sufficient labeled training samples. Our model leverages the information from common diseases and adapts to perform on less common mentions. We propose to use multi-label few-shot learning (FSL) schemes including neighborhood component analysis loss, generating additional samples using distribution calibration and fine-tuning based on multi-label classification loss. We utilize the fact that the widely adopted nearest neighbor-based FSL schemes like ProtoNet are Voronoi diagrams in feature space. In our method, the Voronoi diagrams in the features space generated from multi-label schemes are combined into our geometric DeepVoro Multi-label ensemble. The improved performance in multi-label few-shot classification using the multi-label ensemble is demonstrated in our experiments (The code is publicly available at https://github.com/Saurabh7/Few-shot-learning-multilabel-cxray).

A descriptive appraisal of quality of reporting in a cohort of machine learning studies in anesthesiology.

BACKGROUND: The field of machine learning is being employed more and more in medicine. However, studies have shown that the quality of published studies frequently lacks completeness and adherence to published reporting guidelines. This assessment has not been done in the subspecialty of anesthesiology. METHODS: We appraised the quality of reporting of a convenience sample of 67 peer-reviewed publications sourced from the scoping review by Hashimoto et al. Each publication was appraised on the presence of reporting elements (reporting compliance) selected from 4 peer-reviewed guidelines for reporting on machine learning studies. Results are described in several cross sections, including by section of manuscript (e.g. abstract, introduction, etc.), year of publication, impact factor of journal, and impact of publication. RESULTS: On average, reporting compliance was 64% ± 13%. There was marked heterogeneity of reporting based on section of manuscript. There was a mild trend towards increased quality of reporting with increasing impact factor of journal of publication and increasing average number of citations per year since publication, and no trend regarding recency of publication. CONCLUSION: The quality of reporting of machine learning studies in anesthesiology is on par with other fields, but can benefit from improvement, especially in presenting methodology, results, and discussion points, including interpretation of models and pitfalls therein. Clinicians in today's learning health systems will benefit from skills in appraisal of evidence. Several reporting guidelines have been released, and updates to mainstream guidelines are under development, which we hope will usher in improvement in reporting quality.