Evaluating predictors of kinase activity of STK11 variants identified in primary human non-small cell lung cancers.

Critical evaluation of computational tools for predicting variant effects is important considering their increased use in disease diagnosis and driving molecular discoveries. In the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, a dataset of 28 STK11 rare variants (27 missense, 1 single amino acid deletion), identified in primary non-small cell lung cancer biopsies, was experimentally assayed to characterize computational methods from four participating teams and five publicly available tools. Predictors demonstrated a high level of performance on key evaluation metrics, measuring correlation with the assay outputs and separating loss-of-function (LoF) variants from wildtype-like (WT-like) variants. The best participant model, 3Cnet, performed competitively with well-known tools. Unique to this challenge was that the functional data was generated with both biological and technical replicates, thus allowing the assessors to realistically establish maximum predictive performance based on experimental variability. Three out of the five publicly available tools and 3Cnet approached the performance of the assay replicates in separating LoF variants from WT-like variants. Surprisingly, REVEL, an often-used model, achieved a comparable correlation with the real-valued assay output as that seen for the experimental replicates. Performing variant interpretation by combining the new functional evidence with computational and population data evidence led to 16 new variants receiving a clinically actionable classification of likely pathogenic (LP) or likely benign (LB). Overall, the STK11 challenge highlights the utility of variant effect predictors in biomedical sciences and provides encouraging results for driving research in the field of computational genome interpretation.

Establishing a Validation Infrastructure for Imaging-Based Artificial Intelligence Algorithms Before Clinical Implementation.

With promising artificial intelligence (AI) algorithms receiving FDA clearance, the potential impact of these models on clinical outcomes must be evaluated locally before their integration into routine workflows. Robust validation infrastructures are pivotal to inspecting the accuracy and generalizability of these deep learning algorithms to ensure both patient safety and health equity. Protected health information concerns, intellectual property rights, and diverse requirements of models impede the development of rigorous external validation infrastructures. The authors propose various suggestions for addressing the challenges associated with the development of efficient, customizable, and cost-effective infrastructures for the external validation of AI models at large medical centers and institutions. The authors present comprehensive steps to establish an AI inferencing infrastructure outside clinical systems to examine the local performance of AI algorithms before health practice or systemwide implementation and promote an evidence-based approach for adopting AI models that can enhance radiology workflows and improve patient outcomes.