Discovery of sparse, reliable omic biomarkers with Stabl.

Adoption of high-content omic technologies in clinical studies, coupled with computational methods, has yielded an abundance of candidate biomarkers. However, translating such findings into bona fide clinical biomarkers remains challenging. To facilitate this process, we introduce Stabl, a general machine learning method that identifies a sparse, reliable set of biomarkers by integrating noise injection and a data-driven signal-to-noise threshold into multivariable predictive modeling. Evaluation of Stabl on synthetic datasets and five independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used sparsity-promoting regularization methods while maintaining predictive performance; it distills datasets containing 1,400-35,000 features down to 4-34 candidate biomarkers. Stabl extends to multi-omic integration tasks, enabling biological interpretation of complex predictive models, as it hones in on a shortlist of proteomic, metabolomic and cytometric events predicting labor onset, microbial biomarkers of pre-term birth and a pre-operative immune signature of post-surgical infections. Stabl is available at https://github.com/gregbellan/Stabl .

Spatial subsetting enables integrative modeling of oral squamous cell carcinoma multiplex imaging data.

Oral squamous cell carcinoma (OSCC), a prevalent and aggressive neoplasm, poses a significant challenge due to poor prognosis and limited prognostic biomarkers. Leveraging highly multiplexed imaging mass cytometry, we investigated the tumor immune microenvironment (TIME) in OSCC biopsies, characterizing immune cell distribution and signaling activity at the tumor-invasive front. Our spatial subsetting approach standardized cellular populations by tissue zone, improving feature reproducibility and revealing TIME patterns accompanying loss-of-differentiation. Employing a machine-learning pipeline combining reliable feature selection with multivariable modeling, we achieved accurate histological grade classification (AUC = 0.88). Three model features correlated with clinical outcomes in an independent cohort: granulocyte MAPKAPK2 signaling at the tumor front, stromal CD4+ memory T cell size, and the distance of fibroblasts from the tumor border. This study establishes a robust modeling framework for distilling complex imaging data, uncovering sentinel characteristics of the OSCC TIME to facilitate prognostic biomarkers discovery for recurrence risk stratification and immunomodulatory therapy development.

Stabl: sparse and reliable biomarker discovery in predictive modeling of high-dimensional omic data.

High-content omic technologies coupled with sparsity-promoting regularization methods (SRM) have transformed the biomarker discovery process. However, the translation of computational results into a clinical use-case scenario remains challenging. A rate-limiting step is the rigorous selection of reliable biomarker candidates among a host of biological features included in multivariate models. We propose Stabl, a machine learning framework that unifies the biomarker discovery process with multivariate predictive modeling of clinical outcomes by selecting a sparse and reliable set of biomarkers. Evaluation of Stabl on synthetic datasets and four independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used SRMs at similar predictive performance. Stabl readily extends to double- and triple-omics integration tasks and identifies a sparser and more reliable set of biomarkers than those selected by state-of-the-art early- and late-fusion SRMs, thereby facilitating the biological interpretation and clinical translation of complex multi-omic predictive models. The complete package for Stabl is available online at https://github.com/gregbellan/Stabl.

Validation and algorithmic audit of a deep learning system for the detection of proximal femoral fractures in patients in the emergency department: a diagnostic accuracy study.

BACKGROUND: Proximal femoral fractures are an important clinical and public health issue associated with substantial morbidity and early mortality. Artificial intelligence might offer improved diagnostic accuracy for these fractures, but typical approaches to testing of artificial intelligence models can underestimate the risks of artificial intelligence-based diagnostic systems. METHODS: We present a preclinical evaluation of a deep learning model intended to detect proximal femoral fractures in frontal x-ray films in emergency department patients, trained on films from the Royal Adelaide Hospital (Adelaide, SA, Australia). This evaluation included a reader study comparing the performance of the model against five radiologists (three musculoskeletal specialists and two general radiologists) on a dataset of 200 fracture cases and 200 non-fractures (also from the Royal Adelaide Hospital), an external validation study using a dataset obtained from Stanford University Medical Center, CA, USA, and an algorithmic audit to detect any unusual or unexpected model behaviour. FINDINGS: In the reader study, the area under the receiver operating characteristic curve (AUC) for the performance of the deep learning model was 0·994 (95% CI 0·988-0·999) compared with an AUC of 0·969 (0·960-0·978) for the five radiologists. This strong model performance was maintained on external validation, with an AUC of 0·980 (0·931-1·000). However, the preclinical evaluation identified barriers to safe deployment, including a substantial shift in the model operating point on external validation and an increased error rate on cases with abnormal bones (eg, Paget's disease). INTERPRETATION: The model outperformed the radiologists tested and maintained performance on external validation, but showed several unexpected limitations during further testing. Thorough preclinical evaluation of artificial intelligence models, including algorithmic auditing, can reveal unexpected and potentially harmful behaviour even in high-performance artificial intelligence systems, which can inform future clinical testing and deployment decisions. FUNDING: None.