Interpretable prediction of necrotizing enterocolitis from machine learning analysis of premature infant stool microbiota

Background Necrotizing enterocolitis (NEC) is a common, potentially catastrophic intestinal disease among very low birthweight premature infants. Affecting up to 15% of neonates born weighing less than 1500 g, NEC causes sudden-onset, progressive intestinal inflammation and necrosis, which can lead to significant bowel loss, multi-organ injury, or death. No unifying cause of NEC has been identified, nor is there any reliable biomarker that indicates an individual patient's risk of the disease. Without a way to predict NEC in advance, the current medical strategy involves close clinical monitoring in an effort to treat babies with NEC as quickly as possible before irrecoverable intestinal damage occurs. In this report, we describe a novel machine learning application for generating dynamic, individualized NEC risk scores based on intestinal microbiota data, which can be determined from sequencing bacterial DNA from otherwise discarded infant stool. A central insight that differentiates our work from past efforts was the recognition that disease prediction from stool microbiota represents a specific subtype of machine learning problem known as multiple instance learning (MIL). Results We used a neural network-based MIL architecture, which we tested on independent datasets from two cohorts encompassing 3595 stool samples from 261 at-risk infants. Our report also introduces a new concept called the "growing bag" analysis, which applies MIL over time, allowing incorporation of past data into each new risk calculation. This approach allowed early, accurate NEC prediction, with a mean sensitivity of 86% and specificity of 90%. True-positive NEC predictions occurred an average of 8 days before disease onset. We also demonstrate that an attention-gated mechanism incorporated into our MIL algorithm permits interpretation of NEC risk, identifying several bacterial taxa that past work has associated with NEC, and potentially pointing the way toward new hypotheses about NEC pathogenesis. Our system is flexible, accepting microbiota data generated from targeted 16S or "shotgun" whole-genome DNA sequencing. It performs well in the setting of common, potentially confounding preterm neonatal clinical events such as perinatal cardiopulmonary depression, antibiotic administration, feeding disruptions, or transitions between breast feeding and formula. Conclusions We have developed and validated a robust MIL-based system for NEC prediction from harmlessly collected premature infant stool. While this system was developed for NEC prediction, our MIL approach may also be applicable to other diseases characterized by changes in the human microbiota.