Inferring fungal growth rates from optical density data

Abstract

AbstractQuantifying fungal growth underpins our ability to effectively treat severe fungal infections. Current methods quantify fungal growth rates from time-course morphology-specific data, such as hyphal length data. However, automated large-scale collection of such data lies beyond the scope of most clinical microbiology laboratories. In this paper, we propose a mathematical model of fungal growth to estimate morphology-specific growth rates from easy-to-collect, but indirect, optical density (OD600) data ofAspergillus fumigatusgrowth (filamentous fungus). Our method accounts for OD600being an indirect measure by explicitly including the relationship between the indirect OD600measurements and the calibrating true fungal growth in the model. Therefore, the method does not requirede novogeneration of calibration data. Our model outperformed reference models at fitting to and predicting OD600growth curves and overcame observed discrepancies between morphology-specific rates inferred from OD600versus directly measured data in reference models that did not include calibration.Author summaryQuantifying fungal growth is essential for antifungal drug discovery and monitoring antifungal resistance. As fungal growth is complex, with fungal morphology (shape) dynamically changing over time, previous studies have quantified fungal growth by estimating growth rates during specific fungal morphologies (morphology-specific growth rates) or by mathematically modelling fungal growth. However, collecting time-series data that captures the morphological information required for mathematical model fitting or estimating morphology-specific growth rates is prohibitively time consuming for large-scale drug testing in most microbiology laboratories. Alternatively, fungal growth can be quickly, although indirectly, quantified by measuring the optical density (OD) of a broth culture. However, changes in OD are not always reflective of true changes in fungal growth because OD is an indirect measure. This paper proposes a method to model fungal growth and estimate a morphology-specific growth rate from indirect OD600measurements of the major mould pathogen,Aspergillus fumigatus. We explicitly model the relationship between measured indirect OD600data and true fungal growth (calibration). The presented work serves as the much-needed foundation for estimating and comparing morphology-specific fungal growth rates in varying antifungal drug concentrations using only OD600data.