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Machine learning-guided evaluation of extraction and simulation methods for cancer patient-specific metabolic models.

ABSTRACT: Genome-scale metabolic model (GEM) has been established as an important tool to study cellular metabolism at a systems level by predicting intracellular fluxes. With the advent of generic human GEMs, they have been increasingly applied to a range of diseases, often for the objective of predicting effective metabolic drug targets. Cancer is a representative disease where the use of GEMs has proved to be effective, partly due to the massive availability of patient-specific RNA-seq data. When using a human GEM, so-called context-specific GEM needs to be developed first by using cell-specific RNA-seq data. Biological validity of a context-specific GEM highly depends on both model extraction method (MEM) and model simulation method (MSM). However, while MEMs have been thoroughly examined, MSMs have not been systematically examined, especially, when studying cancer metabolism. In this study, the effects of pairwise combinations of three MEMs and five MSMs were evaluated by examining biological features of the resulting cancer patient-specific GEMs. For this, a total of 1,562 patient-specific GEMs were reconstructed, and subjected to machine learning-guided and biological evaluations to draw robust conclusions. Noteworthy observations were made from the evaluation, including the high performance of two MEMs, namely rank-based 'task-driven Integrative Network Inference for Tissues' (tINIT) or 'Gene Inactivity Moderated by Metabolism and Expression' (GIMME), paired with least absolute deviation (LAD) as a MSM, and relatively poorer performance of flux balance analysis (FBA) and parsimonious FBA (pFBA). Insights from this study can be considered as a reference when studying cancer metabolism using patient-specific GEMs.

SUBMITTER: Lee SM

PROVIDER: S-EPMC9218235 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND AND PURPOSE:MR imaging-based modeling of tumor cell density can substantially improve targeted treatment of glioblastoma. Unfortunately, interpatient variability limits the predictive ability of many modeling approaches. We present a transfer learning method that generates individualized patient models, grounded in the wealth of population data, while also detecting and adjusting for interpatient variabilities based on each patient's own histologic data. MATERIALS AND METHODS:We recruited patients with primary glioblastoma undergoing image-guided biopsies and preoperative imaging, including contrast-enhanced MR imaging, dynamic susceptibility contrast MR imaging, and diffusion tensor imaging. We calculated relative cerebral blood volume from DSC-MR imaging and mean diffusivity and fractional anisotropy from DTI. Following image coregistration, we assessed tumor cell density for each biopsy and identified corresponding localized MR imaging measurements. We then explored a range of univariate and multivariate predictive models of tumor cell density based on MR imaging measurements in a generalized one-model-fits-all approach. We then implemented both univariate and multivariate individualized transfer learning predictive models, which harness the available population-level data but allow individual variability in their predictions. Finally, we compared Pearson correlation coefficients and mean absolute error between the individualized transfer learning and generalized one-model-fits-all models. RESULTS:Tumor cell density significantly correlated with relative CBV (r = 0.33, P < .001), and T1-weighted postcontrast (r = 0.36, P < .001) on univariate analysis after correcting for multiple comparisons. With single-variable modeling (using relative CBV), transfer learning increased predictive performance (r = 0.53, mean absolute error = 15.19%) compared with one-model-fits-all (r = 0.27, mean absolute error = 17.79%). With multivariate modeling, transfer learning further improved performance (r = 0.88, mean absolute error = 5.66%) compared with one-model-fits-all (r = 0.39, mean absolute error = 16.55%). CONCLUSIONS:Transfer learning significantly improves predictive modeling performance for quantifying tumor cell density in glioblastoma.

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Machine learning-guided evaluation of extraction and simulation methods for cancer patient-specific metabolic models.

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