Conflicting Biomedical Assumptions for Mathematical Modeling: The Case of Cancer Metastasis

Computational models in biomedicine rely on biological and clinical assumptions. The selection of these assumptions contributes substantially to modeling success or failure. Assumptions used by experts at the cutting edge of research, however, are rarely explicitly described in scientific publications. One can directly collect and assess some of these assumptions through interviews and surveys. Here we investigate diversity in expert views about a complex biological phenomenon, the process of cancer metastasis. We harvested individual viewpoints from 28 experts in clinical and molecular aspects of cancer metastasis and summarized them computationally. While experts predominantly agreed on the definition of individual steps involved in metastasis, no two expert scenarios for metastasis were identical. We computed the probability that any two experts would disagree on k or fewer metastatic stages and found that any two randomly selected experts are likely to disagree about several assumptions. Considering the probability that two or more of these experts review an article or a proposal about metastatic cascades, the probability that they will disagree with elements of a proposed model approaches 1. This diversity of conceptions has clear consequences for advance and deadlock in the field. We suggest that strong, incompatible views are common in biomedicine but largely invisible to biomedical experts themselves. We built a formal Markov model of metastasis to encapsulate expert convergence and divergence regarding the entire sequence of metastatic stages. This model revealed stages of greatest disagreement, including the points at which cancer enters and leaves the bloodstream. The model provides a formal probabilistic hypothesis against which researchers can evaluate data on the process of metastasis. This would enable subsequent improvement of the model through Bayesian probabilistic update. Practically, we propose that model assumptions and hunches be harvested systematically and made available for modelers and scientists. Author Summary: Mathematical models and scientific theories fail not only from internal inconsistency, but also from the poor selection of basic assumptions. Assumptions in computational models of biomedicine are typically provided by scientists who interact directly with empirical data. If we seek to model the dynamics of cancer metastasis and ask experts regarding valid assumptions, how widely will they agree and on which assumptions? To answer this question, we queried 28 faculty-level experts about the progression of metastasis. We demonstrate an unexpected diversity of assumptions across experts leading to a striking lack of agreement over the basic stages and sequence of metastasis. We suggest a formal model and framework that builds on this diversity and enables researchers to evaluate divergent hypotheses about metastasis with experimental data. We conclude that modeling biomedical processes could be substantially improved by harvesting scientific assumptions and exposing them for formalization and experiment.