The use of evidence in medicine is something we should continuously seek to improve. This book seeks to develop our understanding of evidence of mechanism in evaluating evidence in medicine, public health, and social care; and also offers tools to help implement improved assessment of evidence of mechanism in practice. In this way, the book offers a bridge between more theoretical and conceptual insights and worries about evidence of mechanism and practical means to fit the results into evidence assessment procedures.

A particular tradition in medicine claims that a variety of evidence is helpful in determining whether an observed correlation is causal. In line with this tradition, it has been claimed that establishing a causal claim in medicine requires both probabilistic and mechanistic evidence. This claim has been put forward by Federica Russo and Jon Williamson. As a result, it is sometimes called the Russo–Williamson thesis. In support of this thesis, Russo and Williamson appeal to the practice of the International Agency (...) for Research on Cancer. However, this practice presents some problematic cases for the Russo–Williamson thesis. One response to such cases is to argue in favour of reforming these practices. In this paper, we propose an alternative response according to which such cases are in fact consistent with the Russo–Williamson thesis. This response requires maintaining that there is a role for mechanism-based extrapolation in the practice of the IARC. However, the response works only if this mechanism-based extrapolation is reliable, and some have argued against the reliability of mechanism-based extrapolation. Against this, we provide some reasons for believing that reliable mechanism-based extrapolation is going on in the practice of the IARC. The reasons are provided by appealing to the role of robustness analysis. (shrink)

In this chapter we explore the process of extrapolating causal claims from model organisms to humans in pharmacology. We describe and compare four strategies of extrapolation: enumerative induction, comparative process tracing, phylogenetic reasoning, and robustness reasoning. We argue that evidence of mechanisms plays a crucial role in several strategies for extrapolation and in the underlying logic of extrapolation: the more directly a strategy establishes mechanistic similarities between a model and humans, the more reliable the extrapolation. We present case studies from (...) the research on atherosclerosis and the development of statins, that illustrate these strategies and the role of mechanistic evidence in extrapolation. (shrink)

Synthetic biology research is often described in terms of programming cells through the introduction of synthetic genes. Genetic material is seemingly attributed with a high level of causal responsibility. We discuss genetic causation in synthetic biology and distinguish three gene concepts differing in their assumptions of genetic control. We argue that synthetic biology generally employs a difference-making approach to establishing genetic causes, and that this approach does not commit to a specific notion of genetic program or genetic control. Still, we (...) suggest that a strong program concept of genetic material can be used as a successful heuristic in certain areas of synthetic biology. Its application requires control of causal context, and may stand in need of a modular decomposition of the target system. We relate different modularity concepts to the discussion of genetic causation and point to possible advantages of and important limitations to seeking modularity in synthetic biology systems. (shrink)

Kerry et al. criticize our discussion of causal knowledge in evidence-based medicine (EBM) and our assessment of the relevance of their dispositionalist ontology for EBM. Three issues need to be addressed in response: (1) problems concerning transfer of causal knowledge across heterogeneous contexts; (2) how predictions about the effects of individual treatments based on population-level evidence from RCTs are fallible; and (3) the relevance of ontological theories like dispositionalism for EBM.

This article compares the epistemic roles of theoretical models and model organisms in science, and specifically the role of non-human animal models in biomedicine. Much of the previous literature on this topic shares an assumption that animal models and theoretical models have a broadly similar epistemic role—that of indirect representation of a target through the study of a surrogate system. Recently, Levy and Currie have argued that model organism research and theoretical modelling differ in the justification of model-to-target inferences, such (...) that a unified account based on the widely accepted idea of modelling as indirect representation does not similarly apply to both. I defend a similar conclusion, but argue that the distinction between animal models and theoretical models does not always track a difference in the justification of model-to-target inferences. Case studies of the use of animal models in biomedicine are presented to illustrate this. However, Levy and Currie’s point can be argued for in a different way. I argue for the following distinction. Model organisms function as surrogate sources of evidence, from which results are transferred to their targets by empirical extrapolation. By contrast, theoretical modelling does not involve such an inductive step. Rather, theoretical models are used for drawing conclusions from what is already known or assumed about the target system. Codifying assumptions about the causal structure of the target in external representational media allows one to apply explicit inferential rules to reach conclusions that could not be reached with unaided cognition alone. (shrink)

Inconsistencies between scientific theories have been studied, by and large, from the perspective of paraconsistent logic. This approach considered the formal properties of theories and the structure of inferences one can legitimately draw from theories. However, inconsistencies can be also analysed from the perspective of modelling practices, in particular how modelling practices may lead scientists to form opinions and attitudes that are different, but not necessarily inconsistent. In such cases, it is preferable to talk about disagreement, rather than inconsistency. Disagreement (...) may originate in, or concern, a number of epistemic, socio-political or psychological factors. In this paper, we offer an account of the ‘loci and reasons’ for disagreement at different stages of the scientific process. We then present a controversial episode in the health sciences: the studies on hypercholesterolemia. The causes and effects of high levels of cholesterol in blood have been long and hotly debated, to the point of deserving the name of ‘cholesterol wars’; the debate, to be sure, isn’t settled yet. In this contribution, we focus on some selected loci and reasons for disagreement that occurred between 1920 and 1994 in the studies on hypercholesterolemia. We hope that our analysis of ‘loci and reasons’ for disagreement may shed light on the cholesterol wars, and possibly on other episodes of scientific disagreement. (shrink)

The role of mechanistic evidence tends to be under-appreciated in current evidencebased medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is central (...) to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost-effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies. (shrink)

This article considers interventionist arguments for downward causation and non-fundamental level causal explanation from the point of view of inferring causation from experiments. Several authors have utilised the interventionist theory of causal explanation to argue that the causal exclusion argument is moot and that higher-level as well as downward causation is real. I show that this argument can be made when levels are understood as levels of grain, leaving us with a choice between causal explanations pitched at different levels. Causal (...) proportionality has been suggested as a principle for choosing the correct level of description for causal explanations, but this suggestion has serious problems. I offer an alternative principle, based on the idea that explanations should track actual difference-makers. I then consider claims about systems causally influencing their own parts. Such claims risk conceptual confusion for the same reason as the exclusion argument, by conflating causal and constitutive dependencies. The distinction between causation and constitution is used to give criteria for the correct use of the idea of downward causation. (shrink)

Interventionism is a theory of causation with a pragmatic goal: to define causal concepts that are useful for reasoning about how things could, in principle, be purposely manipulated. In its original presentation, Woodward’s interventionist definition of causation is relativized to an analyzed variable set. In Woodward, Woodward changes the definition of the most general interventionist notion of cause, contributing cause, so that it is no longer relativized to a variable set. This derelativization of interventionism has not gathered much attention, presumably (...) because it is seen as an unproblematic way to save the intuition that causal relations are objective features of the world. This paper first argues that this move has problematic consequences. Derelativization entails two concepts of unmediated causal relation that are not coextensional, but which nonetheless do not entail different conclusions about manipulability relations within any given variable set. This is in conflict with the pragmatic orientation at the core of interventionism. The paper then considers various approaches for resolving this tension but finds them all wanting. It is concluded that interventionist causation should not be derelativized in the first place. Various considerations are offered rendering that conclusion acceptable. (shrink)