Osimani B., Poellinger R. (2020) A Protocol for Model Validation and Causal Inference from Computer Simulation. In: Bertolaso M., Sterpetti F. (eds) A Critical Reflection on Automated Science. Human Perspectives in Health Sciences and Technology, vol 1. Springer, Cham. https://doi.org/10.1007/978-3-030-25001-0_9

The philosophical literature on modelling is increasingly vast, however clear formal analyses of computational modelling in systems biology are still lacking. We present a general, theoretical scheme which (i) visualizes the development and repeated refinement of a computer simulation, (ii) explicates the relation between different key concepts in modelling and simulation, and (iii) facilitates tracing the epistemological dynamics of model validation. To illustrate and motivate our conceptual scheme, we analyse a case study, the discovery of the functional properties of a specific protein, E-cadherin, which seems to have a key role in metastatic processes by way of influencing cell growth and proliferation signalling. To this end we distinguish two types of causal claims inferred from a computer simulation: (i) causal claims as plain combinations of basic rules (capturing the causal interplay of atomic behaviour) and (ii) causal claims on the level of emergent phenomena (tracing population dynamics). In formulating a protocol for model validation and causal inference, we show how, although such macro-level phenomena cannot be subjected to direct causal tests qua intervention (as, e.g., formulated in interventionist causal theories), they possibly suggest further manipulation tests at the basic micro-level. We thereby elucidate the micro-macro-level interaction in systems biology

Real and Virtual Clinical Trials: a Formal Analysis

If well-designed, the results of a Randomised Clinical Trial (RCT) can justify a causal claim between treatment and effect in the study population; however, additional information might be needed to carry over this result to another population. RCTs have been criticized exactly on grounds of failing to provide this sort of information (Cartwright & Stegenga 2011), as well as to black-box important details regarding the mechanisms underpinning the causal law instantiated by the RCT result. On the other side, so-called In-Silico Clinical Trials (ISCTs) face the same criticisms addressed against standard modelling and simulation techniques, and cannot be equated to experiments (see, e.g., Boem & Ratti, 2017, Parker, 2009, Parke, 2014, Diez Roux, 2015 and related discussions in Frigg & Reiss, 2009, Winsberg, 2009, and Beisbart & Norton, 2012). We undertake a formal analysis of both methods in order to identify their distinct contribution to causal inference in the clinical setting. Britton et al.'s study (Britton et al., 2013) on the impact of ion current variability on cardiac electrophysiology is used for illustrative purposes. We deduce that, by predicting variability through interpolation, ISCTs aid with problems regarding extrapolation of RCTs results, and therefore in assessing their external validity. Furthermore, ISCTs can be said to encode “thick” causal knowledge (knowledge about the biological mechanisms underpinning the causal effects at the clinical level) – as opposed to “thin” difference-making information inferred from RCTs. Hence, ISCTs and RCTs cannot replace one another but rather, they are complementary in that the former provide information about the determinants of variability of causal effects, while the latter can, under certain conditions, establish causality in the first place

Erlotinib in patients with previously irradiated, recurrent brain metastases from non-small cell lung cancer: Two case reports

Background: With the current improvements in primary lung care, the long-term control of brain metastases becomes a clinical challenge. No established therapeutic approaches exist for cranial relapse after response to previous radiotherapy and systemic therapy. Tyrosine kinase inhibitors like erlotinib with its proven activity in non-small cell lung cancer may provide clinical benefits in such patients. Patients and Methods: Two case reports are presented illustrating the efficacy of erlotinib in patients with recurrent brain metastases and parallel thoracic progression. Results: Both patients showed lasting partial remissions in the brain and lung, and clinical symptom improvement. Conclusion: The observed survival times of above 18 and 15 months, respectively, since occurrence of cranial disease manifestation in line with the achieved progression-free survival times of 9 and 6 months by the erlotinib third-line therapy are remarkable. The use of targeted therapies after whole-brain irradiation should be investigated more systematically in prospective clinical trials

Epistemology of Causal Inference in Pharmacology: Towards a Framework for the Assessment of Harms

Philosophical discussions on causal inference in medicine are stuck in dyadic camps, each defending one kind of evidence or method rather than another as best support for causal hypotheses. Whereas Evidence Based Medicine advocates invoke the use of Randomised Controlled Trials and systematic reviews of RCTs as gold standard, philosophers of science emphasise the importance of mechanisms and their distinctive informational contribution to causal inference and assessment. Some have suggested the adoption of a pluralistic approach to causal inference, and an inductive rather than hypothetico-deductive inferential paradigm. However, these proposals deliver no clear guidelines about how such plurality of evidence sources should jointly justify hypotheses of causal associations. In this paper, we develop the pluralistic approach along Hill's (1965) famous criteria for discerning causal associations by employing Bovens' and Hartmann's general Bayes net reconstruction of scientific inference to model the assessment of harms in an evidence-amalgamation framework

Mature results of a randomized trial comparing two fractionation schedules of high dose rate endoluminal brachytherapy for the treatment of endobronchial tumors

Purpose: To determine the efficacy of high dose rate endobronchial brachytherapy (HDR-BT) for the treatment of centrally located lung tumors, two different fractionation schedules were compared regarding local tumor response, side effects and survival. Mature retrospective results with longer follow-up and more patients were analyzed. Initial results were published by Huber et al. in 1995. Methods and materials: 142 patients with advanced, centrally located malignant tumors with preferential endoluminal growth were randomized to receive 4 fractions of 3.8 Gy (time interval: 1 week, n = 60, group I) or 2 fractions of 7.2 Gy (time interval: 3 weeks, n = 82, group II) endobronchial HDR-BT. Age, gender, tumor stage, Karnofsky Performance Score and histology were equally distributed between both groups. Results: Local tumor response with 2 fractions of 7.2 Gy was significantly higher as compared to 4 fractions of 3.8 Gy (median 12 vs. 6 weeks; p <= 0.015). Median survival was similar in both groups (19 weeks in the 4 fractions group vs. 18 weeks in the 2 fractions group). Fatal hemoptysis was less frequent following irradiation with 2 x 7.2 Gy than with 4 x 3.8 Gy, although the difference did not achieve statistical significance (12.2% vs. 18.3%, respectively. p = 0,345). Patients presenting with squamous cell carcinoma were at higher risk of bleeding compared to other histology (21.9% vs. 9%, p = 0,035). Multivariate analysis with regard to overall survival, revealed histology (p = 0.02), Karnofsky Performance Score (p < 0.0001) and response to therapy (p < 0.0001) as significant prognostic factors. For patients showing complete response the median survival was 57 weeks, while for patients with progressive disease median survival time was 8 weeks, p < 0.0001. The KPS at the start of the treatment was significantly correlated with survival. Patients presenting with a KPS = 60 at the start had a significantly (p = 0,032) shorter survival time (10 weeks) than patients with a KPS &gt; 60 (29 weeks). Moreover, the Karnofsky Performance Score of most patients improved during therapy (p = 0,001), suggesting successful palliation of cancer associated symptoms. Multivariate analysis with regard to local tumor control found no significant factors. Conclusion: Endobronchial HDR-BT is an effective local treatment for advanced centrally located malignant tumors with endoluminal tumor growth. Local tumor response was significantly higher after HDR-BT with 2 x 7.2 Gy

HIF1α delays premature senescence through the activation of MIF

Premature senescence in vitro has been attributed to oxidative stress leading to a DNA damage response. In the absence of oxidative damage that occurs at atmospheric oxygen levels, proliferation of untransformed cells continues for extended periods of time. We have investigated the role of the hypoxia-inducible factor 1α (HIF1α) transcription factor in preventing senescence in aerobic and hypoxic conditions. Using embryonic fibroblasts from a conditional HIF1α knockout mouse, we found that loss of HIF1α under aerobic conditions significantly accelerated the onset of cellular senescence, and decreased proliferation under hypoxia. Furthermore, we identify the macrophage migration inhibitory factor (MIF) as a crucial effector of HIF1α that delays senescence. Inhibition of MIF phenocopies loss of HIF1α. Our findings highlight a novel role for HIF1α under aerobic conditions, and identify MIF as a target responsible for this function

Th17 cells, not IL-17+ γδ T cells, drive arthritic bone destruction in mice and humans

The mechanism whereby IL-17 drives rheumatoid arthritis remains incompletely understood. We demonstrate that anti-IL-17 therapy in collagen-induced arthritis ameliorates bone damage by reducing the number of osteoclasts in joints. We found equal numbers of CD4(+) Th17 and IL-17 producing γδ T cells in the joints of arthritic mice, and in vitro, both populations similarly induced osteoclastogenesis. However, individual depletion and adoptive transfer studies revealed that in vivo, Th17 cells dominated with regard to bone destruction. Unlike γδ T cells, Th17 cells were found in apposition to tartrate-resistant acid phosphatase positive osteoclasts in subchondral areas of inflamed joints, a pattern reproduced in patient biopsies. This localization was caused by Ag-specific retention, because OVA-primed Th17 cells showed a γδ T cell-like diffuse distribution. Because IL-23, as produced by osteoclasts, enhanced T cell-mediated osteoclastogenesis, we propose that Ag-specific juxtaposition is key to foster the molecular cross talk of Th17 cells and osteoclasts, thus driving arthritic bone destruction