[Accepted Manuscript] Cancer subtypes in aetiological research.

Researchers often attempt to categorize tumors into more homogeneous subtypes to better predict prognosis or understand pathogenic mechanisms. In clinical research, typically the focus is on prognosis: the tumor subtypes are intended to be associated with specific responses to treatment and/or different clinical outcomes. In aetiological research, the focus is on identifying distinct pathogenic mechanisms, which may involve different risk factors. We used directed acyclic graphs to present a framework for considering potential biases arising in aetiological research of tumor subtypes, when there is incomplete correspondence between the identified subtypes and the underlying pathogenic mechanisms. We identified two main scenarios: (1) weak effect, when the tumor subtypes are identified through combinations of characteristics and some of these characteristics are affected by factors that are unrelated with the underlying pathogenic mechanisms; and (2) lack of causality, when the set of characteristics corresponds with a mechanism that is actually not a cause of the tumor of interest. Examples of the magnitude of bias that can be introduced in these situations are provided. Although categorization of tumors into homogenous subtypes may have important implications for aetiological research and identification of risk factors, the characteristics used to classify tumors into subtypes should be as close as possible to the actual pathogenic mechanisms to avoid interpretative biases. Whenever our knowledge of these mechanisms is limited, research into risk factors for tumor subtypes should first aim to causally link the characteristics to the pathogenic mechanisms

Approaches to Daily Monitoring of the SARS-CoV-2 Outbreak in Northern Italy

Italy was the first European country affected by the Sars-Cov-2 pandemic, with the first autochthonous case identified on Feb 21st. Specific control measures restricting social contacts were introduced by the Italian government starting from the beginning of March. In the current study we analyzed public data from the four most affected Italian regions. We (i) estimated the time-varying reproduction number (Rt), the average number of secondary cases that each infected individual would infect at time t, to monitor the positive impact of restriction measures; (ii) applied the generalized logistic and the modified Richards models to describe the epidemic pattern and obtain short-term forecasts. We observed a monotonic decrease of Rt over time in all regions, and the peak of incident cases ~2 weeks after the implementation of the first strict containment measures. Our results show that phenomenological approaches may be useful to monitor the epidemic growth in its initial phases and suggest that costly and disruptive public health controls might have had a positive impact in limiting the Sars-Cov-2 spread in Northern Italy