COVID-19 pandemics modeling with modified determinist SEIR, social distancing, and age stratification. The effect of vertical confinement and release in Brazil.

The ongoing COVID-19 epidemics poses a particular challenge to low and middle income countries, making some of them consider the strategy of "vertical confinement". In this strategy, contact is reduced only to specific groups (e.g. age groups) that are at increased risk of severe disease following SARS-CoV-2 infection. We aim to assess the feasibility of this scenario as an exit strategy for the current lockdown in terms of its ability to keep the number of cases under the health care system capacity. We developed a modified SEIR model, including confinement, asymptomatic transmission, quarantine and hospitalization. The population is subdivided into 9 age groups, resulting in a system of 72 coupled nonlinear differential equations. The rate of transmission is dynamic and derived from the observed delayed fatality rate; the parameters of the epidemics are derived with a Markov chain Monte Carlo algorithm. We used Brazil as an example of middle income country, but the results are easily generalizable to other countries considering a similar strategy. We find that starting from 60% horizontal confinement, an exit strategy on May 1st of confinement of individuals older than 60 years old and full release of the younger population results in 400 000 hospitalizations, 50 000 ICU cases, and 120 000 deaths in the 50-60 years old age group alone. Sensitivity analysis shows the 95% confidence interval brackets a order of magnitude in cases or three weeks in time. The health care system avoids collapse if the 50-60 years old are also confined, but our model assumes an idealized lockdown where the confined are perfectly insulated from contamination, so our numbers are a conservative lower bound. Our results discourage confinement by age as an exit strategy.

Stopping randomized trials early for benefit: a protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2).

BACKGROUND: Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The Study Of Trial Policy Of Interim Truncation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit. METHODS/DESIGN: We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation.Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases. DISCUSSION: A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.