MSMpred: interactive modelling and prediction of individual evolution via multistate models.

BACKGROUND: Modelling the course of a disease regarding severe events and identifying prognostic factors is of great clinical relevance. Multistate models (MSM) can be used to describe diseases or processes that change over time using different states and the transitions between them. Specifically, they are useful to analyse a disease with an increasing degree of severity, that may precede death. The complexity of these models changes depending on the number of states and transitions taken into account. Due to that, a web tool has been developed making easier to work with those models. RESULTS: MSMpred is a web tool created with the shiny R package that has two main features: 1) to allow to fit a MSM from specific data; 2) to predict the clinical evolution for a given subject. To fit the model, the data to be analysed must be upload in a prespecified format. Then, the user has to define the states and transitions as well as the covariates (e.g., age or gender) involved in each transition. From this information, the app returns histograms or barplots, as appropriate, to represent the distributions of the selected covariates and boxplots to show the patient' length of stay (for uncensored data) in each state. To make predictions, the values of selected covariates from a new subject at baseline has to be provided. From these inputs, the app provides some indicators of the subject's evolution such as the probability of 30-day death or the most likely state at a fixed time. Furthermore, visual representations (e.g., the stacked transition probabilities plot) are given to make predictions more understandable. CONCLUSIONS: MSMpred is an intuitive and visual app that eases the work of biostatisticians and facilitates to the medical personnel the interpretation of MSMs.

SARS-Cov-2 incubation period according to vaccination status during the fifth COVID-19 wave in a tertiary-care center in Spain: a cohort study.

BACKGROUND: The incubation period of an infectious disease is defined as the elapsed time between the exposure to the pathogen and the onset of symptoms. Although both the mRNA-based and the adenoviral vector-based vaccines have shown to be effective, there have been raising concerns regarding possible decreases in vaccine effectiveness for new variants and variations in the incubation period. METHODS: We conducted a unicentric observational study at the Hospital Universitari de Bellvitge, Barcelona, using a structured telephone survey performed by trained interviewers to estimate the incubation period of the SARS-CoV-2 Delta variant in a cohort of Spanish hospitalized patients. The distribution of the incubation period was estimated using the generalized odds-rate class of regression models. RESULTS: From 406 surveyed patients, 242 provided adequate information to be included in the analysis. The median incubation period was 2.8 days (95%CI: 2.5-3.1) and no differences between vaccinated and unvaccinated patients were found. Sex and age are neither shown not to be significantly related to the COVID-19 incubation time. CONCLUSIONS: Knowing the incubation period is crucial for controlling the spread of an infectious disease: decisions on the duration of the quarantine or on the periods of active monitoring of people who have been at high risk of exposure depend on the length of the incubation period. Furthermore, its probability distribution is a key element for predicting the prevalence and the incidence of the disease.

Using the geometric average hazard ratio in sample size calculation for time-to-event data with composite endpoints.

BACKGROUND: Sample size calculation is a key point in the design of a randomized controlled trial. With time-to-event outcomes, it's often based on the logrank test. We provide a sample size calculation method for a composite endpoint (CE) based on the geometric average hazard ratio (gAHR) in case the proportional hazards assumption can be assumed to hold for the components, but not for the CE. METHODS: The required number of events, sample size and power formulae are based on the non-centrality parameter of the logrank test under the alternative hypothesis which is a function of the gAHR. We use the web platform, CompARE, for the sample size computations. A simulation study evaluates the empirical power of the logrank test for the CE based on the sample size in terms of the gAHR. We consider different values of the component hazard ratios, the probabilities of observing the events in the control group and the degrees of association between the components. We illustrate the sample size computations using two published randomized controlled trials. Their primary CEs are, respectively, progression-free survival (time to progression of disease or death) and the composite of bacteriologically confirmed treatment failure or Staphylococcus aureus related death by 12 weeks. RESULTS: For a target power of 0.80, the simulation study provided mean (± SE) empirical powers equal to 0.799 (±0.004) and 0.798 (±0.004) in the exponential and non-exponential settings, respectively. The power was attained in more than 95% of the simulated scenarios and was always above 0.78, regardless of compliance with the proportional-hazard assumption. CONCLUSIONS: The geometric average hazard ratio as an effect measure for a composite endpoint has a meaningful interpretation in the case of non-proportional hazards. Furthermore it is the natural effect measure when using the logrank test to compare the hazard rates of two groups and should be used instead of the standard hazard ratio.

Effect of effervescent paracetamol on blood pressure: a crossover randomized clinical trial.

OBJECTIVE: To evaluate the effect of effervescent paracetamol on office and ambulatory blood pressure (BP) compared with noneffervescent paracetamol in hypertensive patients. DESIGN: This was a multicenter open crossover randomized clinical trial. SETTING: Primary care centers in Catalonia and the Basque Country. PARTICIPANTS: Inclusion criteria were office BP 150/95 mmHg or less and daytime ambulatory BP 140/90 mmHg or less, stable pharmacologic or nonpharmacologic antihypertensive treatment, and concomitant chronic osteoarticular pain. INTERVENTIONS: Baseline randomized assignment to 3-week periods of effervescent paracetamol (1 g three times a day) first and noneffervescent paracetamol later, or inversely, during a 7-week study period. At the start and end of each treatment period, 24-h ambulatory BP monitoring was performed. MAIN OUTCOME MEASURES: Differences in 24-h SBP between baseline and end of both treatment periods. The main analyses were performed according to the intention-to-treat principle. RESULTS: In intention-to-treat analysis, 46 patients were analyzed, 21 were treated with paracetamol effervescent and noneffervescent later, and 25 followed the opposite sequence. The difference in 24-h SBP between the two treatments was 3.99 mmHg (95% confidence interval 1.35-6.63; P = 0.004), higher in the effervescent paracetamol treatment period. Similarly, the per-protocol analysis showed a difference in 24-h SBP between the two groups of 5.04 mmHg (95% confidence interval 1.80-8.28; P = 0.004), higher in the effervescent paracetamol treatment period. Self-reported pain levels did not differ between groups and did not vary by treatment period. No serious adverse events were reported in either study arm. CONCLUSION: Effervescent paracetamol tablets are responsible for a significant daytime and overall increase in ambulatory 24-h SBP. TRIAL REGISTRATION: NCT: 02514538 EudraCT: 2010-023485-53.