Applying Joint Modelling Regression Approaches in Biomedical Data Science

In recent years, the technological revolution is allowing the collection of an enormous amount of data of different types, creating enormously complex databases that require the collaboration of statisticians and clinicians to carry out a biomedical study with guarantees, applying the tools of data science. This requires the development of new statistical techniques. This thesis focuses on joint modelling regression models for multivariate responses. Specifically, we study the cases of two and three continuous outcomes, as well as models for longitudinal and survival data. These techniques are applied in three studies of major epidemiological importance: liver damage and survival in COVID-19 patients, perinatal mental health during the COVID-19 pandemic, and the study of thyroid-related hormones

Long-term cardiac reverse remodeling after cardiac resynchronization therapy

Introduction: The benefit of cardiac resynchronization therapy (CRT) in heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF) have been observed in the first year. However, there are few data on long-term follow-up and the effect of changes of LVEF on mortality. This study aimed to assess the LV remodeling after CRT implantation and the probable effect of changes in LVEF with repeated measures on mortality over time in a real-world registry. Methods: Among our cohort of 328 consecutive CRT patients, mixed model effect analysis have been made to describe the temporal evolution of LVEF and LVESV changes over time up with several explanatory variables. Besides, the effect of LVEF along time on the probability of mortality was evaluated using joint modeling for longitudinal and survival data. Results: The study population included 328 patients (253 men; 70.2 ± 9.5 years) in 4.2 (2.9) years follow-up. There was an increase in LVEF of 11% and a reduction in LVESV of 42 mL during the first year. These changes are more important during the first year, but slight changes remain during the follow-up. The largest reduction in LVESV occurred in patients with left bundle branch block (LBBB) and the smallest reduction in patients with NYHA IV. The smallest increase in LVEF was an ischemic etiology, longer QRS, and LV electrode in a nonlateral vein. Besides, the results showed that the LVEF profiles taken during follow-up after CRT were associated with changes in the risk of death. Conclusion: Reverse remodeling of the left ventricle is observed especially during the first year, but it seems to be maintained later after CRT implantation in a contemporary cohort of patients. Longitudinal measurements could give us additional information at predicting the individual mortality risk after adjusting by age and sex compared to a single LVEF measurement after CRTS

Longitudinal relationship of liver injury with inflammation biomarkers in COVID-19 hospitalized patients using a joint modeling approach

The mechanisms underlying liver disease in patients with COVID-19 are not entirely known. The aim is to investigate, by means of novel statistical techniques, the changes over time in the relationship between inflammation markers and liver damage markers in relation to survival in COVID-19. The study included 221 consecutive patients admitted to the hospital during the first COVID-19 wave in Spain. Generalized additive mixed models were used to investigate the influence of time and inflammation markers on liver damage markers in relation to survival. Joint modeling regression was used to evaluate the temporal correlations between inflammation markers (serum C-reactive protein [CRP], interleukin-6, plasma D-dimer, and blood lymphocyte count) and liver damage markers, after adjusting for age, sex, and therapy. The patients who died showed a significant elevation in serum aspartate transaminase (AST) and alkaline phosphatase levels over time. Conversely, a decrease in serum AST levels was observed in the survivors, who showed a negative correlation between inflammation markers and liver damage markers (CRP with serum AST, alanine transaminase [ALT], and gamma-glutamyl transferase [GGT]; and D-dimer with AST and ALT) after a week of hospitalization. Conversely, most correlations were positive in the patients who died, except lymphocyte count, which was negatively correlated with AST, GGT, and alkaline phosphatase. These correlations were attenuated with age. The patients who died during COVID-19 infection displayed a significant elevation of liver damage markers, which is correlated with inflammation markers over time. These results are consistent with the role of systemic inflammation in liver damage during COVID-19S

The impact of COVID-19 on breastfeeding rates: An international cross-sectional study

Background: Breastfeeding promotes children’s health and is associated with positive effects to maternal physical and mental health. Uncertainties regarding SARS-CoV-2 transmission led to worries experienced by women and health professionals which impacted breastfeeding plans. We aimed to investigate the impact of self-reported and country-specific factors on breastfeeding rates during the COVID-19 pandemic. Methods: This study is part of a broader international prospective cohort study about the impact of the COVID-19 pandemic on perinatal mental health (Riseup-PPD-COVID-19). We analysed data from 5612 women, across 12 countries. Potential covariates of breastfeeding (sociodemographic, perinatal, physical/mental health, professional perinatal care, changes in healthcare due to the pandemic, COVID-19 related, breastfeeding support, governmental containment measures and countries’ inequality levels) were studied by Generalized Linear Mixed-Effects Models. Results: A model encompassing all covariates of interest explained 24% of the variance of breastfeeding rates across countries (first six months postpartum). Overall, first child (β = -0.27), age of the child (β = -0.29), preterm birth (β = -0.52), admission to the neonatal/pediatric care (β = -0.44), lack of breastfeeding support (β = -0.18), current psychiatric treatment (β = -0.69) and inequality (β = -0.71) were negatively associated with breastfeeding (p < .001). Access to postnatal support groups was positively associated with breastfeeding (β = 0.59; p < .001). In countries with low-inequality, governmental measures to contain virus transmission had a deleterious effect on breastfeeding (β = -0.16; p < .05) while access to maternity leave protected breastfeeding (β = 0.50; p < .001). Discussion: This study shows that mother’s COVID-19 diagnosis and changes in healthcare and birth/postnatal plans did not influence breastfeeding rates. Virtual support groups help women manage breastfeeding, particularly when their experiencing a first child and for those under psychiatric treatment. The complex associations between covariates and breastfeeding vary across countries, suggesting the need to define context-specific measures to support breastfeeding

A cross‑country study on the impact of governmental responses to the COVID‑19 pandemic on perinatal mental health

This study aimed to analyse the role of governmental responses to the coronavirus disease 2019 (COVID-19) outbreak, measured by the Containment and Health Index (CHI), on symptoms of anxiety and depression during pregnancy and postpartum, while considering the countries’ Inequalityadjusted Human Development Index (IHDI) and individual factors such as age, gravidity, and exposure to COVID-19. A cross-sectional study using baseline data from the Riseup-PPD-COVID-19 observational prospective international study (ClinicalTrials.gov: NCT04595123) was carried out between June and October 2020 in 12 countries (Albania, Brazil, Bulgaria, Chile, Cyprus, Greece, Israel, Malta, Portugal, Spain, Turkey, and the United Kingdom). Participants were 7645 pregnant women or mothers in the postpartum period—with an infant aged up to 6 months—who completed the Edinburgh Postnatal Depression Scale (EPDS) or the Generalised Anxiety Disorder Assessment (GAD-7) during pregnancy or the postpartum period. The overall prevalence of clinically signifcant depression symptoms (EPDS≥ 13) was 30%, ranging from 20,5% in Cyprus to 44,3% in Brazil. The prevalence of clinically signifcant anxiety symptoms (GAD-7≥ 10) was 23,6% (ranging from 14,2% in Israel and Turkey to 39,5% in Brazil). Higher symptoms of anxiety or depression were observed in multigravida exposed to COVID-19 or living in countries with a higher number of deaths due to COVID19. Furthermore, multigravida from countries with lower IHDI or CHI had higher symptoms of anxiety and depression. Perinatal mental health is context-dependent, with women from more disadvantaged countries at higher risk for poor mental health. Implementing more restrictive measures seems to be a protective factor for mental health, at least in the initial phase of the COVID-19

A cross-country study on the impact of governmental responses to the COVID-19 pandemic on perinatal mental health

This study aimed to analyse the role of governmental responses to the coronavirus disease 2019 (COVID-19) outbreak, measured by the Containment and Health Index (CHI), on symptoms of anxiety and depression during pregnancy and postpartum, while considering the countries' Inequality-adjusted Human Development Index (IHDI) and individual factors such as age, gravidity, and exposure to COVID-19. A cross-sectional study using baseline data from the Riseup-PPD-COVID-19 observational prospective international study (ClinicalTrials.gov: NCT04595123) was carried out between June and October 2020 in 12 countries (Albania, Brazil, Bulgaria, Chile, Cyprus, Greece, Israel, Malta, Portugal, Spain, Turkey, and the United Kingdom). Participants were 7645 pregnant women or mothers in the postpartum period-with an infant aged up to 6 months-who completed the Edinburgh Postnatal Depression Scale (EPDS) or the Generalised Anxiety Disorder Assessment (GAD-7) during pregnancy or the postpartum period. The overall prevalence of clinically significant depression symptoms (EPDS ≥ 13) was 30%, ranging from 20,5% in Cyprus to 44,3% in Brazil. The prevalence of clinically significant anxiety symptoms (GAD-7 ≥ 10) was 23,6% (ranging from 14,2% in Israel and Turkey to 39,5% in Brazil). Higher symptoms of anxiety or depression were observed in multigravida exposed to COVID-19 or living in countries with a higher number of deaths due to COVID-19. Furthermore, multigravida from countries with lower IHDI or CHI had higher symptoms of anxiety and depression. Perinatal mental health is context-dependent, with women from more disadvantaged countries at higher risk for poor mental health. Implementing more restrictive measures seems to be a protective factor for mental health, at least in the initial phase of the COVID-19