A percentile approach to time-to-event outcomes

Evaluating survival percentiles is a possible approach for the analysis of time-to-event outcomes that moves the focus from risk to time, as the proportion of events is xed and the time by which that proportion is achieved is investigated. The development of statistical methods for conditional censored quantiles has opened up the possibility to use this approach in epidemiological studies. The aim of this doctoral thesis was to investigate the advantages of this method in epidemiology, by evaluating survival percentiles in observational studies on lifestyle and mortality, and by extending and further developing the statistical tools for the estimation of conditional survival percentiles. The percentile approach was used in a large prospective cohort of about 80.000 middle-aged and elderly Swedish men and women, with 15 years of follow-up during which 20% of the study pop- ulation died. The impact of modi able lifestyle factors such as fruit and vegetables consumption (Study I), sleep duration and physical activity (Study II), and processed and non-processed red meat consumption (Study III) on time to death were evaluated. Statistical modeling of conditional survival percentiles was conducted using Laplace regression. The epidemiological measure of exposure-outcome association was de ned in terms of percentile di erence (PD). Quantitative exposures were exibly modeled using splines to investigate the dose-response shape. Low fruit and vegetables consumption (Study I) was found to be associated with progressively shorter survival up to 3 years (PD: -37 months; 95% CI: -58, -16) when comparing those who con- sumed 5 servings/day and those who never consumed fruit and vegetables. Long sleep duration, over 8 hours/day, (Study II) was associated with shorter survival (PD = -20 months; 95% CI: -30, -11) among those with low physical activity, comparing with those with 7 hours of sleeping per day. In Study III, compared with no consumption, higher intake of processed red meat (200 g/d) was associated with shorter survival (PD: -10 months; 95% CI: -18, -3). High and moderate intakes of non-processed red meat were associated with shorter survival only when accompanied by a high intake of processed red meat. Study IV and Study V introduced novel developments and extensions of the percentile approach. Study IV presented the meaning and evaluation of survival percentiles in those situations where the time variable of interest is attained age at the event rather than follow-up time. This change in the time-scale has important consequences on the de nition and interpretation of the survival curve and related percentiles. The study described how to use multivariable Laplace regression models to esti- mate percentiles of age at death conditioning on age at entry into the study, exposures, and potential confounders. Study V focused on interaction analysis. Interaction can be evaluated on the additive or multiplicative scale, but its assessment in prospective studies is commonly limited to the multiplica- tive scenario. In this study the advantages of using a percentile approach in interaction analysis were presented. A measure of interaction in terms of time was introduced and how Laplace regression can be used to estimate a measure of interaction on the additive scale was described. Evaluating survival percentiles provides an intuitive and exible approach for the analysis of time- to-event outcomes. With this method, results from prospective studies can be presented in terms of di erences in survival time, facilitating both interpretation and communication of scienti c ndings. The introduction of a statistical technique to estimate conditional survival percentiles has substan- tially enriched its potentialities and eased its application in epidemiological research. The percentile approach should be considered as a possible complement to classical approaches and its use should be widespread

Multiplicative models for survival percentiles: estimating percentile ratios and multiplicative interaction in the metric of time

Evaluating percentiles of survival was proposed as a possible method to analyze time-to-event outcomes. This approach sets the cumulative risk of the event of interest to a specific proportion and evaluates the time by which this proportion is attainedIn this context, exposure-outcome associations can be expressed in terms of differences in survival percentiles, expressing the difference in survival time by which different subgroups of the study population experience the same proportion of events, or in terms of percentile ratios, expressing the strength of the exposure in accelerating the time to the event. Additive models for conditional survival percentiles have been introduced, and their use to estimate multivariable-adjusted percentile differences, and additive interaction on the metric of time has been described. On the other hand, the percentile ratio has never been fully described, neither statistical methods have been presented for its models-based estimation. To bridge this gap, we provide a detailed presentation of the percentile ratio as a relative measure to assess exposure-outcome associations in the context of time-to-event analysis, discussing its interpretation and advantages. We then introduce multiplicative statistical models for conditional survival percentiles, and present their use in estimating percentile ratios and multiplicative interactions in the metric of time. The introduction of multiplicative models for survival percentiles allows researchers to apply this approach in a large variety of context where multivariable adjustment is required, enriching the potentials of the percentile approach as a flexible and valuable tool to evaluate time-to-event outcomes in medical research

Histomorphometric evaluation of bone regeneration induced by biodegradable scaffolds as carriers for dental pulp stem cells in a rat model of calvarial "critical size" defect

Objective: The aim of this study was to test specific stem cells that could enhance bone formation in combination with specific scaffolds. Methods: Dental Pulp Stem Cells (DPSCs) were seeded with Granular Deproteinized Bovine Bone (GDPB) or Beta-Tricalcium Phosphate (ß-TCP) in a rat model of calvarial "critical size" defect. DPSCs were isolated from permanent human teeth, obtained and characterized using specific stem cells markers (Nanog and Oct-4) by real time-PCR and immunofluorescence. Cells were differentiated for 10-15 days towards the osteoblastic phenotype with 100μM L-ascorbic acid, added every day in culture medium and 20 vol. percentage of FBS in α-MEM medium. Osteogenic commitment was evaluated with real time-PCR by measuring the expression of specific markers (osteonectin and runx2). When a sufficient cell number was obtained, DPSCs were trypsinized, washed in culture medium and seeded onto the GDPB and ß-TCP scaffold sat a density of 0.5-1×106 cells/scaffold. Two bilateral critical-size circular defects (5 mm diameter; 1 mm thickness) were created from the parietal bone of the 8 athymic T-cell deficient nude rats. One cranial defect for each rat was filled with the scaffold alone and the other defect with the scaffold seeded with stem cells. After 12 weeks post-surgery animals were euthanized and histomorphometric analysis was performed. Differences between groups were analyzed by one-way analysis of variance (ANOVA) followed by Fisher's Protected Least Significant Difference (PLSD) post-hoc test. A p-value <0.05 was considered statistically significant. Results: GDPB group presented higher percentage of lamellar bone than that of GDPB/DPSC, ß-TCP alone had lower levels as compared to ß-TCP/DPSC. The addition of stem cells significantly increased woven bone formation in both scaffold-based implants, although still higher in GDPB based implants. Conclusion: Our findings indicate that GDPB and ß-TCP used as scaffold to induce bone regeneration may benefit from adding DPSC to tissue-engineered constructs

DNA Hypomethylation, Ambient Particulate Matter, and Increased Blood Pressure: Findings From Controlled Human Exposure Experiments

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144592/1/jah3232.pd

Epidemiology and Characteristics of Episodic Breathlessness in Advanced Cancer Patients: An Observational Study

CONTEXT: Episodic breathlessness is a relevant aspect in patients with advanced cancer. OBJECTIVES: The aim of this study was to assess the different aspects of this clinical phenomenon. METHODS: A consecutive sample of patients with advanced cancer admitted to different settings for a period of six months was surveyed. The presence of background breathlessness and episodic breathlessness, their intensity (numerical scale 0-10), and drugs used for treatment were collected. Factors inducing episodic breathlessness and its influence on daily activities were investigated. RESULTS: Of 921 patients, 29.3% (n = 269) had breathlessness and 134 patients (49.8%) were receiving drugs for background breathlessness. In the multivariate analysis, the risk of breathlessness increased with chronic obstructive pulmonary disease, although it decreased in patients receiving disease-oriented therapy and patients with gastrointestinal tumors. The prevalence of episodic breathlessness was 70.9% (n = 188), and its mean intensity was 7.1 (SD 1.6). The mean duration of untreated episodic breathlessness was 19.9 minutes (SD 35.3); 41% of these patients were receiving drugs for episodic breathlessness. The majority of episodic breathlessness events (88.2%) were triggered by activity. In the multivariate analysis, higher Karnofsky Performance Status levels were significantly related to episodic breathlessness, although patients receiving disease-oriented therapy were less likely to have episodic breathlessness. CONCLUSION: This study showed that episodic breathlessness frequently occurs in patients with breathlessness in the advanced stage of disease, has a severe intensity, and is characterized by rapid onset and short duration, which require rapid measures

Mosquito-Borne Diseases and ‘One Health’: The Northwestern Italian Experience

In Italy, the surveillance of Mosquito-Borne Diseases (MBDs) is regulated by two national preparedness plans: (1) for West Nile and Usutu viruses, integrating human and veterinary surveillance in order to early detect viruses circulation and to quickly apply control measures aimed at reducing the risk of transmission through blood and blood components and (2) for Arbovirosis transmitted by Aedes mosquitoes, mainly Chikungunya, Dengue and Zika viruses, based on surveillance of both imported and autochthonous human cases. This chapter reports the results of the application of these National Plans in Northwestern Italy and their impact for human health. In detail, we present the coordinated activities enforced in Piemonte and Liguria Regions, as a good example of the ‘One Health approach’ to control MBDs and prevent human transmission

Delay in sexual maturation in perinatally HIV-infected youths is mediated by poor growth

OBJECTIVE: To evaluate the association between HIV infection and sexual maturation, and mediation of this association by HIV effects on growth. DESIGN: Pooled data were analyzed from two longitudinal cohort studies, the International Maternal Pediatric Adolescent AIDS Clinical Trials P219/219C Study (1993-2007) and the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol (2007-2015), including perinatally HIV-infected (PHIV) and HIV-exposed uninfected (PHEU) youths. METHODS: We evaluated age at sexual maturity among 2539 PHIV and PHEU adolescents based on annual physician-assessed pubertal staging measures. Interval-censored regression models were used to evaluate associations of HIV infection with age at maturity. Mediation analyses accounting for height and BMI Z-scores at specific ages were used to estimate direct and indirect effects of HIV infection on age at sexual maturity. RESULTS: Mean ages at sexual maturity for PHIV girls (n = 1032) were 15.5 years for both female breast and pubic hair and 15.9 and 15.8 years for PHIV boys (n = 1054) for genitalia and pubic hair, respectively. PHIV youths matured approximately 6 months later on average than PHEU (n = 221 girls and 232 boys), and this difference persisted after adjustment for race/ethnicity and birth cohort. BMI and height Z-scores mediated the association between HIV infection and later maturation in girls, accounting for up to 74% of the total HIV effect. Only height Z-scores mediated the effect of HIV on male age at maturity, accounting for up to 98% of the HIV effect. CONCLUSION: PHIV youths attain sexual maturity later on average than PHEU youths. Much of this difference may be attributable to deficient growth, suggesting directions for future interventions

Association between chemical mixtures and female fertility in women undergoing assisted reproduction in Sweden and Estonia

ObjectiveWomen of reproductive age are exposed to ubiquitous chemicals such as phthalates, parabens, and per- and polyfluoroalkyl substances (PFAS), which have potential endocrine disrupting properties and might affect fertility. Our objective was to investigate associations between potential endocrine-disrupting chemicals (EDCs) and female fertility in two cohorts of women attending fertility clinics.MethodsIn a total population of 333 women in Sweden and Estonia, we studied the associations between chemicals and female fertility, evaluating ovarian sensitivity index (OSI) as an indicator of ovarian response, as well as clinical pregnancy and live birth from fresh and frozen embryo transfers. We measured 59 chemicals in follicular fluid samples and detected 3 phthalate metabolites, di-2-ethylhexyl phthalate (DEHP) metabolites, 1 paraben, and 6 PFAS in >90% of the women. Associations were evaluated using multivariable-adjusted linear or logistic regression, categorizing EDCs into quartiles of their distributions, as well as with Bayesian Kernel Machine Regression.ResultsWe observed statistically significant lower OSI at higher concentrations of the sum of DEHP metabolites in the Swedish cohort (Q4 vs Q1, β = -0.21, 95% CI: −0.38, −0.05) and methylparaben in the Estonian cohort (Q3 vs Q1, β = -0.22, 95% CI: −0.44, −0.01). Signals of potential associations were also observed at higher concentrations of PFUnDA in both the combined population (Q2 vs. Q1, β = −0.16, 95% CI -0.31, −0.02) and the Estonian population (Q2 vs. Q1, β = −0.27, 95% CI -0.45, −0.08), and for PFOA in the Estonian population (Q4 vs. Q1, β = −0.31, 95% CI -0.61, −0.01). Associations of chemicals with clinical pregnancy and live birth presented wide confidence intervals.ConclusionsWithin a large chemical mixture, we observed significant inverse associations levels of DEHP metabolites and methylparaben, and possibly PFUnDA and PFOA, with OSI, suggesting that these chemicals may contribute to altered ovarian function and infertility in women