Indiana University-Purdue University Indianapolis (IUPUI) / Randomized studies are designed to estimate the average treatment effect (ATE) of an intervention. Individuals may derive quantitatively, or even qualitatively, different effects from the ATE, which is called the heterogeneity of treatment effect. It is important to detect the existence of heterogeneity in the treatment responses, and identify the different sub-populations. Two corresponding statistical methods will be discussed in this talk: a hypothesis testing procedure and a mixture-model based approach. The hypothesis testing procedure was constructed to test for the existence of a treatment effect in sub-populations. The test is nonparametric, and can be applied to all types of outcome measures. A key innovation of this test is to build stochastic search into the test statistic to detect signals that may not be linearly related to the multiple covariates. Simulations were performed to compare the proposed test with existing methods. Power calculation strategy was also developed for the proposed test at the design stage. The mixture-model based approach was developed to identify and study the sub-populations with different treatment effects from an intervention. A latent binary variable was used to indicate whether or not a subject was in a sub-population with average treatment benefit. The mixture-model combines a logistic formulation of the latent variable with proportional hazards models. The parameters in the mixture-model were estimated by the EM algorithm. The properties of the estimators were then studied by the simulations. Finally, all above methods were applied to a real randomized study in a low ejection fraction population that compared the Implantable Cardioverter Defibrillator (ICD) with conventional medical therapy in reducing total mortality.

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Background: The primary objective of this study was to assess the feasibility of the Healthy Lifestyles Program (HLP), a novel 12-month complex intervention based in cognitive behavioural therapy and theories of behavioural change, delivered in a community-based setting in Hamilton, Canada. The secondary objective was to explore implementation factors. Methods/ design: A pragmatic pilot randomised controlled trial using quantitative and qualitative evaluation methods. Participants were randomly allocated to either intervention group (n=15) or comparator group (n=15). The intervention group attended weekly group education sessions and met in-person with a healthcare team monthly to create personalized health goals and action plans. The comparator group met with a research assistant every three months to develop health goals and action plans. We assessed feasibility of the program by measuring recruitment, participation and retention rates, missing data, and attendance. All participant-directed and clinical outcome measures were analyzed for between and within group changes using Generalized Estimating Equations (GEE). Content analysis was conducted for qualitative data. Results: We recruited and randomized 30 participants to each group (n=15) within 3 months. Retention rate was 60% (9/15) for the intervention group and 47% (7/15) for the comparator group. Less than 1% of participant-directed and clinical outcomes were missing. Participants attended an average of 29 of 43 educational sessions and 100% of one-to-one sessions. The healthcare team valued the program’s holistic approach to care, increased time and interaction with participants, professional collaboration, and the ability to provide counselling and health supports. Location accessibility was an important factor facilitating implementation. Reducing the number of psycho-social education sessions and having access to a gym could improve retention and delivery of the program. Conclusion: This study has demonstrated the feasibility of the HLP with minor modifications recommended for a larger trial and for the intervention. / Thesis / Master of Public Health (MPH) / Rates of chronic physical and mental health illness are rising in Canada. Lifestyle or behavioural changes can prevent or manage chronic diseases. The aim of this pilot study is to test the feasibility of delivering a 12-month Healthy Lifestyles Program to participants in Hamilton, Canada. The Healthy Lifestyles Program is a complex intervention designed to help participants identify health goals and action plans to achieve those goals with the guidance of healthcare professionals. We observed that the program was successfully delivered, accepted by participants and staff and required minor changes to the study design for a scaled-up study. The program showed positive trends for improving goal attainment, depression, and loneliness scores. The results of this study will help inform the design and scale-up of a larger study.

Background and Objectives: HIV in a major public health problem in many countries of the world. Recent advances in care for people living with HIV such as the use of antiretroviral medication have reduced the mortality and morbidity associated with HIV infection. However, many people receiving antiretroviral therapy do not take it as prescribed and still experience sub-optimal health outcomes. Mobile phone text messaging is emerging as an important tool in health care, and HIV in particular. Our objectives were to explore the determining factors for adherence to antiretroviral therapy, test text messaging as an adherence enhancement tool, develop a framework for community ownership of a text messaging program and describe strategies for transfer of evidence in HIV to other conditions. Methods: This research is primarily based in Yaoundé, Cameroon, and employs a variety of methodologies, including a systematic review, two cross- sectional surveys, a randomized controlled trial, an individual patient data meta-analysis, a mixed methods study and a systematic review of systematic reviews. Results and Conclusions: Two-way weekly text messaging is an effective strategy in improving adherence to antiretroviral therapy and enhancing provider-client communication. People living with HIV in Yaoundé, Cameroon like receiving text messages, and are willing to own and run a text messaging program. Text messaging interventions may be transferred to other conditions by integrating services or by copying what works in HIV. Further research on potential harms, cost effectiveness and text messaging for other chronic conditions is warranted. / Thesis / Doctor of Philosophy (PhD)

Preoperative fasting has been practiced prior to cardiac interventions such as cardiac implantable electronic device (CIED) procedures for 4-6 h since their inceptions. However, there is no data available on safety and efficacy of a non-fasting strategy for these procedures. Strict fasting restrictions may be difficult for patients to abide by, and might even be detrimental to overall patient health and recovery. According to previous studies real fasting times are much longer than 4-6h in clinical practice. Prolonged fasting can lead to patient dissatisfaction as well as affect patient health through increased trauma response or changes in patient medication. Strict fasting regulations also hinder rescheduling patients in case of sudden schedule changes or new patient arrivals . Fasting is practiced before procedures due to a fear of vomiting and aspiration, and the associated aspiration pneumonia. This was first described by Curtis Lester Mendelson as the Mendelson-syndrome in 1946. Since then, fasting protocols have been implemented with varying lengths, and have only been remedied slightly even though modern medicine has improved greatly in regards to treating complications from aspiration. CIED implantations also don’t use regular deep sedation for their procedures, but fasting is still often practiced for 6 hours prior to procedures with very little evidence to support this practice. In our investigator-driven, prospective, parallel-group, and single-arm blinded Fast-CIED trial we randomized 201 patients undergoing elective CIED implantations in a tertiary high-volume center into two groups (NCT04389697). Patients were assigned to a non-fasting strategy (100 patients, solids/fluids allowed up to 1h) or a fasting strategy (101 patients, at least 6h no solids and 2h no fluids) before the procedure and analyzed on an intention-to-treat basis. The co-primary outcomes were patients’ wellbeing scores (based on numeric rating scale, NRS 0-10) and incidence of intra-procedural food-related adverse events, including vomiting, perioperative pulmonary aspiration and emergency intubation. Renal, hematologic and metabolic blood parameters and 30-day follow-up data were gathered. The summed pre-procedural patients’ wellbeing score was significantly lower (i.e. better) in the Non-fasting group (Non-fasting: 13.1±9.6 vs. Fasting: 16.5±11.4, 95%CI of Mean Difference (MD) -6.35 - -0.46, P=0.029), which was mainly driven by significantly lower scores for hunger and tiredness in the non-fasting group (Non-fasting versus Fasting; hunger: 0.9±1.9 versus 3.1±3.2, 95% CI of MD -2.86 – -1.42, p < 0.001; tiredness: 1.6±2.3 versus 2.6±2.7, 95% CI of MD -1.68 – -0.29, P=0.023). No intra-procedural food related adverse events were observed. Relevant blood parameters and 30-day follow-up didn’t show significant differences. The study also showed that, in daily practice, fasting times for patients were longer than intended (5.20 ± 4.88 hours and 12.63 ± 6.36 hours for the non-fasting and fasting groups, respectively (P<0.001)) mainly due to standardized meal serving times in hospitals regardless of procedure starting times and short-term schedule changes. The Fast-CIED Study was the first randomized clinical trial to assess the benefits of a non-fasting compared to a fasting strategy before elective cardiac implantable electronic device (CIED) procedures. It showed that a non-fasting strategy is beneficial to a fasting strategy regarding patients’ wellbeing and comparable in terms of safety for CIED-procedures, allowing optimized procedure scheduling with high patient satisfaction. Our Fast-CIED trial made an important step to show that a non-fasting strategy is a viable alternative to a fasting strategy in patients undergoing elective CIED-surgery.:1. Introduction 4 1.1. Purpose of this study 4 1.2. History of preoperative fasting 5 1.3. Modern Practices 7 2. Publication 11 3. Summary/Synopsis 21 4. References 25 5. Spezifizierung des eigenen Beitrags 27 6. Erklärung über die eigenständige Abfassung der Arbeit 29 7. Lebenslauf 30 8. Danksagung 31

The effect of coffee and cocoa on oxidative damage to macromolecules has been investigated in several studies, often with controversial results. This study aimed to investigate the effect of one-month consumption of different doses of coffee or cocoa-based products containing coffee on markers of DNA damage and lipid peroxidation in young healthy volunteers. Twenty-one volunteers were randomly assigned into a three-arm, crossover, randomized trial. Subjects were assigned to consume one of the three following treatments: one cup of espresso coffee/day (1C), three cups of espresso coffee/day (3C), and one cup of espresso coffee plus two cocoa-based products containing coffee (PC) twice per day for 1 month. At the end of each treatment, blood samples were collected for the analysis of endogenous and H2O2-induced DNA damage and DNA oxidation catabolites, while urines were used for the analysis of oxylipins. On the whole, four DNA catabolites (cyclic guanosine monophosphate (cGMP), 8-OH-2′-deoxy-guanosine, 8-OH-guanine, and 8-NO2-cGMP) were detected in plasma samples following the one-month intervention. No significant modulation of DNA and lipid damage markers was documented among groups, apart from an effect of time for DNA strand breaks and some markers of lipid peroxidation. In conclusion, the consumption of coffee and cocoa-based confectionery containing coffee was apparently not able to affect oxidative stress markers. More studies are encouraged to better explain the findings obtained and to understand the impact of different dosages of these products on specific target groups.

Most statistical methods to design and analyze randomized controlled trials with time-to-event data, and synthesize their results in meta-analyses, use the hazard ratio (HR) as the measure of treatment effect. However, the HR relies on the proportional hazard assumption which is often violated, especially in cancer trials. In addition, the HR might be challenging to interpret and is frequently misinterpreted as a risk ratio (RR). In meta-analysis, conventional methods ignore that HRs are estimated over different time supports when the component trials have different follow-up durations. These issues also pertain to advanced statistical methods, such as network meta-analysis and surrogate endpoints validation. Novel methods that rely on the difference in restricted mean survival times (RMST) would help addressing these issues. In this dissertation, I first developed a Bayesian network meta-analysis model using the difference in RMST. This model synthesizes all the available evidence from multiple time points and treatment comparisons simultaneously through within-study covariance and between-study covariance for the differences in RMST. I proposed an estimator of the within-study covariance and estimated the model under the Bayesian framework. The simulation studies showed adequate performance in terms of mean bias and mean squared error. I illustrated the model on a network of randomized trials of second-line treatments of advanced non-small-cell lung cancer. Second, I introduced a novel two-stage meta-analytical model to evaluate trial-level surrogacy. I measured trial-level surrogacy by the coefficient of determination at multiple time points based on the differences in RMST. The model borrows strength across data available at multiple time points and enables assessing how the strength of surrogacy changes over time. Simulation studies showed that the estimates of coefficients of determination are unbiased and have high precision in almost all of the scenarios we examined. I demonstrated my model in two individual patient data meta-analyses in gastric cancer. Both methods, for network meta-analysis and surrogacy evaluation, have the advantage of not involving extrapolation beyond the observed time support in component trials and of not relying on the proportional hazard assumption. Finally, motivated by the common misinterpretation of the HR as a RR, I investigated the theoretical relationship between the HR and the RR and compared empirically the treatment effects measured by the HR and the RR in a large sample of oncology RCTs. When there is evidence of superiority for experimental group, misinterpreting the HR as the RR leads to overestimating the benefits by about 20%. / 2026-02-08T00:00:00Z

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