USING MARGINAL STRUCTURAL MODELS TO CONTROL FOR TIME-DEPENDENT CONFOUNDING AND DETECT EFFECT MODIFICATION IN A RANDOMIZED CONTROL TRIAL WITH A TIME-VARYING EXPOSURE, NON-ADHERENCE AND MISSING DATA

Background: Unlike traditional regression used in the Intention to Treat (ITT) approach, Marginal Structural Models (MSM) can account for joint effects of baseline and subsequent treatments as well as the presence of time-dependent confounding influenced by prior treatment and selection bias due to censoring. In addition, MSMs have been theorized to be able to assist investigators in determining the overall benefit of a drug in the total population as they are able to provide a summary effect size across all strata of an effect modifier which cannot be done via tradition regression techniques. The overall goal of this dissertation is to demonstrate the advantages and disadvantages of using MSM to 1) control for time-dependent confounding and 2) detect effect modification in a randomized controlled trial (RCT) with a time-varying exposure, non-adherence and missing data. Methods: The ITT analysis consisted of a logistic regression model linking the annual rate of acute asthma exacerbations (outcome) to assigned asthma treatment. Weights for the MSM analysis were derived from a pooled logistic regression assessing the probability of staying on assigned treatment (adherence) and, in Aim 1 and 3, of remaining uncensored for subjects at each visit by treatment arm. Poisson regression models using PROC GENMOD were fitted for the annual rate of acute asthma exacerbations (outcome) as a function of the assigned treatment using the weighted sample and a generalized estimating equation (GEE) with an independent correlation matrix in Aims 1 and 3. The final outcome model in Aim 2 also included a treatment covariate interaction term. In all aims, the final models were fit to uncensored cases with complete data. Results: Despite the theoretical advantages of MSMs, my research found that the approach failed to invalidate previous ITT analyses, regardless of adherence level. In Aim 1, the ITT analysis found a 22% increased risk of EPACs for theophylline compared with montelukast (RR=1.22, 95% CI: 0.82-1.86, p=0.35), no increased risk between theophylline and placebo (RR=0.99, 95% CI: 0.67-1.50, p=1.00), and an 18% decreased risk of EPACs between montelukast and placebo (RR=0.82; 95% CI: 0.55-1.21, p=0.31) for the ITT approach. This was in comparison to a 24% increased risk of EPACs for theophylline compared with montelukast (RR=1.24, 95% CI: 0.83-1.84, p=0.28), no increased risk between theophylline and placebo (RR=1.01, 95% CI: 0.70-1.48, p=0.95), and a 17% decreased risk of EPACs between montelukast and placebo (RR=0.83; 95% CI: 0.57-1.19, p=0.27). In Aim 3, despite finding a statistically significant difference in adherence rates between the self-reported group and the blood assay group over time (p=0.001), adjusted rate ratios and corresponding 95% confidence intervals obtained were nearly identical and in both cases non-significant. In the self-report group, those on theophylline were 28% more likely to have an asthma exacerbation than those in the montelukast group (95% CI: 0.85-1.94, p=0.24) compared with 24% in the blood assay group (95% CI: 0.84-1.84, p=0.28). In Aim 2, the MSM analysis was able to detect effect modification by race in one of the treatment groups (montelukast). In the unadjusted analysis, non-whites were twice as likely to have an EPAC on montelukast as their white counterparts (5.75 vs. 2.66 episodes per person year, p=0.0034). Similar findings were seen for increased medication use and health care visits. Results of the MSM also indicated the presence of effect modification for overall EPACs, medication use and unscheduled health care when treated with montelukast instead of placebo. Compared with whites, non-whites were more than twice as likely to suffer from an EPAC on montelukast as on placebo (RR=2.13, 95% CI: 1.08-4.46, p= 0.04) and almost 3 times as likely to increase medication use (RR=2.86, 95% CI: 1.10-7.42, p=0.03). Non-whites were over 5 times more likely to have unscheduled health care visits than whites while on montelukast compared with placebo (RR=5.01, 95% CI: 1.36-18.97, p=0.02). Conclusions: In theory MSMs hold much potential for further analyses of RCTs as it allows adjustment for time-varying exposures, time-dependent confounding and selection bias, issues more traditional regression based methods cannot account for. However, it remains unclear as to whether this is the case in practice. At the very least, MSMs should be conducted as a sensitivity analysis to the ITT approach in RCTs where there is preliminary evidence suggesting the presence of time-varying exposures, time-dependent confounding and/or selection bias and when MSM’s limitations can be reasonably ignored. Conducting a MSM as a sensitivity analysis of the ITT can only bolster one’s confidence of the estimated effects of treatment on an outcome. In terms of effect modification, more research is needed to determine the most appropriate way to calculate inverse probability treatment weights propensity scores as there is no consensus in the literature on how best to calculate the propensity scores required for weighting and achieve accurate subgroup results

Factors predicting treatment of World Trade Center-related lung injury : a longitudinal cohort study

The factors that predict treatment of lung injury in occupational cohorts are poorly defined. We aimed to identify patient characteristics associated with initiation of treatment with inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) >2 years among World Trade Center (WTC)-exposed firefighters. The study population included 8530 WTC-exposed firefighters. Multivariable logistic regression assessed the association of patient characteristics with ICS/LABA treatment for >2 years over two-year intervals from 11 September 2001-10 September 2017. Cox proportional hazards models measured the association of high probability of ICS/LABA initiation with actual ICS/LABA initiation in subsequent intervals. Between 11 September 2001-1 July 2018, 1629/8530 (19.1%) firefighters initiated ICS/LABA treatment for >2 years. Forced Expiratory Volume in 1 s (FEV1), wheeze, and dyspnea were consistently and independently associated with ICS/LABA treatment. High-intensity WTC exposure was associated with ICS/LABA between 11 September 2001-10 September 2003. The 10th percentile of risk for ICS/LABA between 11 September 2005-10 Septmeber 2007 was associated with a 3.32-fold increased hazard of actual ICS/LABA initiation in the subsequent 4 years. In firefighters with WTC exposure, FEV1, wheeze, and dyspnea were independently associated with prolonged ICS/LABA treatment. A high risk for treatment was identifiable from routine monitoring exam results years before treatment initiation

Construction of an ~700-kb transcript map around the Familial Mediterranean Fever locus on human chromosome 16p13.3

We used a combination of cDNA selection, exon amplification, and computational prediction from genomic sequence to isolate transcribed sequences from genomic DNA surrounding the familial Mediterranean fever (FMF) locus. Eighty-seven kb of genomic DNA around D16S3370, a marker showing a high degree of linkage disequilibrium with FMF, was sequenced to completion, and the sequence annotated. A transcript map reflecting the minimal number of genes encoded within the ∼700 kb of genomic DNA surrounding the FMF locus was assembled. This map consists of 27 genes with discreet messages detectable on Northerns, in addition to three olfactory-receptor genes, a cluster of 18 tRNA genes, and two putative transcriptional units that have typical intron–exon splice junctions yet do not detect messages on Northerns. Four of the transcripts are identical to genes described previously, seven have been independently identified by the French FMF Consortium, and the others are novel. Six related zinc-finger genes, a cluster of tRNAs, and three olfactory receptors account for the majority of transcribed sequences isolated from a 315-kb FMF central region (betweenD16S468/D16S3070 and cosmid 377A12). Interspersed among them are several genes that may be important in inflammation. This transcript map not only has permitted the identification of the FMF gene (MEFV), but also has provided us an opportunity to probe the structural and functional features of this region of chromosome 16.Michael Centola, Xiaoguang Chen, Raman Sood, Zuoming Deng, Ivona Aksentijevich, Trevor Blake, Darrell O. Ricke, Xiang Chen, Geryl Wood, Nurit Zaks, Neil Richards, David Krizman, Elizabeth Mansfield, Sinoula Apostolou, Jingmei Liu, Neta Shafran, Anil Vedula, Melanie Hamon, Andrea Cercek, Tanaz Kahan, Deborah Gumucio, David F. Callen, Robert I. Richards, Robert K. Moyzis, Norman A. Doggett, Francis S. Collins, P. Paul Liu, Nathan Fischel-Ghodsian and Daniel L. Kastne

Noncoding deletions reveal a gene that is critical for intestinal function.

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes

From evidence to action to deliver a healthy start for the next generation.

Remarkable progress has been made towards halving of maternal deaths and deaths of children aged 1-59 months, although the task is incomplete. Newborn deaths and stillbirths were largely invisible in the Millennium Development Goals, and have continued to fall between maternal and child health efforts, with much slower reduction. This Series and the Every Newborn Action Plan outline mortality goals for newborn babies (ten or fewer per 1000 livebirths) and stillbirths (ten or fewer per 1000 total births) by 2035, aligning with A Promise Renewed target for children and the vision of Every Woman Every Child. To focus political attention and improve performance, goals for newborn babies and stillbirths must be recognised in the post-2015 framework, with corresponding accountability mechanisms. The four previous papers in this Every Newborn Series show the potential for a triple return on investment around the time of birth: averting maternal and newborn deaths and preventing stillbirths. Beyond survival, being counted and optimum nutrition and development is a human right for all children, including those with disabilities. Improved human capital brings economic productivity. Efforts to reach every woman and every newborn baby, close gaps in coverage, and improve equity and quality for antenatal, intrapartum, and postnatal care, especially in the poorest countries and for underserved populations, need urgent attention. We have prioritised what needs to be done differently on the basis of learning from the past decade about what has worked, and what has not. Needed now are four most important shifts: (1) intensification of political attention and leadership; (2) promotion of parent voice, supporting women, families, and communities to speak up for their newborn babies and to challenge social norms that accept these deaths as inevitable; (3) investment for effect on mortality outcome as well as harmonisation of funding; (4) implementation at scale, with particular attention to increasing of health worker numbers and skills with attention to high-quality childbirth care for newborn babies as well as mothers and children; and (5) evaluation, tracking coverage of priority interventions and packages of care with clear accountability to accelerate progress and reach the poorest groups. The Every Newborn Action Plan provides an evidence-based roadmap towards care for every woman, and a healthy start for every newborn baby, with a right to be counted, survive, and thrive wherever they are born

A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia

Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response