Big Data: Medical Claims Data for Translational Research: Medicaid

Medical claims can be a primary data source for translational research. This presentation provides information on Medicaid as a source of claims data, including a description of Medicaid datasets, the most commonly used variables on each dataset, and examples of translational analyses using Medicaid

Data Acquisition, Management and Tracking

As part of the mini-symposium entitled Data Acquisition, Data Management, and Subject Tracking in Clinical and Translational Research: Seeking Solutions to Persistent Challenges, Drs. Barton and Costanza introduce the symposium with a presentation explaining the importance of data acquisition, management, and tracking of clinical research data

International trends in pancreatic cancer incidence and mortality rates

Background: Pancreatic cancer is a rare disease, with a lifetime risk of 1.45%. However, it is deadly, with a 1-year relative survival rate of 20% and a 5-year rate of 4% in the US. Risk factors for pancreatic cancer are cigarette smoking, obesity, physical inactivity, among others. Associated with developed countries, these risk factors are increasing in less developed and economically transitioning countries. Therefore, the objective of this presentation is to show international trends in pancreatic cancer incidence and mortality rates. Method: The pancreatic cancer incidence rates were collected from the Cancer Incidence in Five Continents (CI5) report and the mortality rates were collected from the World Health Organization cancer mortality database, both by the International Agency for Research on Cancer, for the periods 1988-1992 to 1998-2002 (10-year) and 1978-1982 to 1998-2002 (20-year). The statistics are provided countrywide or for specific regions within a country. Results: In America, 50% of evaluated countries/regions showed decreased pancreatic cancer incidence rates in any or both sexes during the 10-year period. In Northern Europe, one-third of the evaluated countries/regions showed decreased pancreatic cancer incidence rates in any or both sexes during the 10-year period. In Southern Europe, 44% of the evaluated countries/regions showed increased pancreatic cancer incidence rates in any or both sexes during the 10-year period. Both Chinese regions show increased pancreatic cancer incidence rates in both sexes during the 20-year period. Twenty-seven percent of the evaluated world countries/regions show decreased pancreatic cancer mortality rates in both sexes during the 20-year period. Discussion: There is international/regional variation in pancreatic cancer incidence and mortality rates. Specific protective or risk (like acquiring developed-country lifestyles or high life expectancy) factors could explain these differences. Conclusion: The findings of this study provide preliminary evidence to reassess pancreatic cancer prevention strategies worldwide

Differential role of MLKL in alcohol-associated and non-alcohol-associated fatty liver diseases in mice and humans

Hepatocellular death contributes to progression of alcohol-associated (ALD-associated) and non-alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain-like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH. Phospho-MLKL was higher in livers of patients with NASH compared with AH or healthy controls (HCs). MLKL expression, phosphorylation, oligomerization, and translocation to plasma membrane were induced in WT mice fed diets high in fat, fructose, and cholesterol but not in response to Gao-binge (acute on chronic) ethanol exposure. Mlkl-/- mice were not protected from ethanol-induced hepatocellular injury, which was associated with increased expression of chemokines and neutrophil recruitment. Circulating concentrations of RIP1 and RIP3, but not MLKL, distinguished patients with AH from HCs or patients with NASH. Taken together, these data indicate that MLKL is differentially activated in ALD/AH compared with NAFL/NASH in both murine models and patients. Furthermore, plasma RIP1 and RIP3 may be promising biomarkers for distinguishing AH and NASH

Outcome of Hyperkalemia in the Emergency Department: Impact of Hyperkalemic Severity, Renal Function and CHF on Survival

Background: Hyperkalemia is common and lethal electrolyte disorder with little known long-term consequences. This was retrospective, observational study of hospitalized patients with initial serum K \u3e 5.3 mEq/L. 143 consecutive episodes of hyperkalemia were analyzed in 133 patients. Survival was analyzed by parameters of renal dysfunction (admit eGFR), CHF, admit K and EKG abnormalities. Methods: Hazard ratios (HR) for mortality were computed by Cox proportional hazards multivariate regression. Primary end point, all-cause mortality determined by Social Security Death Index and medical record review. Results: Admit eGFR was the most powerful predictor of mortality. The effect of renal function was nonlinear(figure 1). Highest mortality is eGFR group of 15-59 HR 6.92. More severe renal impairment with eGFR(HD) HR 3.67. ESRD had lower mortality HR 1.33(table 1). Hyperkalemic severity had a modest effect(figure 2). Compared to patients Admit K 5.3-5.9 mEq/L, patients with K 6-7, HR 2.21 (p=0.0210) and K \u3e7.0, HR 2.62 (p=0.0521). History of CHF, increased mortality by univariate analysis (p Conclusions: Survival in hyperkalemic patients is predicted by lower admit eGFR in a non-linear fashion. ESRD patients exhibited lower mortality perhaps reflecting adaptation to chronic hyperkalemia. CHF has an additive effect on mortality in non HD patients. We emphasize that 86% of the mortality was after discharge. This extraordinary mortality necessitates the need to develop risk stratification strategies in the long-term care of the hyperkalemic patients

Coronary Evaluation Using Multi-detector Spiral Computed Tomography Angiography: Statistical Design and Analysis

Contrast-enhanced multi-detector row spiral computed tomography (MDCT) has been introduced as a method for non-invasive visualization of coronary artery stenosis. To determine the diagnostic accuracy of MDCT coronary angiography, as compared to the “gold standard” invasive coronary angiography, sensitivity and specificity are estimated (95% Confidence Intervals). Three separate levels of estimation are computed: at the patient level, at the coronary artery level, and at the coronary artery segment level. We review the methodology for the estimation of sensitivity and specificity of non-clustered binary data (patient level analysis) and present a methodology for the estimation of sensitivity and specificity that considers the patient as a cluster and the coronary arteries (or coronary artery segments) as the diagnostic units of the study (DUOS) within each cluster. We also present how to estimate the weighted kappa for the comparison of ordinal measures of stenosis when non-clustered and clustered data are considered and the mean difference for the comparison of continuous measures of stenosis when non-clustered and clustered data are considered. Finally, we present a methods for determining the statistical precision of estimates sensitivity and specificity, weighted kappa and mean difference when clustered data are considered

Response of sea bream to handling

Understanding how gilthead sea bream, Sparus aurata L., an important Mediterranean Sea species for aquaculture, respond physiologically to stressors commonly encountered in intensive rearing is important for eiective production, as managing for stress is a major factor in maintaining healthy ¢sh stocks. Our objective was to determine whether holding juvenile gilthead sea bream at a high density (HD), as a chronic stressor, would aiect their physiological responses to a subsequent acute handling stressor. After acclimation at a low density (LD) of 6k g m 3 in 200-L circular tanks containing 33^ 36 g L 1 recirculating seawater at 191C under a normal photoperiod, juvenile 37-g gilthead sea bream were con¢ned for 14 days at a HD of 26 kg m 3 an

Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice

There is mounting evidence that microbes residing in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, finding elevated levels of the microbial metabolite trimethylamine (TMA) in AH. In subsequent studies, we treated mice with non-lethal bacterial choline TMA lyase (CutC/D) inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. We show the gut microbial choline metabolite TMA is elevated in AH patients and correlates with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial CutC/D activity protects mice from ethanol-induced liver injury. CutC/D inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome and host liver transcriptome. The microbial metabolite TMA is elevated in patients with AH, and inhibition of TMA production from gut microbes can protect mice from ethanol-induced liver injury

Biostatistics, Epidemiology & Research Design (BERD)

This seminar describes the Biostatistics, Epidemiology, and Research Design component of the UMCCTS, including the Quantitative Methods Core (QMC). An overview of the new Department of Quantitative Health Sciences is also presented

The Per2 Negative Feedback Loop Sets the Period in the Mammalian Circadian Clock Mechanism

Processes that repeat in time, such as the cell cycle, the circadian rhythm, and seasonal variations, are prevalent in biology. Mathematical models can represent our knowledge of the underlying mechanisms, and numerical methods can then facilitate analysis, which forms the foundation for a more integrated understanding as well as for design and intervention. Here, the intracellular molecular network responsible for the mammalian circadian clock system was studied. A new formulation of detailed sensitivity analysis is introduced and applied to elucidate the influence of individual rate processes, represented through their parameters, on network functional characteristics. One of four negative feedback loops in the model, the Per2 loop, was uniquely identified as most responsible for setting the period of oscillation; none of the other feedback loops were found to play as substantial a role. The analysis further suggested that the activity of the kinases CK1δ and CK1ɛ were well placed within the network such that they could be instrumental in implementing short-term adjustments to the period in the circadian clock system. The numerical results reported here are supported by previously published experimental data