Detecting clinically meaningful biomarkers with repeated measurements in an Electronic Health Record

Electronic health record (EHR) data are becoming an increasingly common data source for understanding clinical risk of acute events. While their longitudinal nature presents opportunities to observe changing risk over time, these analyses are complicated by the sparse and irregular measurements of many of the clinical metrics making typical statistical methods unsuitable for these data. In this paper, we present an analytic procedure to both sample from an EHR and analyze the data to detect clinically meaningful markers of acute myocardial infarction (MI). Using an EHR from a large national dialysis organization we abstracted the records of 64,318 individuals and identified 5,314 people that had an MI during the study period. We describe a nested case-control design to sample appropriate controls and an analytic approach using regression splines. Fitting a mixed-model with truncated power splines we perform a series of goodness-of-fit tests to determine whether any of 11 regularly collected laboratory markers are useful clinical predictors. We test the clinical utility of each marker using an independent test set. The results suggest that EHR data can be easily used to detect markers of clinically acute events. Special software or analytic tools are not needed, even with irregular EHR data.Comment: 23 pages, 3 figure

Effects of the glutamate carboxypeptidase II (GCP2 1561C>T) and reduced folate carrier (RFC1 80G>A) allelic variants on folate and total homocysteine levels in kidney transplant patients

Effects of the glutamate carboxypeptidase II (GCP2 1561C>T) and reduced folate carrier (RFC1 80G>A) allelic variants on folate and total homocysteine levels in kidney transplant patients.BackgroundThe effect of the glutamate carboxypeptidase II GCP2 1561C>T and the reduced folate carrier 1 RFC1 80G>A polymorphisms on folate and total homocysteine (tHcy) plasma levels of kidney transplant patients are unknown.MethodsIn a cross-sectional study of 730 kidney allograft recipients, GCP2 1561C>T, RFC1 80G>A, folate, and tHcy plasma levels were analyzed using linear regression models that allowed dependent covariates to follow a gamma distribution for univariate and multivariate analyses.ResultsThe allele frequency for GCP2 1561C>T was 0.05, and 0.43 for RFC1 80G>A. Heterozygosity or homozygosity for GCP2 1561C>T was associated with higher folate plasma levels compared to patients without mutation (P < 0.0001), while RFC1 80G>A showed no influence. Multiple testing, also including MTHFR 677C>T and MTHFR 1298A>C, revealed no interaction between the different genotypes and the folate plasma concentration. Neither GCP2 1561C>T nor RFC1 80G>A showed an association with tHcy plasma levels.ConclusionWe conclude that GCP2 1561C>T is associated with elevated folate levels. GCP2 1561C>T and RFC1 80G>A are no major determinants of tHcy plasma levels in kidney transplant patients

Effects of TCN2 776C>G on vitamin B12, folate, and total homocysteine levels in kidney transplant patients

Effects of TCN2 776C>G on vitamin B12, folate, and total homocysteine levels in kidney transplant patients.BackgroundControversy exists regarding the possible associations between a single nucleotide polymorphism of the transcobalamin II encoding gene (TCN2 776C>G) and plasma levels of vitamin B12, folate, or total homocysteine.MethodsIn a cross-sectional study of 732 kidney allograft recipients, patients were categorized by TCN2 776C>G genotype. In univariate and multivariate linear regression models that allowed the outcome variables vitamin B12, folate, and total homocysteine plasma levels to follow a gamma distribution, we tested for possible associations of allelic variants of the TCN2 776C>G gene and these three dependent variables.ResultsThe allele frequency for TCN2 776C>G was 0.46. Heterozygosity or homozygosity for TCN2 776C>G was not associated with plasma levels of vitamin B12 (776CG, P = 0.22; 776GG, P = 0.89), folate (776CG, P = 0.91; 776GG, P = 0.84), or total homocysteine (776CG, P = 0.11; 776GG, P = 0.33) even after adjustment for several possible confounders.ConclusionWe conclude from this largest study on the subject thus far that there are no associations between allelic variants of TCN2 776C>G and plasma vitamin B12, folate, or total homocysteine plasma levels in kidney transplant patients

Associations between MTHFR 1793G>A and plasma total homocysteine, folate, and vitamin B12 in kidney transplant recipients

Associations between MTHFR 1793G>A and plasma total homocysteine, folate, and vitamin B12 in kidney transplant recipients.BackgroundCurrently, no evidence is available on the putative associations between a novel single nucleotide polymorphism of the 5,10-methylenetetrahydrofolate reductase gene MTHFR 1793G>A and plasma levels of vitamin B12, folate, or total homocysteine (tHcy).MethodsIn a cross-sectional study of 730 kidney allograft recipients, patients were categorized by MTHFR 1793G>A genotype. In univariate and multivariate linear regression models that allowed the outcome variables vitamin B12, folate, and tHcy plasma levels to follow a gamma distribution, we tested for possible associations of allelic variants of MTHFR 1793G>A and these three dependent variables. As hypothesized in previous work, we specifically evaluated possible effect modification between the MTHFR 1793G>A and 1298A>C mutations on these outcomes.ResultsThe allele frequency for MTHFR 1793G>A was 0.052. Heterozygosity (N = 72) or homozygosity (N = 2) for MTHFR 1793G>A was not independently associated with plasma levels of vitamin B12 (P = 0.33) or tHcy (P = 0.70), but a borderline association with higher folate concentrations was detected (Δfolate = 1.91 nmol/L) (95% CI -0.03 to 3.86 nmol/L) (P = 0.05). Further, we found strong and significant positive interactions between the MTHFR 1793G>A and 1298A>C mutations on vitamin B12 concentrations.ConclusionHigher folate concentrations in kidney transplant recipients with MTHFR 1793GA or 1793AA and markedly higher concentrations of vitamin B12 in patients with combined MTHFR 1793G>A and 1298A>C mutations may contribute to the survival advantage that has been postulated for such patients showing these genotypes

Erythropoiesis-stimulating Agent Use among Patients with Lupus Nephritis Approaching End-stage Renal Disease

Objectives: Little is known about erythropoiesis-stimulating agents (ESAs) utilization among lupus nephritis (LN) patients with incipient ESRD. We aimed to identify sociodemographic and clinical factors associated with ESA use among incident LN ESRD patients. Methods: Among all individuals age ≥18 with incident ESRD from 1995-2008 in the U.S. Renal Data System (USRDS), we identified those with systemic lupus erythematosus (ICD-9 code 710.0) as the cause of ESRD. ESA use at ESRD onset was ascertained from the Medical Evidence Report. Year of onset, age, sex, race/ethnicity, medical insurance, employment status, residential region, clinical factors and comorbidities were considered potentially associated with ESA use in multivariable-adjusted logistic regression analyses. Results: We identified 12,533 individuals with incident LN ESRD (1% of entire population). Of those, 4,288 (34%) received an ESA preceding ESRD. In multivariable-adjusted models, ESA users had higher serum albumin and hemoglobin concentrations, were more likely to be women, and to live in the Northeast. Conversely, Medicaid beneficiaries, the uninsured, unemployed, African Americans, Hispanics, and those with IV drug use, congestive heart failure and obesity had lower ESA use. Conclusion: Among all U.S. patients and those with LN who developed ESRD, approximately one third received ESAs. Patient sex, race, age, medical insurance, residential region and clinical factors were significantly associated with ESA therapy. While there are no guidelines for ESA use in LN patients approaching ESRD, there has been wide sociodemographic variation, raising questions about ESA prescription practices

The Effect of Altitude Change on Anemia Treatment Response in Hemodialysis Patients

Hemodialysis patients who live at high altitude use less exogenous erythropoietin but achieve higher hematocrit levels than those living at a lower altitude. The authors hypothesized that the effect of altitude would be strongest in hemodialysis patients with poor anemia treatment response. To explore this hypothesis, they studied anemia-related outcomes in US hemodialysis patients who move to higher altitudes. Using Medicare and US Geological Survey data, in 1992–2004 they identified instances in which a patient moved from a dialysis center at an altitude of <2,000 feet (600 m) to one at a higher elevation. Of these moves, 5,274 were ≥3,000 feet (900 m; the altitude group) and 25,345 were 250–500 feet (75–150 m; the control group). Among patients with poor treatment response at baseline, large increases in hematocrit and decreases in erythropoietin dosing were observed in the altitude relative to the control group. At 6 months, hematocrit had increased more in the altitude group (5.1%, 95% confidence interval (CI): 4.1, 6.2 vs. 3.7%, 95% CI: 3.5, 3.9), and erythropoietin dosing decreased more (4,600 units/week, 95% CI: 500, 8,700 vs. 1,700 units/week, 95% CI: 1,000, 2,400). No effect of altitude was observed in patients with better treatment response at baseline. These results support the hypothesis that altitude-induced hypoxia reduces erythropoietin requirements in hemodialysis patients with treatment-refractory anemia

Trends in Anemia Care in Older Patients Approaching End-Stage Renal Disease in the United States (1995-2010)

Anemia is common in patients with advanced chronic kidney disease. While the treatment of anemia in patients with end-stage renal disease (ESRD) has attracted considerable attention, relatively little is known about patterns and trends in the anemia care received by patients before initiating maintenance dialysis or pre-emptive kidney transplantation

The Comparative Short-term Effectiveness of Iron Dosing and Formulations in US Hemodialysis Patients

Intravenous iron is used widely in hemodialysis, yet there are limited data on the effectiveness of contemporary dosing strategies or formulation type