Stacey Knight

A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)

Background— Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager. Methods and Results— A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios ≥4 and ⩽1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance. Conclusions— These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.

Epidemiology of a pediatric emergency medicine research network: the PECARN Core Data Project.

Objective: To examine the epidemiology of pediatric patient visits to emergency departments (ED). Methods: We conducted a cross-sectional study of pediatric ED visits at the participating Pediatric Emergency Care Applied Research Network (PECARN) hospitals in 2002. We provide descriptive characteristics of pediatric ED visits and a comparison of the study database to the National Hospital Ambulatory Medical Care Survey (NHAMCS). Bivariate analyses were calculated to assess characteristics associated with hospital admission, death in the ED, and length of ED visit. We also performed multivariate regression to model the likelihood of admission to the hospital. Results: Mean patient age was 6.2 years; 53.5% were boys; 47.5% black; and 43.2% had Medicaid insurance. The most common ED diagnoses were fever, upper respiratory infection, asthma, otitis media, and viral syndromes. The inpatient admission rate was 11.6%. The most common diagnoses requiring hospitalization were asthma, dehydration, fever, bronchiolitis, and pneumonia. In multivariate analysis, patients who were black or Hispanic, had Medicaid insurance or were uninsured, or were older than 1 year were less likely to be hospitalized. Demographics of the PECARN population were similar to NHAMCS, with notable exceptions of a larger proportion of black patients and of admitted patients from the PECARN EDs. Conclusion: We describe previously unavailable epidemiological information about childhood illnesses and injuries that can inform development of future studies on the effectiveness, outcomes, and quality of emergency medical services for children. Most pediatric ED patients in our study sought care for infectious causes or asthma and were discharged from the ED. Hospital admission rate differed according to age, payer type, race/ethnicity, and diagnosis.

HDL cholesterol subclasses, myocardial infarction, and mortality in secondary prevention: the lipoprotein investigators collaborative

AIMS High-density lipoprotein (HDL) is highly heterogeneous and the link of its subclasses to prognosis remains controversial. We aimed to rigorously examine the associations of HDL subclasses with prognosis in secondary prevention. METHODS AND RESULTS We collaboratively analysed data from two, complementary prospective cohorts: the TRIUMPH study of 2465 acute myocardial infarction patients, and the IHCS study of 2414 patients who underwent coronary angiography. All patients had baseline HDL subclassification by vertical-spin density gradient ultracentrifugation. Given non-linearity, we stratified by tertiles of HDL-C and its two major subclasses (HDL2-C, HDL3-C), then compared multivariable-adjusted hazard ratios for mortality and mortality/myocardial infarction. Patients were middle-aged to elderly (TRIUMPH: 58.2 ± 12.2 years; IHCS: 62.6 ± 12.6 years), and the majority were men (TRIUMPH: 68.0%; IHCS: 65.5%). IHCS had lower mean HDL-C levels (34.6 ± 10.1 mg/dL) compared with TRIUMPH (40 ± 10.6 mg/dL). HDL3-C accounted for >3/4 of HDL-C (mean HDL3-C/HDL-C 0.78 ± 0.05 in both cohorts). During 2 years of follow-up in TRIUMPH, 226 (9.2%) deaths occurred, while death/myocardial infarction occurred in 401 (16.6%) IHCS patients over 5 years. No independent associations with outcomes were observed for HDL-C or HDL2-C. In contrast, the lowest tertile of HDL3-C was independently associated with >50% higher risk in each cohort (TRIUMPH: with middle tertile as reference, fully adjusted HR for mortality of HDL3-C, 1.57; 95% CI, 1.13-2.18; IHCS: fully adjusted HR for mortality/myocardial infarction, 1.55; 95% CI, 1.20-2.00). CONCLUSION In secondary prevention, increased risk for long-term hard clinical events is associated with low HDL3-C, but not HDL2-C or HDL-C, highlighting the potential value of subclassifying HDL-C.

Motor vehicle crash characteristics and medical outcomes among older drivers in Utah, 1992-1995

STUDY OBJECTIVE We sought to compare the characteristics and medical outcomes of motor vehicle crashes for drivers 70 years and older with those of drivers between the ages of 30 and 39 years. METHODS We probabilistically linked statewide motor vehicle crash and hospital discharge data between the years of 1992 and 1995 for the state of Utah. We calculated the odds of older drivers exhibiting certain motor vehicle crash characteristics compared with younger drivers. Adjusting for nighttime crash, high-speed crash, and seatbelt use, we calculated the odds of an older driver being killed or hospitalized compared with those of a younger driver. RESULTS During the study years, there were 14,466 drivers older than 69 years and 68,706 drivers between the ages of 30 and 39 years involved in motor vehicle crashes in Utah. Older drivers were less likely to have crashes involving drug or alcohol use (odds ratio [OR] 0.1; 95% confidence interval [CI] 0.1 to 0.2) and less likely to have crashes at high speed (OR 0.6; 95% CI 0.6 to 0.7). Although older drivers were no more likely to have a crash involving a right-hand turn (OR 1.0; 95% CI 0.9 to 1.1) than younger drivers, they were over twice as likely to have a crash involving a left-hand turn (OR 2.3; 95% CI 2.2 to 2.5). Also, older drivers were more likely to be killed or hospitalized than younger drivers (OR, 3.5; P <.001). Among belted drivers, an older driver was nearly 7 times more likely to be killed or hospitalized than a younger driver (OR 6. 9; 95% CI 5.4 to 8.9). CONCLUSION Older drivers do have distinctive motor vehicle crash patterns. Interventions must be taken to reduce the number of left-hand turn crashes involving older drivers. In addition, further research is needed to design, implement, and evaluate countermeasures that may enable older drivers to continue driving while keeping public safety in the forefront.

Prediction of child abuse risk from emergency department use.

OBJECTIVE To examine whether pre-abuse rates and patterns of emergency department (ED) visits between children with supported child abuse and age-matched control subjects are useful markers for abuse risk. STUDY DESIGN A population-based case-control study using probabilistic linkage of four statewide data sets. Cases were abused children <13 years of age, identified between January 1, 2002, and December 31, 2002. For each case, a birth date-matched, population-based control was obtained. Outcome measures were rate ratios of ED visits in cases compared with control subjects. RESULTS Cases (n = 9795) and control subjects (n = 9795) met inclusion criteria; 4574 cases (47%) had an ED visit; thus linked to the ED database versus 2647 control subjects (27%). The crude ED visit rate per 10,000 person-days of exposure was 8.2 visits for cases compared with 3.9 visits for control subjects. Cases were almost twice as likely as control subjects (adjusted rate ratio = 1.8; 95% CI, 1.5, 1.8) to have had a prior ED visit. Leading ED discharge diagnoses were similar for both groups. CONCLUSIONS Children with supported child abuse have higher ED use before abuse diagnosis, when compared with the general pediatric population. However, neither the rate of ED use nor the pattern of diagnoses offers sufficient specificity to be useful markers of risk for abuse.

Health insurance, neighborhood income, and emergency department usage by Utah children 1996–1998

BackgroundIt is estimated that approximately half of emergency department (ED) usage in the U.S. and other developed countries is for non-urgent conditions and that this usage is related to availability, social, and economic factors. We examined pediatric ED usage in a U.S. state with respect to income, health insurance status, types of medical conditions, and whether introduction of managed care affected utilization by Medicaid children.MethodsEmergency department usage rates were calculated from 1996 through 1998 using Utah ED data for children with commercial health insurance, Medicaid, for uninsured children, and by income group estimating neighborhood household income from Zip code of residence. We analyzed usage following the July 1996 transition of Utah Medicaid to managed care.ResultsChildren with Medicaid had approximately 50% greater ED utilization rates than children with commercial health insurance or uninsured children. The majority of usage for Medicaid and uninsured children was for non-traumatic conditions. Only 35% of total ED usage was for non-emergent or non-urgent conditions and this was related to both Medicaid and low household income. Children lacking health insurance were more likely to be discharged against medical advice (OR = 2.36, 95% C.I. 1.88–2.96). There was no reduction in Medicaid ED usage following the transition to managed care.ConclusionUsage of ED services is related to both health insurance status and income. Children lacking health insurance and Medicaid children have excessive usage for conditions which could be treated in a primary care setting. That managed care does not reduce Medicaid ED usage is consistent with findings of other studies.

Re: Red cell distribution width is predictive of mortality in trauma patients.

BACKGROUND Red blood cell distribution width (RDW) is a component of the complete blood count (CBC) that is traditionally used to identify iron-deficiency anemia. RDW has been shown to predict mortality in patients with multiple different medical conditions and in general populations. It is unknown whether RDW predicts outcomes in trauma patients. This study tested whether RDW predicts mortality in a trauma population at a Level I trauma center. METHODS Trauma patients with a CBC from October 2005 to December 2011 were evaluated. Sex-specific 30-day and 1-year all-cause mortality and RDW were studied using Cox regression adjusted for age, Injury Severity Score (ISS), hospital length of stay, blunt versus penetrating trauma, and other CBC parameters. RESULTS A total of 3,637 females and 5,901 males were evaluated at 30 days and 1 year. With full adjustment, RDW predicted 30-day mortality in males (for RDW quintiles 1–5: 2.2%, 1.8%, 3.6%, 4.8%, 10.1%, respectively; p < 0.001) but not in females (3.4%, 1.9%, 3.0%, 3.9%, 6.2%; p = 0.036). At 1 year, RDW predicted mortality in both males (p < 0.001; 0.5%, 0.4%, 0.8%, 1.7%, and 8.3%) and females (p < 0.001; 0.5%, 2.1%, 3.0%, 4.2%, and 8.8%). Receiver operating characteristic analysis found c = 0.705 in males and c = 0.625 in females at 30 days and c = 0.820 in males and c = 0.723 in females at 1 year. CONCLUSION RDW independently predicted mortality in trauma patients at this single Level I trauma center. RDW may reveal underlying health status and be clinically useful for prognostication. The mechanistic relationship between RDW and mortality in trauma remains unknown and should be further evaluated. LEVEL OF EVIDENCE Prognostic and epidemiological study, level III.

Against all advice: An analysis of out-of-hospital refusals of care

STUDY OBJECTIVE We examine the characteristics of patients involved in out-of-hospital emergency medical services (EMS) incidents that result in refusal of care and determine the rates of subsequent EMS, emergency department (ED), and inpatient care, as well as death within 7 days. METHODS Utah statewide EMS data identifying refusals of care were probabilistically linked to Utah statewide ED, inpatient, and death certificate data within 7 days of the initial EMS refusals for 1996 to 1998. Refusals were defined as incidents in which field treatment or transport was refused and did not include incidents in which EMS providers deemed care or transport unnecessary. RESULTS Of 277244 EMS incidents, 14109 (5.1%) resulted in refusals of care. For all age groups, motor vehicle crash dispatches resulted in the highest rate of refusal of care, ranging from 8.0% to 11.7%. Slightly more than 3% of patients involved in a refusal of care incident had a subsequent EMS dispatch within a week. One fifth of the patients involved in EMS refusals of care had a subsequent ED visit. Less than 2% of the EMS refusal patients were hospitalized; hospitalization was highest among children younger than 3 years and adults older than 64 years. Twenty-five adults died within a week of refusing EMS care, of whom 19 (76.0%) were older than 64 years. CONCLUSION Refusal of care incidents are a small segment of all EMS incidents. They arise from a variety of situations, and the risk for missed intervention may be minimal.

Linkage Analysis of Tourette Syndrome in a Large Utah Pedigree

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple motor and phonic tics. The heritability of TS has been well established, yet there is a lack of consensus in genome‐wide linkage studies. The purpose of this study was to conduct a genome‐wide linkage analysis on a unique, large, high‐risk TS Utah pedigree. We examined a qualitative trait (TS1) where cases had a definitive diagnosis of TS as observed by a clinical interviewer (n = 66) and a quantitative phenotype based on the total Yale global motor and phonic tic severity scores (n = 102). Both parametric and non‐parametric multipoint linkage analyses based on MCMC methods were performed using a 10 cM spaced micro‐satellite autosomal marker set. Two regions of interest were identified under affecteds‐only recessive models; a LOD score of 3.3 on chromosome 1p for Yale tic severity and a LOD score of 3.1 on chromosome 3p for the TS1 phenotype. Twenty‐seven individuals shared linked segregating haplotypes for the 1p region. They had significantly higher Yale tic phonic scores than non‐sharers (P = 0.01). There were 46 haplotype sharers on chromosome 3p with significantly higher percentage of females among these individuals compared to the non‐sharers (P = 0.03). The significant linkage peaks on chromosomes 1p and 3p are in new areas of the genome for TS, and replication of these findings is necessary.

Evaluation of genetic risk scores for lipid levels using genome-wide markers in the Framingham Heart Study

BackgroundMultiple single-nucleotide polymorphisms have been associated with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels. In this paper, we evaluate a weighted and an unweighted approach for estimating the combined effect of multiple markers (using genotypes and haplotypes) on lipid levels for a given individual.MethodsUsing data from the Framingham Heart Study SHARe genome-wide association study, we tested genome-wide genotypes and haplotypes for association with lipid levels and constructed genetic risk scores (GRS) based on multiple markers that were weighted according to their estimated effects on LDL-C, HDL-C, and TG. These scores (GRS-LDL, GRS-HDL, and GRS-TG) were then evaluated for associations with LDL-C, HDL-C, and TG, and compared with results of an unweighted method based on risk-allele counts. For comparability of metrics, GRS variables were divided into quartiles.ResultsGRS-LDL quartiles were associated with LDL-C levels (p = 2.1 × 10-24), GRS-HDL quartiles with HDL-C (p = 5.9 × 10-22), and GRS-TG quartiles with TG (p = 5.4 × 10-25). In comparison, these p-values were considerably lower than those for the associations of the unweighted GRS quartiles for LDL-C (p = 3.6 × 10-7), HDL-C (p = 6.4 × 10-16), and TG (p = 4.1 × 10-10).ConclusionGRS variables were highly predictive of LDL-C, HDL-C, and TG measurements, especially when weighted based on each markers individual association with those intermediate risk phenotypes. The allele-count GRS approach that does not weight the GRS by individual marker associations was considerably less predictive of lipid and lipoprotein measures when the same genetic markers were utilized, suggesting that substantially more risk-associated genetic marker information is encapsulated by the weighted GRS variables.