A pharmacogenetic versus a clinical algorithm for warfarin dosing.

BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

Low Vision Rehabilitation for Adult African Americans in Two Settings.

PURPOSE: The Vision Rehabilitation for African Americans with Central Vision Impairment (VISRAC) study is a demonstration project evaluating how modifications in vision rehabilitation can improve the use of functional vision. METHODS: Fifty-five African Americans 40 years of age and older with central vision impairment were randomly assigned to receive either clinic-based (CB) or home-based (HB) low vision rehabilitation services. Forty-eight subjects completed the study. The primary outcome was the change in functional vision in activities of daily living, as assessed with the Veteran's Administration Low-Vision Visual Function Questionnaire (VFQ-48). This included scores for overall visual ability and visual ability domains (reading, mobility, visual information processing, and visual motor skills). Each score was normalized into logit estimates by Rasch analysis. Linear regression models were used to compare the difference in the total score and each domain score between the two intervention groups. The significance level for each comparison was set at 0.05. RESULTS: Both CB and HB groups showed significant improvement in overall visual ability at the final visit compared with baseline. The CB group showed greater improvement than the HB group (mean of 1.28 vs. 0.87 logits change), though the group difference is not significant (p = 0.057). The CB group visual motor skills score showed significant improvement over the HB group score (mean of 3.30 vs. 1.34 logits change, p = 0.044). The differences in improvement of the reading and visual information processing scores were not significant (p = 0.054 and p = 0.509) between groups. Neither group had significant improvement in the mobility score, which was not part of the rehabilitation program. CONCLUSIONS: Vision rehabilitation is effective for this study population regardless of location. Possible reasons why the CB group performed better than the HB group include a number of psychosocial factors as well as the more standardized distraction-free work environment within the clinic setting.

Prematurity and respiratory outcomes program (PROP): study protocol of a prospective multicenter study of respiratory outcomes of preterm infants in the United States.

BACKGROUND: With improved survival rates, short- and long-term respiratory complications of premature birth are increasing, adding significantly to financial and health burdens in the United States. In response, in May 2010, the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) funded a 5-year $18.5 million research initiative to ultimately improve strategies for managing the respiratory complications of preterm and low birth weight infants. Using a collaborative, multi-disciplinary structure, the resulting Prematurity and Respiratory Outcomes Program (PROP) seeks to understand factors that correlate with future risk for respiratory morbidity. METHODS/DESIGN: The PROP is an observational prospective cohort study performed by a consortium of six clinical centers (incorporating tertiary neonatal intensive care units [NICU] at 13 sites) and a data-coordinating center working in collaboration with the NHLBI. Each clinical center contributes subjects to the study, enrolling infants with gestational ages 23 0/7 to 28 6/7 weeks with an anticipated target of 750 survivors at 36 weeks post-menstrual age. In addition, each center brings specific areas of scientific focus to the Program. The primary study hypothesis is that in survivors of extreme prematurity specific biologic, physiologic and clinical data predicts respiratory morbidity between discharge and 1 year corrected age. Analytic statistical methodology includes model-based and non-model-based analyses, descriptive analyses and generalized linear mixed models. DISCUSSION: PROP incorporates aspects of NICU care to develop objective biomarkers and outcome measures of respiratory morbidity in the <29 week gestation population beyond just the NICU hospitalization, thereby leading to novel understanding of the nature and natural history of neonatal lung disease and of potential mechanistic and therapeutic targets in at-risk subjects. TRIAL REGISTRATION: Clinical Trials.gov NCT01435187.

Factors associated with a willingness to accept rapid HIV testing in an urban emergency department.

Emergency Departments (EDs) provide primary healthcare to many underserved persons without access to preventive healthcare elsewhere. We conducted a cross-sectional study to test the hypothesis that patients are more likely to express a willingness to accept rapid HIV testing in the ED if they lack access to preventive healthcare elsewhere. Medicaid insurance, younger age, lack of a usual place of healthcare, high perceived HIV risk, and actual HIV risk were associated with increased HIV test acceptance. These results support the need for and acceptability of rapid HIV testing in the ED particularly for individuals who may lack access to this preventive healthcare screening elsewhere.

Rationale and design of the Clarification of Optimal Anticoagulation through Genetics trial.

BACKGROUND: Current dosing practices for warfarin are empiric and result in the need for frequent dose changes as the international normalized ratio gets too high or too low. As a result, patients are put at increased risk for thromboembolism, bleeding, and premature discontinuation of anticoagulation therapy. Prior research has identified clinical and genetic factors that can alter warfarin dose requirements, but few randomized clinical trials have examined the utility of using clinical and genetic information to improve anticoagulation control or clinical outcomes among a large, diverse group of patients initiating warfarin. METHODS: The COAG trial is a multicenter, double-blind, randomized trial comparing 2 approaches to guiding warfarin therapy initiation: initiation of warfarin therapy based on algorithms using clinical information plus an individual's genotype using genes known to influence warfarin response ("genotype-guided dosing") versus only clinical information ("clinical-guided dosing") (www.clinicaltrials.gov Identifier: NCT00839657). RESULTS: The COAG trial design is described. The study hypothesis is that, among 1,022 enrolled patients, genotype-guided dosing relative to clinical-guided dosing during the initial dosing period will increase the percentage of time that patients spend in the therapeutic international normalized ratio range in the first 4 weeks of therapy. CONCLUSION: The COAG will determine if genetic information provides added benefit above and beyond clinical information alone.

The association of cerebral palsy with birth asphyxia: a definitional quagmire.

AIM: The aim of this study was to investigate whether current literature provides a useful body of evidence reflecting the proportion of cerebral palsy (CP) that is attributable to birth asphyxia. METHOD: We identified 23 studies conducted between 1986 and 2010 that provided data on intrapartum risks of CP. RESULTS: The proportion of CP with birth asphyxia as a precursor (case exposure rate) varied from less than 3% to over 50% in the 23 studies reviewed. The studies were heterogeneous in many regards, including the definitions for birth asphyxia and the outcome of CP. INTERPRETATIONS: Current data do not support the belief, widely held in the medical and legal communities, that birth asphyxia can be recognized reliably and specifically, or that much of CP is due to birth asphyxia. The very high case exposure rates linking birth asphyxia to CP can probably be attributed to several factors: the fact that the clinical picture at birth cannot specifically identify birth asphyxia; the definition of CP employed; and confusion of proximal effects - results - with causes. Further research is needed.

Association between efavirenz-based compared with nevirapine-based antiretroviral regimens and virological failure in HIV-infected children.

IMPORTANCE: Worldwide, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with human immunodeficiency virus (HIV) infection. Data on the comparative effectiveness of these medications in children are limited. OBJECTIVE: To investigate whether virological failure is more likely among children who initiated 1 or the other NNRTI-based HIV treatment. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of children (aged 3-16 years) who initiated efavirenz-based (n = 421) or nevirapine-based (n = 383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana. MAIN OUTCOMES AND MEASURES: The primary outcome was time from initiation of therapy to virological failure. Virological failure was defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression. Cox proportional hazards regression analysis compared time to virological failure by regimen. Multivariable Cox regression controlled for age, sex, baseline immunologic category, baseline clinical category, baseline viral load, nutritional status, NRTIs used, receipt of single-dose nevirapine, and treatment for tuberculosis. RESULTS: With a median follow-up time of 69 months (range, 6-112 months; interquartile range, 23-87 months), 57 children (13.5%; 95% CI, 10.4%-17.2%) initiating treatment with efavirenz and 101 children (26.4%; 95% CI, 22.0%-31.1%) initiating treatment with nevirapine had virological failure. There were 11 children (2.6%; 95% CI, 1.3%-4.6%) receiving efavirenz and 20 children (5.2%; 95% CI, 3.2%-7.9%) receiving nevirapine who never achieved virological suppression. The Cox proportional hazard ratio for the combined virological failure end point was 2.0 (95% CI, 1.4-2.7; log rank P < .001, favoring efavirenz). None of the measured covariates affected the estimated hazard ratio in the multivariable analyses. CONCLUSIONS AND RELEVANCE: Among children aged 3 to 16 years infected with HIV and treated at a clinic in Botswana, the use of efavirenz compared with nevirapine as initial antiretroviral treatment was associated with less virological failure. These findings may warrant additional research evaluating the use of efavirenz and nevirapine for pediatric patients.

Concurrent validity and reliability of retrospective scoring of the Pediatric National Institutes of Health Stroke Scale.

BACKGROUND AND PURPOSE: The Pediatric National Institutes of Health Stroke Scale (PedNIHSS), an adaptation of the adult National Institutes of Health Stroke Scale, is a quantitative measure of stroke severity shown to be reliable when scored prospectively. The ability to calculate the PedNIHSS score retrospectively would be invaluable in the conduct of observational pediatric stroke studies. The study objective was to assess the concurrent validity and reliability of estimating the PedNIHSS score retrospectively from medical records. METHODS: Neurological examinations from medical records of 75 children enrolled in a prospective PedNIHSS validation study were photocopied. Four neurologists of varying training levels blinded to the prospective PedNIHSS scores reviewed the records and retrospectively assigned PedNIHSS scores. Retrospective scores were compared among raters and to the prospective scores. RESULTS: Total retrospective PedNIHSS scores correlated highly with total prospective scores (R(2)=0.76). Interrater reliability for the total scores was "excellent" (intraclass correlation coefficient, 0.95; 95% CI, 0.94-0.97). Interrater reliability for individual test items was "substantial" or "excellent" for 14 of 15 items. CONCLUSIONS: The PedNIHSS score can be scored retrospectively from medical records with a high degree of concurrent validity and reliability. This tool can be used to improve the quality of retrospective pediatric stroke studies.

Infusion of statistical science in comparative effectiveness research.

PURPOSE: We present a general introduction to comparative effectiveness research (CER) from a statistician's viewpoint and focus on how statisticians can contribute to the methodology of CER. CONCLUSIONS: The statistical science community needs to determine the priorities for methodological research in CER, in collaboration with our colleagues in the aligned medical fields. CER requires that we apply a new paradigm - a focus on the patient. The emphasis on the patient is driven by patients themselves, the federal government, and private payers, in addition to the fact that there is a rising chronic disease burden that is making patient populations more heterogeneous. The availability of new technology and data sources introduces not only complexity but also opportunity. Statistical scientists should rise to meet these new demands and develop optimal, statistically valid approaches to CER, just as they have in agriculture and clinical trials.

Exogenous estrogen does not attenuate the association between rofecoxib and myocardial infarction in perimenopausal women.

Rofecoxib has been proposed to increase the risk of myocardial infarction (MI) through suppression of cyclooxygenase 2­mediated prostacyclin. Estrogen may have protective effects through augmenting cyclooxygenase 2 expression and subsequently increasing prostacyclin. Estrogen may attenuate the association between rofecoxib and MI. We used 1999­2002 Medicaid claims data to measure the MI hazard ratio (HR) attributed to rofecoxib exposure in estrogen-exposed and unexposed 45- to 65-year-old women.We identified 184,169 female rofecoxib users who contributed 309,504 person-years and experienced 1217 first MIs. Estrogen exposure seemed protective [MI-HR 0.72; 95% confidence interval (CI), 0.62­0.84] in this cohort. Rofecoxib was associated with an elevated MI-HR in both estrogen-exposed (2.01; 95% CI, 1.60­2.54) and estrogen-unexposed women (1.69; 95% CI, 1.43­1.99). The rofecoxib­estrogen interaction ratio was not significantly different from 1 (1.19; 95% CI, 0.91­1.57). Although estrogen use was associated with a lower risk of MI, it did not seem to attenuate the association between rofecoxib and MI.

The National Children's Study (NCS): establishment and protection of the inferential base.

The National Children's Study (NCS) is a unique study of environment and health that will follow a cohort of 100 000 women from prior to or early in pregnancy and then their children until 21 years of age. The NCS cohort will be a national multi-stage probability sample, using a U.S. Census Bureau geographic sampling frame unrelated to factors that might influence selection into the sample (e.g. access to health care). I present the case for the use of a national probability sample as the design base for the NCS, arguing that selection of the original cohort should be as free from selection bias as possible. The dangers of using a selected or nonprobability sample approach are demonstrated by an example of its use in outlining the clinical management of children with febrile seizures, an infrequent disorder, which was so wrong for decades. In addition, I stress the importance of and the NCS approach to avoiding selection bias that might occur after the initial selection of the cohort. The selection of and maintenance of an unselected cohort is an important element for the validity of inferences in this major undertaking.

Prospective alpha allocation in the Clarification of Optimal Anticoagulation through Genetics (COAG) trial.

BACKGROUND: The Clarification of Optimal Anticoagulation through Genetics (COAG) trial is a large, multicenter, double-blinded, randomized trial to determine whether use of a genotype-guided dosing algorithm (using clinical and genetic information) to initiate warfarin treatment will improve anticoagulation status when compared to a dosing algorithm using only clinical information. PURPOSE: This article describes prospective alpha allocation and balanced alpha allocation for the design of the COAG trial. METHODS: The trial involves two possibly heterogeneous populations, which can be distinguished by the difference in warfarin dose as predicted by the two algorithms. A statistical approach is detailed, which allows an overall comparison as well as a comparison of the primary endpoint in the subgroup for which sufficiently different doses are predicted by the two algorithms. Methods of allocating alpha for these analyses are given - a prospective alpha allocation and allocating alpha so that the two analyses have equal power, which we call a 'balanced alpha allocation.' RESULTS: We show how to include an analysis of the primary endpoint in a subgroup as a co-primary analysis. Power can be improved by incorporating the correlation between the overall and subgroup analyses in a prospective alpha allocation approach. Balanced alpha allocation for the full cohort and subgroup tests to achieve the same desired power for both of the primary analyses is discussed in detail. LIMITATIONS: In the COAG trial, it is impractical to stratify the randomization on subgroup membership because genetic information may not be available at the time of randomization. If imbalances in the treatment arms in the subgroup are found, they will need to be addressed. CONCLUSIONS: The design of the COAG trial assures that the subgroup in which the largest treatment difference is expected is elevated to a co-primary analysis. Incorporating the correlation between the full cohort and the subgroup analyses provides an improvement in power for the subgroup comparison, and further improvement may be achieved via a balanced alpha allocation approach when the parameters involved in the sample size calculation are reasonably well estimated.