Christopher S Coffey

University of Iowa, Iowa City, Iowa, United States

Are you Christopher S Coffey?

Claim your profile

Publications (97)489.81 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Interventional Management of Stroke (IMS) III is a randomized, parallel arm trial comparing the approach of intravenous tissue plasminogen activator followed by endovascular treatment with intravenous tissue plasminogen activator alone in patients with acute ischemic stroke presenting <3 hours of symptom onset. The trial intended to enroll 900 subjects to ensure adequate statistical power to detect an absolute 10% difference in the percentage of subjects with good outcome, defined as modified Rankin Scale score of 0 to 2 at 3 months. In April 2012, after 656 subjects were randomized, further enrollment was terminated by the National Institute of Neurological Disorders and Stroke based on the prespecified criterion for futility using conditional power <20%. Conditional power was defined as the likelihood of finding statistical significance at the end of the study, given the accumulated data to date and with the assumption that a minimum hypothesized difference of 10% truly exists between the 2 groups. The evolution of study data leading to futility determination is described, including the interaction between the unblinded study statisticians and the Data and Safety Monitoring Board in the complex deliberation of analysis results. The futility boundary was crossed at the trial's fourth interim analysis. At this point, based on the conditional power criteria, the Data and Safety Monitoring Board recommended termination of the trial. Even in spite of prespecified interim analysis boundaries, interim looks at data pose challenges in interpretation and decision making, underscoring the importance of objective stopping criteria. http://www.clinicaltrials.gov. Unique identifier: NCT00359424.
    Stroke 04/2014; · 6.16 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.
    Journal of the American Society for Experimental NeuroTherapeutics 11/2013; · 5.38 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: BACKGROUND: Studies have demonstrated that physician/pharmacist collaboration can improve management of chronic conditions. OBJECTIVE: The purpose of this study was to determine whether a correlation exists between existing clinical pharmacy services within a practice-based research network (PBRN) and provider attitudes and beliefs regarding implementing a new pharmacy intervention based on the Theory of Planned Behavior (TPB). METHODS: A validated survey was completed by one clinical pharmacist from each office. This instrument evaluated the current clinical pharmacy services provided in the medical office. TPB instruments were developed that measured beliefs concerning implementation of a clinical pharmacy intervention for either blood pressure or asthma. The pharmacy services and TPB surveys were then administered to physicians and pharmacists in 32 primary care offices throughout the United States. RESULTS: Physicians returned 321 (35.9%) surveys, while pharmacists returned 40 (75.5%). The Cronbach's alpha coefficients generally ranged from 0.65 to 0.98. TPB subscale scores were lower in offices rated with lower pharmacy service scores, but these differences were not statistically significant. There was no correlation between clinical pharmacy service score and providers' TPB subscale scores. In both the hypertension and asthma groups, pharmacists scores were significantly higher than physicians' scores on the attitudes subscale in the multivariate analysis (P < 0.001 and P < 0.05, respectively). CONCLUSIONS: Pharmacists consistently scored higher than physicians on the TPB, indicating that they felt the hypertension or asthma intervention would be more straightforward for them to implement than did physicians. There was no significant correlation between clinical pharmacy service scores and attitudes toward implementing a future physician/pharmacist collaborative intervention using the TPB. Future studies should investigate the ability of the TPB instrument to predict implementation of a similar intervention in offices of physicians never exposed to clinical pharmacy services.
    Research in Social and Administrative Pharmacy 03/2013; · 2.35 Impact Factor
  • Leslie A McClure, Christopher S Coffey, George Howard
    [show abstract] [hide abstract]
    ABSTRACT: BACKGROUND: For studies with two-by-two factorial designs, the complexity of determining an appropriate futility analysis plan is increased as compared to studies where patients are randomized to one treatment. Issues that must be addressed include the possibility of a significant interaction and the need to determine how to proceed given evidence of futility in one arm. Suggested approaches include a two-stage plan, which first assesses futility of the interaction term and proceeds to examine the main effects, given sufficient evidence that no interaction is present, and variations on one-stage plans, which assume the trial will not be stopped for futility in the interaction. PURPOSE: To discuss different approaches to monitoring futility in two-by-two factorial clinical trials and compare their properties. METHODS: We utilized a simulation study, designed to mimic the Secondary Prevention of Small Subcortical Strokes (SPS3) Study, to determine which approach to monitoring futility in two-by-two factorial studies had the most desirable statistical properties. RESULTS: We found that in most scenarios typical of clinical trials, monitoring futility in each arm simultaneously was superior to or as good as monitoring the interaction and then assessing futility in each arm only when the interaction was deemed futile. Monitoring each arm simultaneously lead to early stopping more often when no treatment effect was present, and lower average sample numbers (ASNs). The exception to this was the unlikely case when a qualitative interaction was present. LIMITATIONS: We assumed that one-sided tests were to be performed, and only assessed some of the possible methods for monitoring futility under the study design. CONCLUSIONS: Futility monitoring in two-by-two factorial studies should proceed by assessing each arm simultaneously, rather than monitoring the interaction first. If sizeable interactions are anticipated, study design, rather than study monitoring, should account for this.
    Clinical Trials 02/2013; · 2.20 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. (Funded by the National Institute of Neurological Disorders and Stroke and others; SPS3 ClinicalTrials.gov number, NCT00059306.).
    New England Journal of Medicine 08/2012; 367(9):817-25. · 51.66 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. However, improper adaptations can lead to biased studies. A broad definition of adaptive designs allows for countless variations, which creates confusion as to the statistical validity and practical feasibility of many designs. Determining properties of a particular adaptive design requires careful consideration of the scientific context and statistical assumptions. We first review several adaptive designs that garner the most current interest. We focus on the design principles and research issues that lead to particular designs being appealing or unappealing in particular applications. We separately discuss exploratory and confirmatory stage designs in order to account for the differences in regulatory concerns. We include adaptive seamless designs, which combine stages in a unified approach. We also highlight a number of applied areas, such as comparative effectiveness research, that would benefit from the use of adaptive designs. Finally, we describe a number of current barriers and provide initial suggestions for overcoming them in order to promote wider use of appropriate adaptive designs. Given the breadth of the coverage all mathematical and most implementation details are omitted for the sake of brevity. However, the interested reader will find that we provide current references to focused reviews and original theoretical sources which lead to details of the current state of the art in theory and practice.
    Trials 08/2012; 13(1):145. · 2.21 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Object The authors hypothesized that cooling before evacuation of traumatic intracranial hematomas protects the brain from reperfusion injury and, if so, further hypothesized that hypothermia induction before or soon after craniotomy should be associated with improved outcomes. Methods The National Acute Brain Injury Study: Hypothermia I (NABIS:H I) was a randomized multicenter clinical trial of 392 patients with severe brain injury treated using normothermia or hypothermia for 48 hours with patients reaching 33°C at 8.4 ± 3 hours after injury. The National Acute Brain Injury Study: Hypothermia II (NABIS:H II) was a randomized, multicenter clinical trial of 97 patients with severe brain injury treated with normothermia or hypothermia for 48 hours with patients reaching 35°C within 2.6 ± 1.2 hours and 33°C within 4.4 ± 1.5 hours of injury. Entry and exclusion criteria, management, and outcome measures in the 2 trials were similar. Results In NABIS:H II among the patients with evacuated intracranial hematomas, outcome was poor (severe disability, vegetative state, or death) in 5 of 15 patients in the hypothermia group and in 9 of 13 patients in the normothermia group (relative risk 0.44, 95% CI 0.22-0.88; p = 0.02). All patients randomized to hypothermia reached 35°C within 1.5 hours after surgery start and 33°C within 5.55 hours. Applying these criteria to NABIS:H I, 31 of 54 hypothermia-treated patients reached a temperature of 35°C or lower within 1.5 hours after surgery start time, and the remaining 23 patients reached 35°C at later time points. Outcome was poor in 14 (45%) of 31 patients reaching 35°C within 1.5 hours of surgery, in 14 (61%) of 23 patients reaching 35°C more than 1.5 hours of surgery, and in 35 (60%) of 58 patients in the normothermia group (relative risk 0.74, 95%, CI 0.49-1.13; p = 0.16). A meta-analysis of 46 patients with hematomas in both trials who reached 35°C within 1.5 hours of surgery start showed a significantly reduced rate of poor outcomes (41%) compared with 94 patients treated with hypothermia who did not reach 35°C within that time and patients treated at normothermia (62%, p = 0.009). Conclusions Induction of hypothermia to 35°C before or soon after craniotomy with maintenance at 33°C for 48 hours thereafter may improve outcome of patients with hematomas and severe traumatic brain injury. Clinical trial registration no.: NCT00178711.
    Journal of Neurosurgery 07/2012; 117(4):714-20. · 3.15 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: When planning clinical trials, decisions regarding sample size are often based on educated guesses of parameters, which may in fact prove to be over- or under-estimates. For example, after initiation of the SPS3 study, published data indicated that the recurrent stroke rates might be lower than initially planned for the study. Failure to account for this could result in an under-powered study. Thus, we performed a sample size re-estimation, and describe the experience herein. We evaluated different scenarios based on a re-estimated overall event rate, including increasing the sample size and increasing the follow-up time, to determine their impact on both type I error and the power to detect the initially planned treatment difference. We found that by increasing the sample size from 2500 to 3000 and by following the patients for one year after the end of recruitment, we would maintain our planned type I error rate, and increase the power to detect the prespecified clinically meaningful difference to between 67% and 87%, depending on the rate of recruitment. We successfully implemented this unplanned design modification in the SPS3 study, in order to allow for sufficient power to detect the planned treatment differences. CLINICAL TRIALS REGISTRATION INFORMATION: Clinical Trials Registration - http://clinicaltrials.gov/show/NCT00059306. Unique identifier: NCT00059306.
    Contemporary clinical trials 06/2012; 33(5):1088-93. · 1.51 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: This study examined the baseline characteristics, racial/ethnic differences, and geographic differences among participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) study. The SPS3 trial enrolled patients who experienced a symptomatic small subcortical stroke (lacunar stroke) within the previous 6 months and an eligible lesion on detected on magnetic resonance imaging. The patients were randomized, in a factorial design, to antiplatelet therapy (aspirin 325 mg daily plus clopidogrel 75 mg daily vs aspirin 325 mg daily plus placebo) and to one of two levels of systolic blood pressure targets ("intensive" [<130 mmHg] or "usual" [130-149 mmHg]). A total of 3020 participants were recruited from 81 clinical sites in 8 countries. In this cohort, the mean age was 63 years, 63% were men, 75% had a history of hypertension, and 37% had diabetes. The racial distribution was 51% white, 30% Hispanic, and 16% black. Compared with white subjects, black subjects were younger (mean age, 58 years vs 64 years; P <.001) and had a higher prevalence of hypertension (87% vs 70%; P <.001). The prevalence of diabetes was higher in the Hispanic and black subjects compared with the white subjects (42% and 40% vs 32%; both P <.001). Tobacco smoking at the time of qualifying stroke was much more frequent in the Spanish participants than in subjects from North America and from Latin America (32%, 22%, and 9%, respectively; P <.001). Mean systolic blood pressure at study entry was 4 mmHg lower in the Spanish subjects compared with the North American subjects (P <.01). The SPS3 cohort is the largest magnetic resonance imaging-defined series of patients with S3. Among the racially/ethnically diverse SPS3 participants, important differences in patient features and vascular risk factors could influence prognosis for recurrent stroke and response to interventions.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 04/2012;
  • [show abstract] [hide abstract]
    ABSTRACT: Lowering blood pressure for secondary stroke prevention remains a challenge. These analyses were conducted to identify factors predicting achievement of SBP targets in the Secondary Prevention of Small Subcortical Strokes (SPS3) study. SPS3 is a randomized trial assigning patients with lacunar stroke to two targets of SBP control (130-149 mmHg or <130 mmHg). Logistic regression models were used to identify patient and SPS3 site characteristics predictive of lowering SBP to target at the 12-month study visit. Of those above target at baseline (n = 1041), 69% were within their assigned target at 12 months. In the model with baseline characteristics only, those receiving treatment for hypertension at baseline were 68% less likely to achieve target [odds ratio (OR) = 0.32; 95% confidence interval (CI) = 0.17-0.60], whereas those of Hispanic ethnicity were 1.49 times more likely (95% CI = 1.09-2.03) to achieve SBP target. When clinical site characteristics were added to the model, only treated hypertension at baseline remained significant. In addition, management at a larger site (OR = 1.51; 95% CI = 1.03-2.20), SBP in target at 6 months (OR = 2.39; 95% CI = 1.79-3.19), and medication adherence (OR = 2.73; 95% CI = 1.51-4.95) were positively associated with achieving target SBP. Missed appointments (OR = 0.55; 95% CI = 0.41-0.73) were negatively associated with lowering SBP to target at 12 months. These results demonstrate that it is feasible to achieve targets of SBP control in this multiethnic stroke cohort across multiple sites and countries. The results highlight the important variables reflecting clinical site management.
    Journal of hypertension 04/2012; 30(6):1233-40. · 4.02 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The clinical trials community has a never-ending search for dependable and reliable ways to improve clinical research. This exploration has led to considerable interest in adaptive clinical trial designs, which provide the flexibility to adjust trial characteristics on the basis of data reviewed at interim stages. Statisticians and clinical investigators have proposed or implemented a wide variety of adaptations in clinical trials, but specific approaches have met with differing levels of support. Within industry, investigators are actively exploring the benefits and pitfalls associated with adaptive designs (ADs). For example, a Drug Information Association (DIA) working group on ADs has engaged regulatory agencies in discussions. Many researchers working on publicly funded clinical trials, however, are not yet fully engaged in this discussion. We organized the Scientific Advances in Adaptive Clinical Trial Designs Workshop to begin a conversation about using ADs in publicly funded research. Held in November of 2009, the 1&frac12;-day workshop brought together representatives from the National Institutes of Health (NIH), the Food and Drug Administration (FDA), the European Medicines Agency (EMA), the pharmaceutical industry, nonprofit foundations, the patient advocacy community, and academia. The workshop offered a forum for participants to address issues of ADs that arise at the planning, designing, and execution stages of clinical trials, and to hear the perspectives of influential members of the clinical trials community. The participants also set forth recommendations for guiding action to promote the appropriate use of ADs. These recommendations have since been presented, discussed, and vetted in a number of venues including the University of Pennsylvania Conference on Statistical Issues in Clinical Trials and the Society for Clinical Trials annual meeting. To provide a brief overview of ADs, describe the rationale behind conducting the workshop, and summarize the main recommendations that were produced as a result of this workshop. There is a growing interest in the use of adaptive clinical trial designs. However, a number of logistical barriers need to be addressed in order to obtain the potential advantages of an AD. Currently, the pharmaceutical industry is well ahead of academic trialists with respect to addressing these barriers. Academic trialists will need to address important issues such as education, infrastructure, modifications to existing funding models, and the impact on Data and Safety Monitoring Boards (DSMB) in order to achieve the possible benefits of adaptive clinical trial designs.
    Clinical Trials 01/2012; 9(6):671-80. · 2.20 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Small subcortical strokes, also known as lacunar strokes, comprise more than 25% of brain infarcts, and the underlying vasculopathy is the most common cause of vascular cognitive impairment. How to optimally prevent stroke recurrence and cognitive decline in S3 patients is unclear. The aim of the Secondary Prevention of Small Subcortical Strokes study (Trial registration: NCT00059306) is to define strategies for reducing stroke recurrence, cognitive decline, and major vascular events. Secondary Prevention of Small Subcortical Strokes is a randomised, multicentre clinical trial (n = 3000) being conducted in seven countries, and sponsored by the US NINDS/NIH. Patients with symptomatic small subcortical strokes in the six-months before and an eligible lesion on magnetic resonance imaging are simultaneously randomised, in a 2 × 2 factorial design, to antiplatelet therapy--325 mg aspirin daily plus 75 mg clopidogrel daily, vs. 325 mg aspirin daily plus placebo, double-blind--and to one of two levels of systolic blood pressure targets--'intensive' (<130 mmHg) vs. 'usual' (130-149 mmHg). Participants are followed for an average of four-years. Time to recurrent stroke (ischaemic or haemorrhagic) is the primary outcome and will be analysed separately for each intervention. The secondary outcomes are the rate of cognitive decline and major vascular events. The primary and most secondary outcomes are adjudicated centrally by those unaware of treatment assignment. Secondary Prevention of Small Subcortical Strokes will address several important clinical and scientific questions by testing two interventions in patients with recent magnetic resonance imaging-defined lacunar infarcts, which are likely due to small vessel disease. The results will inform the management of millions of patients with this common vascular disorder.
    International Journal of Stroke 04/2011; 6(2):164-75. · 2.75 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2·5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35°C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33°C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1·6 h (SD 0·5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35°C for the 52 patients in the hypothermia group was 2·6 h (SD 1·2) and to 33°C was 4·4 h (1·5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1·08, 95% CI 0·76-1·53; p=0·67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1·30, 95% CI 0·58-2·52; p=0·52). This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury.
    The Lancet Neurology 02/2011; 10(2):131-9. · 23.92 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Background. We used a random sample (n = 2, 495) from the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study population to examine the association of the metabolic syndrome (Met S) with plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) antigen levels. Results. The overall prevalence of the Met S was 18%, was dependent on age and gender, and was positively associated with higher antigen levels of both PAI-1 and t-PA. These significant effects were maintained after adjustment for age, gender, BMI, elevated C-reactive protein, smoking status, urinary albumin excretion, and insulin levels. We found no significant interactions between the Met S and other covariates on PAI-1 and t-PA levels. Conclusions. Our study demonstrates that those with the Met S have significantly higher levels of PAI-1 and t-PA antigen, factors known to increase the risk of cardiovascular disease.
    Cardiology research and practice. 01/2011; 2011:541467.
  • Source
    John A Kairalla, Keith E Muller, Christopher S Coffey
    [show abstract] [hide abstract]
    ABSTRACT: An internal pilot with interim analysis (IPIA) design combines interim power analysis (an internal pilot) with interim data analysis (two stage group sequential). We provide IPIA methods for single df hypotheses within the Gaussian general linear model, including one and two group t tests. The design allows early stopping for efficacy and futility while also re-estimating sample size based on an interim variance estimate. Study planning in small samples requires the exact and computable forms reported here. The formulation gives fast and accurate calculations of power, type I error rate, and expected sample size.
    Communication in Statistics- Theory and Methods 12/2010; 39(20):3717-3738. · 0.30 Impact Factor
  • Matthew J Gurka, Christopher S Coffey, Kelly K Gurka
    [show abstract] [hide abstract]
    ABSTRACT: Study planning often involves selecting an appropriate sample size. Power calculations require specifying an effect size and estimating "nuisance" parameters, e.g. the overall incidence of the outcome. For observational studies, an additional source of randomness must be estimated: the rate of the exposure. A poor estimate of any of these parameters will produce an erroneous sample size. Internal pilot (IP) designs reduce the risk of this error - leading to better resource utilization - by using revised estimates of the nuisance parameters at an interim stage to adjust the final sample size. In the clinical trials setting, where allocation to treatment groups is pre-determined, IP designs have been shown to achieve the targeted power without introducing substantial inflation of the type I error rate. It has not been demonstrated whether the same general conclusions hold in observational studies, where exposure-group membership cannot be controlled by the investigator. We extend the IP to observational settings. We demonstrate through simulations that implementing an IP, in which prevalence of the exposure can be re-estimated at an interim stage, helps ensure optimal power for observational research with little inflation of the type I error associated with the final data analysis.
    Biometrical Journal 10/2010; 52(5):590-603. · 1.15 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Factors that determine survival in pulmonary arterial hypertension (PAH) drive clinical management. A quantitative survival prediction tool has not been established for research or clinical use. Data from 2716 patients with PAH enrolled consecutively in the US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) were analyzed to assess predictors of 1-year survival. We identified independent prognosticators of survival and derived a multivariable, weighted risk formula for clinical use. One-year survival from the date of enrollment was 91.0% (95% confidence interval [CI], 89.9 to 92.1). In a multivariable analysis with Cox proportional hazards, variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units (hazard ratio [HR], 4.1; 95% CI, 2.0 to 8.3), PAH associated with portal hypertension (HR, 3.6; 95% CI, 2.4 to 5.4), modified New York Heart Association/World Health Organization functional class IV (HR, 3.1; 95% CI, 2.2 to 4.4), men >60 years of age (HR, 2.2; 95% CI, 1.6 to 3.0), and family history of PAH (HR, 2.2; 95% CI, 1.2 to 4.0). Renal insufficiency, PAH associated with connective tissue disease, functional class III, mean right atrial pressure, resting systolic blood pressure and heart rate, 6-minute walk distance, brain natriuretic peptide, percent predicted carbon monoxide diffusing capacity, and pericardial effusion on echocardiogram all predicted mortality. Based on these multivariable analyses, a prognostic equation was derived and validated by bootstrapping technique. We identified key predictors of survival based on the patient's most recent evaluation and formulated a contemporary prognostic equation. Use of this tool may allow the individualization and optimization of therapeutic strategies. Serial follow-up and reassessment are warranted. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.
    Circulation 07/2010; 122(2):164-72. · 15.20 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Inflammation is increasingly recognised as playing a central role in atherosclerosis, and peripheral blood markers of inflammation have been associated with incident and recurrent cardiac events. The relationship of these potentially modifiable risk markers to prognosis after ischaemic stroke is less clear. The Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) study will address hypotheses related to the role of inflammatory markers in secondary stroke prevention in an efficient manner using the well-established framework of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (NCT00059306). SPS3 is an ongoing Phase III multicentre secondary prevention trial focused on preventing recurrent stroke in patients with small vessel ischaemic stroke, or lacunes. In SPS3, patients are assigned in a factorial design to aspirin vs. aspirin plus clopidogrel, and to usual vs. aggressive blood pressure targets. The purpose of LIMITS is to determine whether serum levels of inflammatory markers - including high-sensitivity C-reactive protein, serum amyloid A, CD40 ligand, and monocyte chemoattractant protein-1 - predict recurrent stroke and other vascular events among lacunar stroke patients. The project will also determine whether these markers predict which people will respond best to dual antiplatelet therapy with clopidogrel and aspirin, as well the relationship to cognitive function. plan Multivariable Cox proportional hazard regression modeling will be used to estimate hazard ratios for the effect of marker levels on risk of recurrent stroke and other outcomes after adjusting for additional potential risk factors, including age, gender, ethnicity, treatment arm, and traditional stroke risk factors. Interactions between marker levels and treatment assignment for both arms of the SPS3 study will be assessed. Observations will be censored at the time of last follow-up visit. LIMITS represents an efficient approach to the identification of novel inflammatory biomarkers for use in risk prediction and treatment selection in patients with small vessel disease.
    International Journal of Stroke 04/2010; 5(2):117-25. · 2.75 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Vascular fibrinolytic balance is maintained primarily by interplay of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous research has shown that polymorphisms in genes from the renin-angiotensin (RA), bradykinin, and fibrinolytic systems affect plasma concentrations of both t-PA and PAI-1 through a set of gene-gene interactions. In the present study, we extend this finding by exploring the effects of polymorphisms in genes from these systems on incident cardiovascular disease, explicitly examining two-way interactions in a large population-based study. Data from the population-based PREVEND study in Groningen, The Netherlands (n = 8,138) were analyzed. The effects of the polymorphisms and their interactions on cardiovascular events were analyzed via Cox proportional hazards models. There was no association between five of the six polymorphisms singly and risk of cardiovascular disease. There was a significant main effect for the ACE I/D polymorphism for both dominant and additive coding schemes. There were significant interactions between the following polymorphism pairs even after adjustment for known risk factors: ACE I/D & PAI-1 4G/5G (p = 0.012), BDKRB2 C181T & ACE I/D (p = 0.016), BDKRB2 C58T & ACE I/D (p = 0.025), BDKRB2 exon 1 I/D & AT1R A1166C (p = 0.017), and BDKRB2 C58T & AT1R A1166C (p = 0.015). This study suggests possible interactions between genes from the RA, bradykinin, and fibrinolytic systems on the risk of cardiovascular disease, extending previous research that has demonstrated that interactions among genes from these systems influence plasma concentrations of both t-PA and PAI-1. Further explorations of these interactions are needed.
    PLoS ONE 01/2010; 5(9):e12757. · 3.73 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: There is a survival disparity between African Americans and Caucasians who have colon cancer. The objectives of the current study were to quantify the impact of comorbidity and body mass index (BMI) on survival and to assess whether these 2 variables account for the decreased survival among African Americans. Data from patients (n=496) who underwent surgery for a first primary colon cancer at the University of Alabama at Birmingham Hospital from 1981 to 2002 were analyzed. Hazard ratios (HRs) with 95% confidence intervals (CI) were obtained using Cox proportional hazards models for the association of race, comorbidity, BMI, and covariates with all-cause mortality. The confounding influence of comorbidity and BMI for the increased risk of death associated with African-American race was evaluated, and effect modification by disease stage for the association of comorbidity and BMI with mortality also was assessed. African Americans experienced an increased risk of death compared with Caucasians (HR, 1.34; 95% CI, 1.06-1.68). The highest comorbidity burden was associated with an increased risk of all-cause mortality (HR, 1.63; 95% CI, 1.24-2.15). For BMI, being underweight increased the risk of death (HR, 1.54; 95% CI, 0.96-2.45); however, being overweight/obese was protective (HR, 0.77; 95% CI, 0.61-0.97). The effect of comorbidity was observed among those with early stage tumors, whereas the effect of BMI was confined to patients who had advanced tumors. Although comorbidity and BMI had an impact on the survival of patients with colon cancer after surgery, these variables were not contributing factors to the decreased survival observed among African Americans.
    Cancer 11/2009; 115(24):5798-806. · 5.20 Impact Factor

Publication Stats

2k Citations
489.81 Total Impact Points

Institutions

  • 2010–2013
    • University of Iowa
      • Department of Biostatistics
      Iowa City, Iowa, United States
    • University of Florida
      • Department of Biostatistics
      Gainesville, FL, United States
  • 2001–2012
    • University of Alabama at Birmingham
      • • Department of Biostatistics
      • • Department of Epidemiology
      • • Department of Medicine
      Birmingham, AL, United States
    • Baylor College of Medicine
      Houston, Texas, United States
  • 2008
    • Kansas State University
      • Department of Statistics
      Manhattan, KS, United States
  • 2006–2007
    • University of Groningen
      • Department of Cardiology
      Groningen, Province of Groningen, Netherlands
  • 2001–2007
    • Vanderbilt University
      • • Center for Human Genetics Research (CHGR)
      • • Department of Medicine
      • • Division of Urologic Surgery
      Nashville, MI, United States
  • 2005
    • University of Alabama
      Tuscaloosa, Alabama, United States
  • 2004
    • University of Toronto
      • Division of Cardiology
      Toronto, Ontario, Canada
  • 2003
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
    • University of Missouri
      • Department of Mathematics
      Columbia, MO, United States
  • 2002
    • Yale University
      • Section of Cardiovascular Medicine
      New Haven, CT, United States
    • Centers for Disease Control and Prevention
      • Epidemiology and Analysis Program Office
      Druid Hills, GA, United States