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1.
Pharm Stat ; 15(6): 471-485, 2016 11.
Article in English | MEDLINE | ID: mdl-27620652

ABSTRACT

Biostatisticians recognize the importance of precise definitions of technical terms in randomized controlled clinical trial (RCCT) protocols, statistical analysis plans, and so on, in part because definitions are a foundation for subsequent actions. Imprecise definitions can be a source of controversies about appropriate statistical methods, interpretation of results, and extrapolations to larger populations. This paper presents precise definitions of some familiar terms and definitions of some new terms, some perhaps controversial. The glossary contains definitions that can be copied into a protocol, statistical analysis plan, or similar document and customized. The definitions were motivated and illustrated in the context of a longitudinal RCCT in which some randomized enrollees are non-adherent, receive a corrupted treatment, or withdraw prematurely. The definitions can be adapted for use in a much wider set of RCCTs. New terms can be used in place of controversial terms, for example, subject. We define terms specifying a person's progress through RCCT phases and that precisely define the RCCT's phases and milestones. We define terms that distinguish between subsets of an RCCT's enrollees and a much larger patient population. 'The intention-to-treat (ITT) principle' has multiple interpretations that can be distilled to the definitions of the 'ITT analysis set of randomized enrollees'. Most differences among interpretations of 'the' ITT principle stem from an RCCT's primary objective (mainly efficacy versus effectiveness). Four different 'authoritative' definitions of ITT analysis set of randomized enrollees illustrate the variety of interpretations. We propose a separate specification of the analysis set of data that will be used in a specific analysis. Copyright © 2016 John Wiley & Sons, Ltd.


Subject(s)
Randomized Controlled Trials as Topic/methods , Research Design , Terminology as Topic , Data Interpretation, Statistical , Humans , Intention to Treat Analysis , Longitudinal Studies , Research Subjects
2.
Blood ; 119(17): 3925-32, 2012 Apr 26.
Article in English | MEDLINE | ID: mdl-22318199

ABSTRACT

Stroke is a devastating complication of sickle cell anemia (SCA) with high recurrence if untreated. Chronic transfusions reduce recurrent strokes but have associated morbidities including iron overload. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) was a multicenter phase 3 randomized trial comparing standard treatment (transfusions/chelation) to alternative treatment (hydroxyurea/phlebotomy) for children with SCA, stroke, and iron overload. SWiTCH was a noninferiority trial with a composite primary end point, allowing an increased stroke risk but requiring superiority for removing iron. Subjects on standard treatment received monthly transfusions plus daily deferasirox iron chelation. Subjects on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose (MTD), followed by monthly phlebotomy. Subjects on standard treatment (N = 66) maintained 30% sickle hemoglobin (HbS) and tolerated deferasirox at 28.2 ± 6.0 mg/kg/d. Subjects on alternative treatment (N = 67) initiated hydroxyurea and 60 (90%) reached MTD at 26.2 ± 4.9 mg/kg/d with 29.1% ± 6.7% fetal hemoglobin (HbF). Adjudication documented no strokes on transfusions/chelation but 7 (10%) on hydroxyurea/phlebotomy, still within the noninferiority stroke margin. The National Heart, Lung, and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content, indicating futility for the composite primary end point. Transfusions and chelation remain a better way to manage children with SCA, stroke, and iron overload.


Subject(s)
Anemia, Sickle Cell/complications , Antisickling Agents/therapeutic use , Hydroxyurea/therapeutic use , Secondary Prevention , Stroke/drug therapy , Stroke/etiology , Transfusion Reaction , Adolescent , Anemia, Sickle Cell/mortality , Anemia, Sickle Cell/therapy , Child , Female , Humans , Male , Maximum Tolerated Dose , Phlebotomy , Prognosis , Stroke/mortality , Survival Rate , Treatment Outcome
4.
Pediatr Blood Cancer ; 57(6): 1011-7, 2011 Dec 01.
Article in English | MEDLINE | ID: mdl-21826782

ABSTRACT

BACKGROUND: Stroke occurs in 5-10% of children with sickle cell anemia (SCA) and has a high (>50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long-term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload. METHODS: Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) is an NHLBI-sponsored Phase III multicenter randomized controlled clinical trial for children with SCA, stroke, and iron overload (NCT00122980). The primary goal of SWiTCH is to compare 30 months of alternative therapy (hydroxyurea and phlebotomy) with standard therapy (transfusions and chelation) for the prevention of secondary stroke and reduction of transfusional iron overload. DISCUSSION: SWiTCH has several distinctive study features including novel methodological and design components: (1) composite primary endpoint including both stroke recurrence rate and iron burden; (2) non-inferiority design with an "acceptable" increased stroke risk; (3) transfusion goals based on current academic community practices; (4) special oversight for the enrollment and randomization process; (5) overlap treatment period within the alternative treatment arm; (6) masking of the overall trial Principal Investigator to treatment results; (7) inclusive independent stroke adjudication process for all suspected new neurological events; and (8) periodic therapeutic phlebotomy program to alleviate iron overload. CONCLUSION: Investigation of alternative treatments in SWiTCH could lead to changes in the management of cerebrovascular disease for selected patients with SCA, stroke, and iron overload.


Subject(s)
Anemia, Sickle Cell/therapy , Erythrocyte Transfusion , Hydroxyurea/therapeutic use , Iron Overload/therapy , Stroke/therapy , Adolescent , Adult , Anemia, Sickle Cell/complications , Chelation Therapy , Child , Child, Preschool , Erythrocyte Transfusion/adverse effects , Humans , Iron Overload/etiology , Iron Overload/prevention & control , Stroke/etiology , Stroke/prevention & control , Young Adult
5.
Blood ; 117(24): 6681-4, 2011 Jun 16.
Article in English | MEDLINE | ID: mdl-21515823

ABSTRACT

Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A(-) variant deficiency, and ß-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA.


Subject(s)
Anemia, Sickle Cell/genetics , Genetic Markers , Genetic Predisposition to Disease , Stroke/genetics , Adolescent , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/diagnosis , Child , Child, Preschool , Cohort Studies , Female , Genetic Markers/physiology , Glucosephosphate Dehydrogenase/genetics , Glucosephosphate Dehydrogenase Deficiency/complications , Glucosephosphate Dehydrogenase Deficiency/diagnosis , Glucosephosphate Dehydrogenase Deficiency/genetics , Humans , Male , Polymorphism, Single Nucleotide/physiology , Risk Factors , Stroke/diagnosis , Stroke/etiology , beta-Globins/genetics
6.
J Biopharm Stat ; 21(2): 226-51, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21390998

ABSTRACT

Missing not at random (MNAR) post-dropout missing data from a longitudinal clinical trial result in the collection of "biased data," which leads to biased estimators and tests of corrupted hypotheses. In a full rank linear model analysis the model equation, E[Y] = Xß, leads to the definition of the primary parameter ß = (X'X)(-1)X'E[Y], and the definition of linear secondary parameters of the form θ = Lß = L(X'X)(-1)X'E[Y], including, for example, a parameter representing a "treatment effect." These parameters depend explicitly on E[Y], which raises the questions: What is E[Y] when some elements of the incomplete random vector Y are not observed and MNAR, or when such a Y is "completed" via imputation? We develop a rigorous, readily interpretable definition of E[Y] in this context that leads directly to definitions of ß, Bias(ß) = E[ß] - ß, Bias(θ) = E[θ] - Lß, and the extent of hypothesis corruption. These definitions provide a basis for evaluating, comparing, and removing biases induced by various linear imputation methods for MNAR incomplete data from longitudinal clinical trials. Linear imputation methods use earlier data from a subject to impute values for post-dropout missing values and include "Last Observation Carried Forward" (LOCF) and "Baseline Observation Carried Forward" (BOCF), among others. We illustrate the methods of evaluating, comparing, and removing biases and the effects of testing corresponding corrupted hypotheses via a hypothetical but very realistic longitudinal analgesic clinical trial.


Subject(s)
Clinical Trials as Topic , Data Interpretation, Statistical , Algorithms , Computer Simulation , Humans , Longitudinal Studies , Models, Statistical , Patient Dropouts
7.
Br J Haematol ; 145(4): 524-8, 2009 May.
Article in English | MEDLINE | ID: mdl-19344396

ABSTRACT

Chronic transfusions to maintain haemoglobin S (HbS) < or =30% are the mainstay of treatment for children with sickle cell anaemia (SCA) and previous stroke. This HbS target is often hard to maintain, however, and values achieved in current practice are unknown. In preparation for the Phase III Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, we collected data on 295 children with SCA and stroke who received transfusions at 23 institutions. The overall average pre-transfusion %HbS was 35 +/- 11% (institutional range 22-51%). Receiving scheduled transfusions on time was the most predictive variable for maintaining HbS at the < or =30% goal.


Subject(s)
Anemia, Sickle Cell/therapy , Blood Transfusion/methods , Adolescent , Anemia, Sickle Cell/blood , Child , Hemoglobin, Sickle/analysis , Humans , Practice Guidelines as Topic , Retrospective Studies , Stroke/blood , Stroke/prevention & control , Treatment Outcome , United States
8.
Stat Med ; 25(3): 513-27, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16158407

ABSTRACT

The linear mixed model has become a widely used tool for longitudinal analysis of continuous variables. The use of regression splines in these models offers the analyst additional flexibility in the formulation of descriptive analyses, exploratory analyses and hypothesis-driven confirmatory analyses. We propose a method for fitting piecewise polynomial regression splines with varying polynomial order in the fixed effects and/or random effects of the linear mixed model. The polynomial segments are explicitly constrained by side conditions for continuity and some smoothness at the points where they join. By using a reparameterization of this explicitly constrained linear mixed model, an implicitly constrained linear mixed model is constructed that simplifies implementation of fixed-knot regression splines. The proposed approach is relatively simple, handles splines in one variable or multiple variables, and can be easily programmed using existing commercial software such as SAS or S-plus. The method is illustrated using two examples: an analysis of longitudinal viral load data from a study of subjects with acute HIV-1 infection and an analysis of 24-hour ambulatory blood pressure profiles.


Subject(s)
Data Interpretation, Statistical , Linear Models , Longitudinal Studies , Blood Pressure Monitoring, Ambulatory , HIV Infections/blood , HIV Infections/immunology , HIV-1/immunology , Humans , Hypertension/diet therapy , RNA, Viral/blood , Viral Load
9.
J Biopharm Stat ; 14(4): 947-67, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15587974

ABSTRACT

In this article, we present methodology for making inferences about projected completors in the presence of attrition. The approach is motivated by a clinical trial that investigates a treatment for disability among individuals who sustain severe head injuries. Although most studies attempt to make inferences about the entire study population, our application poses important scientific questions targeting individuals who are likely to complete the study or to remain on protocol for a specified time period. We propose using measures of each individual's dropout inclination to identify projected completors and then building a stratified response model based on projected completion status. We present several prediction measures along with procedures for evaluating accuracy with respect to observed dropout. Estimation of model parameters proceeds using maximum likelihood and restricted maximum likelihood methods. We illustrate the utility of our proposed analysis by using the motivating disability data example.


Subject(s)
Antineoplastic Agents/therapeutic use , Dacarbazine/analogs & derivatives , Neoplasm Transplantation/physiology , Algorithms , Animals , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bayes Theorem , Brain Neoplasms/drug therapy , Camptothecin/therapeutic use , Dacarbazine/therapeutic use , Humans , Likelihood Functions , Longitudinal Studies , Markov Chains , Mice , Models, Statistical , Monte Carlo Method , Neuroblastoma/drug therapy , Predictive Value of Tests , Temozolomide , Transplantation, Heterologous
10.
Stat Med ; 22(9): 1457-64, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12704609

ABSTRACT

Estimating the correlation coefficient between two outcome variables is one of the most important aspects of epidemiological and clinical research. A simple Pearson's correlation coefficient method is usually employed when there are complete independent data points for both outcome variables. However, researchers often deal with correlated observations in a longitudinal setting with missing values where a simple Pearson's correlation coefficient method cannot be used. General linear mixed models (GLMM) techniques were used to estimate correlation coefficients in a longitudinal data set with missing values. A random regression mixed model with unstructured covariance matrix was employed to estimate correlation coefficients between concentrations of HIV-1 RNA in blood and seminal plasma. The effects of CD4 count and antiretroviral therapy were also examined. We used data sets from three different centres (650 samples from 238 patients) where blood and seminal plasma HIV-1 RNA concentrations were collected from patients; 137 samples from 90 different patients without antiviral therapy and 513 samples from 148 patients receiving therapy were considered for analysis. We found no significant correlation between blood and semen HIV-1 RNA concentration in the absence of antiviral therapy. However, a moderate correlation between blood and semen HIV-1 RNA was observed among subjects with lower CD4 counts receiving therapy. Our findings confirm and extend the idea that the concentrations of HIV-1 in semen often differ from the HIV-1 concentration in blood. Antiretroviral therapy administered to subjects with low CD4 counts result in sufficient concomitant reduction of HIV-1 in blood and semen so as to improve the correlation between these compartments. These results have important implications for studies related to the sexual transmission of HIV, and development of HIV prevention strategies.


Subject(s)
HIV Infections/virology , HIV-1/genetics , Linear Models , RNA, Viral/isolation & purification , Semen/virology , Anti-HIV Agents/therapeutic use , CD4 Lymphocyte Count , Disease Transmission, Infectious , HIV Infections/blood , HIV Infections/transmission , Humans , Longitudinal Studies , Male , RNA, Viral/blood
11.
J Pediatr ; 140(2): 225-9, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11865275

ABSTRACT

OBJECTIVES: Although hydroxyurea is effective in treating adults with sickle-cell anemia (SCA), there is concern that it may adversely affect growth in children. We report the growth characteristics of patients in the Phase I-II pediatric hydroxyurea trial (HUG-KIDS) before and during treatment at the maximum tolerated dose for one year. STUDY DESIGN: Children and adolescents with SCA (n = 68), aged 5 to 16 years at baseline, reached the maximum tolerated dose and had serial height, weight, and Tanner stage measurements. Data from the Cooperative Study of Sickle Cell Disease (CSSCD) were used for comparison. Mixed-effects models were used to compare serial measurements as a function of age and group. RESULTS: In girls, there were no significant differences in height or weight among the pretreatment, on-treatment, and CSSCD groups. Compared with the CSSCD group, HUG-KIDS boys were heavier starting at age 9 years, and pretreatment HUG-KIDS boys were taller starting at age 7 years. The Tanner stage transitions took place at appropriate ages. CONCLUSIONS: Hydroxyurea treatment had no adverse effect on height or weight gain or pubertal development in school-aged children with SCA.


Subject(s)
Anemia, Sickle Cell/physiopathology , Antisickling Agents/pharmacology , Hydroxyurea/pharmacology , Puberty/drug effects , Adolescent , Anemia, Sickle Cell/drug therapy , Antisickling Agents/therapeutic use , Child , Child, Preschool , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Female , Humans , Hydroxyurea/therapeutic use , Male
12.
Blood ; 99(1): 10-4, 2002 Jan 01.
Article in English | MEDLINE | ID: mdl-11756146

ABSTRACT

In the phase I/II pediatric hydroxyurea safety trial (HUG-KIDS), school-aged children with sickle cell anemia receiving hydroxyurea at the maximally tolerated dose (MTD) had variable increases in the percentage of fetal hemoglobin (%HbF). To identify predictors of the HbF response to hydroxyurea therapy, baseline clinical and laboratory values (age, sex, hemoglobin concentration, %HbF, reticulocytes, white blood cell [WBC], platelets, and serum chemistries), as well as treatment variables (number of toxicities, noncompliance, MTD dose, and MTD blood counts) were analyzed in 53 HUG-KIDS children who achieved MTD. Baseline %HbF values (P =.001), baseline hemoglobin concentration (P =.01), MTD dose (P =.02), and compliance (P =.02) were significantly associated with a higher %HbF at MTD; in contrast, age, sex, number of toxicities, and other baseline hematologic parameters were not. After adjusting for variations in baseline %HbF, the baseline reticulocyte count (P =.05) and baseline WBC count (P =.05) were also significantly associated with a higher %HbF at MTD. Hydroxyurea-induced increases in the hemoglobin concentration and mean corpuscular volume (both higher absolute values at MTD and larger positive changes from baseline values), as well as hydroxyurea-induced decreases in reticulocytes and WBC count, were significantly associated with a higher %HbF at MTD. These data suggest that selected baseline laboratory parameters, a higher MTD dose with attention to compliance, and greater therapy-related changes in blood counts may predict the HbF response to hydroxyurea therapy for children with sickle cell anemia. The HbF response to hydroxyurea is variable and complex, however, and even children with low baseline %HbF values can develop substantial increases in %HbF at MTD.


Subject(s)
Anemia, Sickle Cell/blood , Anemia, Sickle Cell/drug therapy , Antisickling Agents/therapeutic use , Fetal Hemoglobin/analysis , Hydroxyurea/therapeutic use , Antisickling Agents/administration & dosage , Antisickling Agents/adverse effects , Child , Hemoglobins/analysis , Humans , Hydroxyurea/administration & dosage , Hydroxyurea/adverse effects , Leukocyte Count , Maximum Tolerated Dose , Patient Compliance , Platelet Count , Reticulocyte Count , Treatment Outcome
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