Completed Research Projects

A Clinical Trial in Overt Nephropathy (ACTION)

Principal Investigator:  Oliver M. Bautista, Ph.D.

The Biostatistics Center served as the Biostatistical Analysis Center for A Clinical Trial in Overt Nephropathy (ACTION); two multi- center clinical trials on the pharmacological inhibition of the formation of advanced glycated endproducts (AGE) in diabetics with chronic renal disease using pimagedine. ACTION I was conducted in insulin dependent diabetes mellitus (IDDM) participants; ACTION II was conducted in non-insulin dependent diabetes mellitus (NIDDM) participants. 

ACTION I and II were double-masked, multiple-dose, placebo-controlled, randomized clinical trials designed to evaluate the safety and efficacy of advanced glycosylated endproduct inhibition (AGEi) using pimagedine in retarding the rate of progression of renal disease in participants with overt diabetic nephropathy. In ACTION I and II, one-third of the participants were randomized to placebo and two-thirds were randomized to either a low or high dose of pimagedine. The primary endpoint in both ACTION I and II is the time from randomization to the doubling of baseline serum creatinine. Efficacy is evaluated by comparing the placebo group versus the combined low and high pimagedine dose groups with respect to the primary outcome. In addition to the progression of renal disease, ACTION included evaluations of fundus photographs and a pharmacoeconomic evaluation. 

During 31 months from February 1994 to September 1996, 56 clinical sites in the US and Canada randomized a total of 690 participants into ACTION I. Randomized participants were followed with quarterly visits until the scheduled administrative censoring period during the third quarter of 1998. With over 1,700 participant-years of follow-up accumulated in ACTION I, the combined pimagedine dose group showed a tendency of having a lower risk of doubling of serum creatinine. However, the observed difference between the placebo group and the combined pimagedine dose group with respect to the primary outcome did not reach statistical significance. The combined pimagedine dose group was also observed to have statistically significant lower levels of triglycerides, LDL cholesterol, and urine protein. 

During 17 months from July 1995 to December 1996, 84 clinical sites in the US and Canada enrolled a total of 599 participants into ACTION II. Participants were followed with quarterly visits, with administrative censoring scheduled during the third quarter of 1999. On March of 1998, having accumulated 50% of the total information anticipated for ACTION II, the ACTION I and II External Safety Monitoring Committee (ESMC) recommended the early termination of the ACTION II trial due to safety concerns and apparent lack of efficacy. 

Funding for ACTION I and II was provided by Alteon, Inc., 1993- 1998; IND 29,629

A Linked and Enhanced SDR for Modeling Scientific Workforce Dynamics (MODSCI)

Principal Investigator:  Michael Larsen, Ph.D.

In the U.S. women are severely underrepresented in many academic and nonacademic career areas of science and engineering (S&E). This is a serious problem because women and minorities form a significant portion of the potential scientific workforce and maintaining a strong and vibrant scientific workforce is critical to economic and scientific progress. To understand the factors affecting participation of women and minorities in S&E careers on needs data. One also needs data in order to formulate and evaluate policies seeking to increase representation of women and minorities at all levels of S&E careers. The principal goal of this proposal is to use existing sources of information in novel ways to address key questions about the S&E workforce. The methods and products of this research will yield unique insights and be a key building block for future studies of polices and lifting interventions that aim to encourage the participation of women and minorities in the scientific workforce. Successful policies that lead to increased sustainability and productivity in science, engineering, and health careers are anticipated to have significant, positive impacts on science research, public health, and the economy. Funded by NIGMS Cooperative Agreement 1-U01 GM 094142-01

Angiotensin Converting Enzyme Inhibition (ACEi) with Captopril in Diabetic Nephropathy (ACEI)

Principal Investigator:  Raymond P. Bain, Ph.D.

The Biostatistics Center served as the biostatistical coordinating center for the trial of angiotensin converting enzyme inhibition (ACEi) in diabetic nephropathy; a multi-center clinical trial of ACEi with captopril in diabetics with chronic renal disease. ACEi in diabetic nephropathy was a double-masked, placebo-controlled randomized clinical trial designed to evaluate the safety and efficacy of ACEi with captopril in retarding the rate of progression of chronic renal disease in insulin dependent diabetes mellitus (IDDM) participants with overt diabetic nephropathy. Over a three-year period in 30 clinical sites in the U.S. and Canada, the ACEi trial randomized a total of 409 participants. Participants were randomized to placebo or ACEi with captopril and followed for two to five years with quarterly visits. The trial concluded that ACEi with captopril protects against deterioration in renal function in IDDM nephropathy and is significantly more effective than blood pressure control alone (The New England Journal of Medicine 1993;329:1456-1462). 

Funded by NIH/NIDDK (R01-DK-39826) and Bristol-Myers Squibb Company, 1987-1993; IND 12,928

Blood Pressure Management with Ramipril in Diabetic Nephropathy (BPMR)

Principal Investigator:  Raymond P. Bain, Ph.D.

The Biostatistics Center was the biostatistical coordinating center for the Blood Pressure Management with Ramipril in Diabetic Nephropathy; a multi-center clinical trial of moderate versus intensive blood pressure control in diabetics with chronic renal disease. The blood pressure management trial was a randomized clinical trial designed to evaluate the safety and efficacy of two levels of blood pressure control with the angiotensin converting enzyme inhibitor (ACEi) ramipril on renal function changes in participants with overt diabetic nephropathy. Over a one-year period, 17 clinical sites in the US randomized a total of 129 insulin-dependent diabetes mellitus (IDDM) participants who completed follow-up in the trial of Angiotensin Converting Enzyme Inhibition (ACEi) with Captopril in Diabetic Nephropathy Nephropathy. The follow-on participants were randomized to one of two blood pressure control groups: moderate goal (mean arterial pressure of between 100 and 107 mmHg, inclusive) or intensive goal (mean arterial pressure of 92 mmHg or less). Participants were followed for two years with quarterly visits (J. Am. Soc. Nephrol. 1995;5:1775-1781). 

Funded by NIH/NIDDK (R01-DK-39826), Hoechst-Roussel Pharmaceuticals Inc and Hoechst Marion Roussel Inc, 1993-1996

Chorionic Villus Sampling and Amniocentesis Study

Principal Investigator:  Sarah E. Fowler, Ph.D.

This project included three multicenter trials of the safety and accuracy of prenatal diagnosis procedures, chorionic villus sampling and amniocentesis: 1) a nonrandomized comparison of Transcervical (TC) CVS and amniocentesis procedures in 8,000 obstetrical patients at 7 clinics which found an estimated excess risk of pregnancy loss after TC CVS compared with amniocentesis of 0.8% (NEJM, 1989); 2) a randomized Transabdominal (TA) vs. Transcervical (TC) CVS study of 4000 patients at 8 clinics which revealed low overall pregnancy loss rates and indicated that when practitioners are experienced, the two methods are equally safe (NEJM, 1992); 3) a study of 3,000 Danish patients randomized between amniocentesis, TA and TC CVS which found risk of fetal loss was similar after TA CVS and amniocentesis procedures, but was considerably greater following TC CVS (Lancet, 1992). 

NIH/NICHD Cooperative Agreement, 1984-1992

Clinical Study of Intermittent Positive Pressure Breathing

Principal Investigator:  Elizabeth C. Wright, Ph.D

The Clinical Study of Intermittent Positive Pressure Breathing was a randomized, controlled, multicenter clinical trial of 985 subjects to evaluate methods of delivery of a bronchodilator to subjects with chronic obstructive pulmonary disease. The study found no advantages of IPPB over compressor nebulizer therapy in reducing mortality or hospitalizations or improving lung function or quality of life. 

NIH/NHLBI Contract N01-HR-7-2901, 1976-1984.

CNV Atlas of Human Development (CNV)

Principal Investigator:  Kathleen Jablonski, Ph.D.

The goal of CNV Atlas of Human Development project is to develop mechanisms to automate the ongoing collection and storage of very large volumes of genotypic and phenotypic data from clinical laboratories and provide access to this resource for researchers and clinicians. The origins of these data are both pediatric and prenatal populations. While pediatric microarray data files are currently held at Emory University, prenatal data collected under the grant entitled "Prenatal Cytogenetic Diagnosis by Array-based Copy Number Analysis" (NIH" R01 HD055651) are currently collected and stored at the GEORGE WASHINGTON UNIVERSITY BIOSTATISTICS CENTER (GWU-BSC), which acts as the Data Coordinating Center for that study. The scope of work described below focuses largely on the planning and development of systems to fulfill the goals of the CNV Atlas of Human Development project as they pertain to prenatal data. 

The GWU-BSC will collaborate with the grantee and with co-investigators at Columbia University to develop standard terminology relevant to phenotype. Appropriate prenatal methods for collection will be investigated and defined. The extent of the requirement for data validation checking for the prenatal phenotypic data will be identified and plans for implementation will be put in place. The GWU-BSC will have a specialized role in collaborating with personnel at the NCBI/dbGaP repository to achieve the correct format of phenotypic data files (for both pediatric and prenatal data) to allow easy integration into the repository structure. 

In collaboration with IT staff at Emory University, the GWU-BSC will develop systems to de-identify and link the prenatal data files of different types for submission. While Emory staff will take the lead in handling the microarray analyzer-generated files, the GWU-BSC will implement similar systems for the prenatal group. A close working relationship will be maintained with the grantee in order to resolve together commonly shared problems in the systems development phase. 

During the final 6 months of the grant period, GWU-BSC personnel will undertake extensive testing of systems developed. A limited number of new contributing sites will be involved in the testing of the system, but the software, processes and documentation will need to be developed to allow expansion to all current study centers and laboratories, and then to others. This study is funded by a subcontract with the Emory University under Grant awareded by NICHD 1RC2HD064525, 93.701 (2010-2012)

Collaborative Study of the Treatment of Lactic Acidosis with Dichloroacetat (TLAD)

Principal Investigator:  Elizabeth C. Wright, Ph.D

The Collaborative Study of the Treatment of Lactic Acidosis with Dichloroacetat was a randomized, controlled, multicenter study of 252 patients at 8 centers to evaluate the effectiveness of DCA in the treatment of acute lactic acidosis. The study showed that DCA had some beneficial effects on the acute biochemical imbalance but failed to improve survival (NEJM, 1992). 

NIH/NIDDK Grant R01-AM-35448, 1986-1992

Diabetes Control and Complications Trial (DCCT)

Principal Investigator:  John M. Lachin, Sc.D.

The Diabetes Control and Complications Trial was launched by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 1981 when requests for proposals were issued for clinical centers and a central Data Coordinating Center. In early 1982 the Biostatistics Center of the George Washington University was awarded the contract to serve as the Coordinating Center with Dr. John M. Lachin as Principal Investigator and Director, and Ms. Patricia Cleary as Co-Director. In addition, 29 clinical centers in the United States and Canada, and 8 central laboratories and units participated in the trial. The Coordinating Center contract spanned the period 1982-1998. The complete study group is listed in the Appendix to the principal publication of study results in The New England Journal of Medicine

Since the discovery of insulin in 1921, the medical community debated the glucose hypothesis that the marked elevation of blood glucose (hyperglycemia) associated with diabetes mellitus was responsible for the development and progression of the microvascular complications of type 1 or insulin-dependent diabetes: retinopathy leading to blindness, nephropathy leading to end-stage kidney disease, and neuropathy leading to loss of sensation, ulceration and amputation. The DCCT was designed to definitively answer whether a program of intensive therapy aimed at near normal levels of glycemia, when compared to conventional therapy aimed at maintenance of clinical well being, would affect the risk of onset and progression of these complications. 

During the period 1983-1989, 1441 subjects were enrolled in the study, half the subjects assigned at random to intensive therapy and half to conventional therapy. All subjects were scheduled to be followed until the fall of 1993. However, the dramatic beneficial results of the trial lead to its termination one year early. The results were presented at the June 1993 meeting of the American Diabetes Association and the initial principal results paper appeared in the New England Journal of Medicine in September of that year (DCCT, 1993). The risks of the microvascular complications over the average of 6.5 years of follow-up were reduced by 26-63% with intensive versus conventional therapy. Intensive therapy, however, was associated with an excess weight gain of about 1 kg per year greater than that with conventional therapy, and a 3-fold greater risk of episodes of hypoglycemia where patients experience seizures and/or loss of consciousness, compared to conventional therapy (DCCT, 1995a). 

Subsequent extensive statistical epidemiologic investigations showed that the risk of development of microvascular complications was principally determined by the lifetime exposure to hyperglycemia (DCCT, 1995b, 1996). However, the risk of hypoglycemia was weakly related to the level of glycemia, and more strongly related to intensive versus conventional therapy (DCCT, 1997). All total, more than 55 papers have been published that present the various methods and results of the DCCT. The complete DCCT bibliography can be obtained below. 

The Harvard Health Letter named the DCCT the number one advance in medicine during 1993. In 1994, the DCCT Research Group was awarded the Charles H. Best Medal for distinguished service in the cause for diabetes, named for the co-founder of insulin. The DCCT has been used to set standards of care for diabetes mellitus worldwide (see links below). 

As Coordinating Center, the Biostatistics Center participated in all aspects of the design, conduct and analysis of the study. In addition to Dr. Lachin and Ms. Cleary, statisticians who participated in the study included Jye-Yu Backlund, Oliver Bautista, Peter Gilbert, Max Halperin, David Kenny, James Knoke, K.K.Gordon Lan, Shuping Lan, and Desmond Thompson. 

After the close of the DCCT, the NIDDK launched the study of the Epidemiology Of Diabetes Interventions And Complications(EDIC), for which the Biostatistics Center also serves as the Data Coordinating Center. Under the EDIC, the original DCCT cohort is being followed to assess the development of significant microvascular disease and the development of cardiovascular and other macrovascular diseases. 

The DCCT Research Group (1997). Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes45: 271-286. 
The DCCT Research Group (1996). The absence of a glycemic threshold for the development of long-term complication: the perspective of the Diabetes Control and Complications Trial. Diabetes45: 1289-1298. 
The DCCT Research Group (1995a). Adverse events and their association with treatment regimens in the Diabetes Control and Complications Trial. Diabetes Care18: 1415-1427. 
The DCCT Research Group (1995b). The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes44: 968-983. 
The DCCT Research Group (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The New England Journal of Medicine329: 977-986. 


The following are links to additional information about the DCCT: 
DCCT Bibliography 
DCCT Protocol
National Institutes of Health (NIH) NIDDK summary of the DCCT results can be found on the National Diabetes Information Clearinghouse page. 

Many materials from the DCCT have been archived with the National Technical Information Service - Database. Each document or data set is accessable by an NTIS accession number to determine the price of each item, go to the NTIS site and then search for the product with that accession number. To order the item over the worldwide web, follow the instructions on the NTIS page for that item. The following are the principal study materials that are available: 

DCCT Manual of Diabetes Tests, Terms and Procedures, November 1987. 
DCCT Research Volunteer's Information Handbook, November 1987. 
The DCCT Manual of Operations, final version, May 1993. 
The DCCT Data Tape Archives of all raw study data, April 1996. 
The DCCT Baseline Data Set, July 1995. 

Specific subsets of the DCCT data that formed the basis for the principal DCCT papers, and the documentation of the analyses performed for some of those papers, are also available from the NTIS. 

Main Results Paper, NEJM, 1993: Analysis Documentation 
Diabetic Retinopathy Paper, Archives of Ophthalmology, 1995: Data Set 
Diabetic Retinopathy Paper: Analysis Documentation 
Diabetic Nephropathy Paper, Kidney International, 1995: Data Set 
Diabetic Nephropathy Paper: Analysis Documentation 
Diabetic Neuropathy Paper, Annals of Internal Medicine, 1995: Data Set 
Diabetic Neuropathy Paper: Analysis Documentation 
Adverse Events Paper, Diabetes Care, 1995: Data Sets 
Adverse Events Paper: Analysis Documentation 
Neurobehavioral Results Paper, Annals of Internal Medicine, 1996: Data Sets 
Neurobehavioral Results Paper: Analysis Documentation 
Macrovascular Outcomes Paper, The American Journal of Cardiology, 1995: Data set 
Relationship to Glycemic Exposure Paper, Diabetes, 1995: Data Set 
Relationship to Glycemic Exposure Paper: Analysis Documentation 
Familial Clustering Paper Diabetes, 1997: Data Set 
Familial Clustering Paper: Analysis documentation 
Economic Evaluation Paper, Journal of the American Medical Association, 1996: Analysis Documentation

Dysfunctional Uterine Bleeding Intervention Trial (DUBIT)

Principal Investigator:  Sarah E. Fowler, Ph.D.
Co-Investigator:  Kathryn Hirst, Ph.D.

The Biostatistics Center served as coordinating center for the Dysfunctional Uterine Bleeding Intervention Trial (DUBIT), funded by the Agency for Healthcare Research and Quality (AHRQ). Dysfunctional uterine bleeding can be simply defined as abnormal uterine bleeding that occurs in the absence of systemic or reproductive organ disease. DUBIT offers eligible women a choice of three treatment regimens: hysterectomy, endometrial ablation, or medical management with gonadotropin releasing hormone agonist (GnRH) followed by oral contraceptives. The primary objective of DUBIT is to compare the three treatments on control of bleeding, satisfaction, and health related quality of life. 

Funded by the HHS/AHRQ U01-HS09502A- 02, Cooperative Agreement, 1999

Principal Investigator:  Elizabeth Thom, Ph.D.

This study was a multicenter randomized clinical trial of amniocentesis and transabdominal chorionic villus sampling (TA CVS) at 77-104 days gestation. The Biostatistics Center serves as the Data Coordinating Center for the study. The purpose of this study was to compare the two prenatal diagnosis techniques with regard to safety, measured primarily by a combined endpoint of fetal loss or preterm delivery before 196 days gestation and also by total fetal loss, amniotic fluid loss, gestational age at delivery, perinatal morbidity, neonatal morbidity and congenital abnormalities, including limb reduction defects. Success in obtaining a diagnosis from the two procedures was compared. A total of 6400 healthy pregnant women at 77 to 104 days gestation, whose only indication for prenatal diagnosis is advanced maternal age of at least 34 years at enrollment, will be randomized to receive either TA CVS or amniocentesis following the baseline ultrasound. Eligibility criteria were revised in 1998 to restrict participation to women at 91-104 days gestation. 

In 1998 investigators initiated the First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening Study (BUN). The purpose is to assess in the U.S. a system for 1st trimester screening which uses combined serum biochemistry and ultrasound measurement of nuchal translucency together with maternal age and gestational age to calculate the risk of Down Syndrome and Trisomy 18. BUN was a prospective observational study of approximately 60,000 women to test the sensitivity and specificity of this screen for genetic abnormality. Supported by appropriate counseling any risk positive mother choosing an invasive diagnostic procedure is asked for consent to randomize into the EATA Trial. 

Grant funded by NIH/NICHD, 1-R01-HD32109-01A1, 1996-2000

Principal Investigator:  Raymond P. Bain, Ph.D.
Co-Investigator:  Joel I. Verter, Ph.D.

The Effects of Maternal Lifestyles on Infant Outcomes study was a cross-sectional screening and prospective cohort study to evaluate the relationship between maternal use of cocaine and/or opiates during pregnancy and the incidence of acute neonatal complications and long-term neurodevelopmental outcome of both premature and full-term infants. Based on results of screening over 19,000 mothers for in-utero exposure to cocaine/opiate by meconium and maternal self-report in 4 clinical centers, 658 infants, and their mothers, positive for in-utero exposure and 742 matched controls, have been enrolled in a 3-year neurobehavioral, neurodevelopmental and environmental follow-up evaluation. The EMLI study was sponsored by the National Institute of Child Health and Development (NICHD), National Institute on Drug Abuse & Addiction (NIDA), Center for Substance Abuse Treatment (CSAT) and the U.S. Department of Health and Human Services Administration for Children and Families(ACYF). 

NIH/NICHD Cooperative Agreement 5-U01-HD-19897, 1992-1998

Effects of Vesnarinone in Patients with Heart Failure

Principal Investigator:  Raymond P. Bain, Ph.D.

For the Effects of Vesnarinone in Patients with Heart Failure trail The Biostatistics Center was the Biostatistical analysis center of this multi-center clinical trial of the oral inotropic agent vesnarinone. The vesnarinone trial was a double-masked, placebo-controlled, multiple-dose, randomized clinical trial designed to evaluate the safety and efficacy of the oral inotropic agent vesnarinone on cardiovascular morbidity and mortality in participants with symptomatic chronic heart failure and left ventricular dysfunction. Over a two-year period in 22 clinical sites, the vesnarinone trial randomized a total of 564 participants. Participants were randomized to placebo or either a low or high dose of vesnarinone. Randomized participants were followed for six months. The vesnarinone trial concluded that six months of therapy with 60 mg of vesnarinone per day resulted in lower morbidity and mortality and improved the quality of life of patients with congestive heart failure (NEJM 1993;329:149-155). 

Funded by Otsuka America Pharmaceutical, Inc., 1989-1992

FIRST Award: Statistical Methods in Cancer Research (FIRST)

Principal Investigator:  Zhaohai Li, Sc.D.

This research project was to develop, implement and test random effects (RE) models (continuous and binary) to improve analysis of correlated data encountered in clinical oncology research. Correlated clinical data are common in meta analyses, family studies, and risk assessments. For example two summary statistics (e.g. means) from the same study are correlated data. Measurements of cancer risk for members within a family tend to be more alike than cancer risk measurements from members of different families. Assumption of a common random component shared by outcomes of the same study or members of the same family was proposed. Two types of random effects models based on whether outcomes are continuous or binary (yes/no) were developed theoretically and numerically. These statistical methods were compared with the existing methods through analysis and simulation. These methods were applied to epidemiological and clinical oncology research data sets. 

Grant from NIH/NCI 5-R29-CA64363, 1997-2000

Principal Investigator:  Patricia A. Cleary, M.S.

The Coordinating Center is viewed as a long-term collection and distribution resource for the diabetes research community, and plays an important role in support of research targeted at finding a cure for Type 1 diabetes and its complications. Coordinating Center studies will assemble, maintain, and distribute samples and information from populations that may be used to study the genetics of Type 1 diabetes. 

The first project of the Coordinating Center was a collaboration with the Diabetes UK (previously known as the British Diabetic Association, BDA) on the study of the genetics of susceptibility to diabetic nephropathy. This study is called The Genetics of Kidneys in Diabetes, or GOKIND, Study. 

The risk of kidney complications in type 1 diabetes appears to have a considerable genetic component. This study assembled a large data resource for researchers attempting to identify causative genetic variants. The types of data collected allowed traditional case-control testing, a rapid and often powerful approach, and family-based analysis, a robust approach that is not influenced by population substructure. 

In total, 600 case trios, 500 control trios, 500 singleton cases and 500 singleton controls were collected. Half of the samples were collected at the Joslin Diabetes Center and the other half were collected from around the country by researchers at The George Washington University. DNA samples were processed by scientists at the University of Minnesota and stored at the U.S. Centers for Disease Control and Prevention. Stored samples were available to the research community through a mechanism that has been determined by JDF. Clinical characteristics of patients, which are stored in a central database, are also made available to participating scientists. A similar collection is being carried out in the United Kingdom. 

We collected the specified number of samples within a three year period, at which time qualified researchers were allowed to access samples. The JDF considered making a portion of the samples available at an earlier point in time. 

Diabetic nephropathy is a major concern in type 1 diabetes. Those afflicted with end-stage renal disease often face dialysis or renal transplant. Mortality among this group is also high. This data resource allows researchers to test hypotheses that might explain why diabetic kidney disease clusters in families. This resource also is suitable for studying other complications and type 1 diabetes itself. For example, a total of 1,110 diabetes case trios was available at the end of three years.

Girls Health Enrichment Multi-Site Studies (GEMS)

Principal Investigator:  James Rochon, Ph.D.

The Girl's Health Enrichment Multi-site Studies (GEMS) was a collection of studies designed to develop and test interventions to prevent excessive weight gain by African-American girls as they enter and proceed through puberty. The research was conducted as four inter-dependent, clinical trials. They were "inter-dependent" in the sense that they considered similar study populations, followed similar follow-up schedules and used a "core" set of evaluation procedures. Nonetheless, GEMS was not a "multi-center clinical trial" in the usual sense - each field center evaluated its own intervention (and corresponding control). As a result, each study had high internal validity and was designed and analyzed as a study in its own right. 

Each study wass designed as a parallel-group, randomized, controlled study. At the Baylor College of Medicine, the University of Minnesota and Stanford University, there were two treatment arms under consideration and each study included a sample of 240 girls. The study at the University of Memphis incorporates three arms and will included 360 girls. Given the nature of the intervention and control conditions, it was not be possible to mask study participants or GEMS staff members to the treatment assignments. 

Interventions provided a 24-month period and core follow-up evaluations performed at baseline, and at 12 and 24 months following randomization. Body-mass index (BMI) was the primary endpoint in all four studies. Secondary outcomes include anthropometric measures (e.g., waist circumference), measures of physical activity (recalled and recorded directly), diet and nutritional data (e.g., micro- and macronutrients from a 24-hr dietary recall), and behavioral and psychosocial evaluations. 

This research was conducted in four distinct phases. The "developmental phase" included a formative assessment phase which used qualitative methods to understand the specific needs of this population of girls and their families. A validity and reliability study was designed to compare two physical activity recall instruments and to determine whether a Digimax pedometer can measure physical activity as well as that provided by the CSA accelerometer device. A "pilot study" was performed prior to the main study. The purpose of the pilot was to demonstrate the feasibility of conducting this research program and to obtain data for planning the main study. The final component was the full-scale implementation of the different studies. 

NIH/NHLBI Cooperative Agreement 5-U01- HL62732

Hierarchical Models for Record Linkage (HIERMOD)


Intraprostatic Injection Of Botulinum Toxin For The Management Of Benign Prostatic Hyperplasia (MIST2)

Principal Investigator:  Michael Larsen, Ph.D.

Record linkage, or exact matching, is the process of bringing together records from two or more databases that pertain to common individuals. Often there is not a unique common identifier on the files and information can be partially or fully missing or recorded with error. The primary goal of this proposal is to fully develop, implement, and evaluate hierarachical models with and without one-to-one restrictions for record linkage. In order to achieve the desired goals, progress is needed in specification of statistical models, computational methods for these models, and application oriented implementation of procedures. Anticipated innovations are expected to yield significant improvements in record linkage methods, including methods of computation. The anticipated improvements in record linkage methods are expected to significantly impact record linkage operations in many agencies of the federal government and beyond. Funded by National Security Agency Agreement #98230-10-1-0232.)

Lung HIV Microbiome Project (LHMP)

Principal Investigator:  Mary Foulkes, Ph.D.
Principal Investigator:  Kathleen Jablonski, Ph.D.

The Biostatistics Center serves as the Data Coordinating Center (DCC) for the Lung HIV Microbiome Project (LHMP). The NIH Roadmap Human Microbiome Project is beginning to take advantage of metagenomic analysis to study microbiome-host interactions, and the LHMP will further contribute to that effort by focusing on the diseases that, alone or concurrently, interact with the microbiome of the lung. With its specific focus on the microbiome of the lung alone or in combination with the nasal and/or oropharyngeal cavities in HIV-infected individuals, the LHMP augments and expands the HMP efforts. The LHMP consists of 6 clinical/sequencing centers, the DCC and the National Heart, Lung, and Blood Institute (NHLBI) program staff. The aim of the LHMP network is to bring the distinct efforts at multiple clinical/sequencing centers together under a single infrastructure, combining the expertise accumulated across the range of involved disciplines in a focused and concentrated collaboration.)

Management Of Myelomeningocele (MOMS)

Principal Investigator:  Elizabeth Thom, Ph.D.
Co-Investigator:  Pamela Katzen Burrows, M.S.
Homepage:  MOMS website

The Biostatistics Center serves as the Coordinating Center for MOMS the 'Management of Myelomeningocele Study, a multi-center randomized clinical trial comparing prenatal closure of myelomeningocele defects with the standard treatment which is closure after birth (postnatal closure). Recruitment started in February 2003. 

There are three participating medical institutions which are designated as MOMS Centers: Children's Hospital of Philadelphia, Vanderbilt University Medical Center and the University of California at San Francisco. One hundred eighty-three women carrying a fetus with myelomeningocele were enrolled with equal randomization to each arm; prenatal or postnatal surgery. Follow-up takes place at 12 and 30 months of age and will continue through 2013. Primary outcomes include death or the need for ventricular decompressive shunting by one year of life and measures of neurodevelopmental function at 30 months. The study was stopped early for efficacy in December 2010. Preliminary results were reported in the New England Journal of Medicine in February 2011. Funded by NICHD, U01-HD041665, 2002-2012.)

Markers and Mechanisms of Macrovascular Disease in IDDM (MMMD)

Principal Investigator:  Patricia A. Cleary, M.S.

Markers and Mechanisms of Macrovascular Disease in IDDM was a Program Project sponsored by National Institutes of Healthand the Juvenile Diabetes Research Foundation International (JDRF) . The Program Project was coordinated by the Medical College of the University of South Carolina (MCUSC). The overall objectives of the Program Project were to define and elucidate underlying biochemical, metabolic and genetic determinants of macrovascular disease in IDDM patients. In order to accomplish the objectives, the MCUSC elected to interact with Epidemiology Of Diabetes Interventions And Complications (EDIC), which is following a large cohort of IDDM patients with a rigorous assessment of diabetic complications. The Biostatistics Center assisted the MCUSC in the design and implemention of the project and assisted in the analysis of the results. 

NIH 1P01HL55782-OIAI, JDRF 996001 1996-2001

Medical Therapy of Prostatic Symptoms (MTOPS)

Principal Investigator:  Pamela Katzen Burrows, M.S.
Principal Investigator:  Oliver M. Bautista, Ph.D.

Enlargement of the prostate is a common part of a man's aging process. The prostate gland is in a process of continual growth through most of a man's adult life. Medical doctors refer to the condition of having an enlarged prostate as benign prostatic hyperplasia (BPH), or benign prostatic hypertrophy. Though prostate enlargement is an ongoing process, it does not usually present problems until late in a man's life. Many of the problems that occur as a result of BPH can be attributed to the obstruction of the urethra and loss of bladder function, two conditions that are directly related to the enlargement of the prostate. There are various symptoms of BPH, but the common ones involve changes or problems with urination. 

Treatment options available to men who have BPH symptoms fall into three general categories: surgical, non-surgical, and drug therapy. The U.S. Food and Drug Administration (FDA) has approved four drugs for the treatment of BPH. These drugs alleviate the symptoms of BPH by relieving the obstruction of the urethra. 

Finasteride ( Proscar (R) ), a 5(alpha)-reductase inhibitor, was approved by the FDA in 1992. Finasteride inhibits the production of hormones that causes the enlargement of the prostate. Finasteride can also shrink the prostate in some men. 

Three other FDA-approved drugs belonging to the class of drugs known as alpha-blockers relieve BPH symptoms by relaxing the smooth muscle of the prostate and the bladder neck. Terazosin (Hytrinÿ) was approved by the FDA in 1993, doxazosin ( Cardura (R) ) in 1995, and tamsulosin (Flomaxÿ) in 1997. 

The Medical Therapy of Prostatic Symptoms ( MTOPS) was a multi-center clinical trial designed to assess the long-term benefits of pharmacotherapy of BPH. MTOPS was a double-masked, placebo-controlled randomized clinical trial designed to evaluate the long-term efficacy of finasteride, or doxazosin, or the combination of both, in delaying or preventing the clinical progression of symptomatic BPH. MTOPS was the largest and longest study to test whether drug therapy can prevent or delay the noncancerous growth of the prostate. 

The George Washington University Biostatistics Center serves as the Biostatistical Coordinating Center (BCC) of the MTOPS trial. 

A limited six-center randomized clinical trial was conducted during 1992-95 in 141 participants with symptomatic BPH to determine the feasibility of conducting a full-scale trial. Upon successful completion of the feasibility phase, the full-scale trial was initiated with 17 US clinical sites participating. From December 1995 through March 1998, the 17 MTOPS clinics enrolled 2,931 participants with a diagnosis of symptomatic BPH. 

Participants were randomized to one of four treatment groups: double-placebo, finasteride, doxazosin or the combination of finasteride and doxazosin. A total of 3,047 participants randomized during the pilot and full-scale phases are currently being followed with quarterly visits. Follow-up phase of the full-scale trial will continue until the end of November 2001. Closeout and analysis phase will commence immediately after the last follow-up visit is completed and is projected to last until the first quarter of the year 2002. 

Unique feature of MTOPS that has not been done in prior studies of pharmacotherapy of BPH is the biopsy substudy. A total of 1,082 volunteers from the 2,931 participants randomized during the full-scale phase are currently participating in this substudy. Biopsies of the prostate will be obtained on these volunteers at predetermined times during the course of the trial to evaluate the status of the prostate at key event times. The purpose of the substudy was to provide additional information regarding the histopathobiology of BPH and to test existing biomarkers for their prognostic ability regarding response to drug therapy. 

Funding for MTOPS NIH/NIDDK (UO1-DK-46472; IND 43,564)

Minimally Invasive Surgical Therapies for Benign Prostatic Hyperplasia (MIST)

Principal Investigator:  Kathryn Hirst, Ph.D.

Benign prostatic hyperplasia is a common condition in older men characterized by voiding symptoms and prostate abnormalities. Treatment ranges from `watchful waiting' to invasive surgical therapy with potentially serious side effects. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has sponsored a collaborative group of seven clinical centers and a coordinating center to investigate the efficacy and safety of surgeries considered minimally invasive to treat benign prostatic hyperplasia (BPH). Minimally invasive surgical therapies use heat effects to alter or destroy prostatic tissue in situ. Basic approaches include laser, microwave, or ultrasound energy to deliver heat to the target area. In its first year, the collaborative group designed and developed a protocol to conduct a clinical trial. The Biostatistics Center serves as the coordinating center for the collaborative group.

Myocardial Infarction and the Role of Oral Contraceptives

Principal Investigator:  Dean E. Krueger, M.S.

A case-control study of the risk of cardiac death for users of oral contraceptives. 

NIH/NICHD Contract N01-HD-6-2808, 1975-1980.

National Cooperative Gallstone Study (NCGS)

Principal Investigator:  John M. Lachin, Sc.D.

The National Cooperative Gallstone Study (NCGS) was double-blind, randomized, controlled, multicenter clinical trial of 1,044 subjects to study the efficacy and safety of using the bile salt chenodiol (chenodeoxycholic acid) to dissolve gallstones. The study was funded through a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). An initial study of 128 patients randomized to high or low dose chenodiol included liver biopsy periodically to assess potential hepatotoxicity. Subsequently, in a full-scale study, 916 patients were followed for 2 years of treatment, approximately one-third assigned to high dose chenodiol, low-dose chenodiol or placebo. The principal results (Schoenfield, Lachin et al., Annals of Internal Medicine, 1981) showed that chenodiol was marginally effective, achieving complete dissolution of gallstones in 13% of patients treated with the high dose, versus only 1% among those treated with placebo. Chenodiol, however, was potentially hepatotoxic and also lead to slight elevations in serum lipids. Based largely on the results of the NCGS, chenodiol was approved by the U.S. Food and Drug Administration as the first non-surgical treatment for gallstones. All total, 20 papers have been published by the LNCS group. 

NIH/NIDDK Contract N01- AM-0-2205, 1973-1984.

National Exercise and Heart Disease Project

Principal Investigator:  Lawrence Shaw, A.M.

A randomized, controlled, multicenter clinical trial of the effect of intensive supervised exercise activity for 650 post-myocardial infarction patients. 

NIH/NIHR Grant, 1972-1980.

Natural History of Posttransfusion Non-A, Non-B Hepatitis

Principal Investigator:  Elizabeth C. Wright, Ph.D

A follow-up study of 1764 patients enrolled between 1968 and 1980 in five multicenter studies of posttransfusion hepatitis. 

NIH/NHLBI Contract N01-HB-87047, 1988-1992.

Neonatal Intensive Care Units Network (NICU)

Principal Investigator:  Raymond P. Bain, Ph.D.
Co-Investigator:  Joel I. Verter, Ph.D.

In 1985, the National Institute of Child Health and Development (NICHD) of the National Institutes of Health (NIH) established the Neonatal Intensive Care Units (NICU) Network. The NICU Network conducted clinical trials and epidemiologic studies in neonatal medicine. Many of the current treatment and management strategies in perinatal medicine have become standards of care without proper evaluation through well designed research protocols. For many of the regimens needing evaluation, the sample size required for adequate power to detect clinically important differences exceeds the patient population resources of individual clinical centers. Thus, the Neonatal Intensive Care Units (NICU) Network focused on those questions in perinatal medicine which require a multicenter effort to obtain adequate numbers of eligible patients, and which have the potential for affecting major risk factors for perinatal morbidity and mortality. The Biostatistics Center was the Biostatistical Coordinating Center for the NICU Network December 1986 until September 1998. 

The NICU Network consisted of 14 NICU clinics and implemented, executed or analyzed multiple projects simultaneously (registries, randomized clinical trials, and cohort studies). The purpose of these studies was to evaluate various aspects or interventions related to the management of infants in neonatal intensive care units. 

The randomized clinical trials included: 1) Steroid Trial: an investigation of the use of dexamethasone therapy in reducing the risk of chronic lung disease (371 mothers at 12 centers), 2) Phenobarbital Trial: a trial testing the ability of prelabor use of phenobarbital in reducing the early risk of neonatal mortality and hemorrhage (610 mothers and 668 infants at 9 centers), 3) Nitric Oxide Trial: a trial evaluating the use of nitric oxide to reduce the risk of death or the need for ECMO (235 infants at 18 US and Canadian clinical centers), 4) Vitamin A Trial: a randomized trial to evaluate the use of vitamin A to reduce the risk of death or chronic lung disease (800 infants at 14 clinical centers). Other studies in recruitment include: assessment of physical and neurodevelopmental status at 18 months of age for babies born 401-1000 grams; a non-randomized prospective study of the impact of the use of antenatal magnesium sulfate in mothers delivering babies 401-1000 grams. In addition, the Very Low Birthweight Registry (VLBW) and the Extremely Low Birthweight Registry (ELBW), are generic data bases of information and outcome measures on over 20,000 infants born weighing between 401 and 1500 gms which are being managed by the Center. 

Three studies completed in 1995-1996 reported the following results: the Dexamethasone Trial reported no difference in the time to extubation between a group of neonates given steroids on day 14 of age versus the group receiving steroids on day 28, if still needed; the Phenobarbital Trial was stopped early after a finding of no difference in the risk of early death or intraventricular hemorrhage; the Nitric Oxide Trial was terminated early after a significant reduction in the risk of death or the need for ECMO was found. 

NIH/NICHD Cooperative Agreement 5-U01-HD19897, 1986-1998.

Optic Neuritis Treatment Trial (ONTT)

Principal Investigator:  Patricia A. Cleary, M.S.

The Biostatistics Center served as the data coordinating center for the ONTT, a randomized, distributed data entry, 15-center clinical trial of 457 patients to evaluate the benefit of corticosteroid treatment of optic neuritis and to investigate the relationship between optic neuritis and multiple sclerosis. The study's structure consisted of 15 clinical centers and three central units: Study Headquarters, Data Coordinating Center and Visual Field Reading Center. The trial established that intravenous methylprednisolone sped recovery of visual function without significantly improving long-term visual outcomes and was also associated with a reduced incidence of symptomatic multiple sclerosis; oral prednisone not only failed to demonstrate any benefit compared to placebo but was further associated with an increased risk of recurrence of optic neuritis (NEJM 326:9, 1992; and NEJM 329:24, 1993). 

The ONTT has published more than 25 ONTT Publications presenting its results. 

Grant from NHI/NEI, 1987-1993

Peptide T in HIV-Positive Individuals with Cognitive Impairment

Principal Investigator:  James Rochon, Ph.D.
Co-Investigator:  Raymond P. Bain, Ph.D.

The Peptide T Trial was a double-masked, placebo-controlled, multicenter randomized clinical trial to determine the safety and efficacy of intranasaly administered Peptide T, an octapeptide, on neuropsychological performance in HIV seropositive individuals with cognitive impairment. The 200 randomized participants were followed for a fixed duration of six months of double-blind therapy followed by open-label Peptide T. Secondary clinical measures included motor and sensory neurologic function and laboratory measures of HIV caused immunologic dysfunction. 

NIH/NIMH Contract N01-MH10012, 1994-1996

Planning a Multi-Center Trial of Tamsulosin for Urolithiasis (STONE PLANNING)

Principal Investigator:  Pamela Katzen Burrows, M.S.
The Biostatistics Center serves as the Biostatistical Coordinating Center for the planning grant of the multi-center continuation to the Randomized Trial To Study Tamsulosin For Urolithiasis In The Emergency Department (STONE). There are three participating Departments of Emergency Medicine: The George Washington University Hospital continues as the lead institution along with the University of Pittsburgh Medical Center, and the Hospital of The University of Pennsylvania. This grant is for planning the conversion of the original STONE study from a single center to a multi-center study. Funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant # NIH U34 DK090957-01 (2010-2012)

Prenatal Cytogenetic Diagnosis by Array-Based Copy Number Analysis (MICROARRAY)

Principal Investigator:  Elizabeth Thom, Ph.D.

 The Biostatistics Center serves as the coordinating center for this observational study designed to assess the utility of array-base copy number analysis (microarray) technology in comparison with conventional cytogenetic diagnosis in chorionic villus and amniotic fluid samples drawn for prenatal diagnosis of chromosomal abnormalities in the fetus. It is expected that microarray will detect all clinically useful abnormalities currently diagnosed by conventional cytogenetics, as well as less common but clinically significant syndromes. The study began in 2008 with plans to enroll 4,000 women who will undergo a prenatal diagnosis procedure. Their specimens will be tested at four specialized microarray laboratories with results compared to conventional cytogenetics laboratory results. Matched controls will be followed until the age of 2 years in order to assess the infants for potential physical anomalies and developmental delay. 

This study is funded by a subcontract with Columbia University under a Grant awarded by NIH/NICHD R01-HD05565-01 (2007-2012)

Preventative Estradiol for Inhibition of Angioplasty Restenosis Lesions in (PEARL)

Principal Investigator:  Kathryn Hirst, Ph.D.

 The Biostatistics Center served as coordinating center for PEARL, funded by the National Institute on Aging (NIA). The primary goal was to investigate the potential of estrogen replacement therapy to inhibit or prevent restenosis in post-menopausal women who have undergone balloon angioplasty with intra-coronary stent insertion. This study was designed to provide pilot data to assess the feasibility and guide the design of a larger multi- center clinical trial. A sample of 100 women at seven clinical centers were randomized to a twelve-week regimen of estradiol administered as a topical patch vs a control patch. The primary outcome is minimum luminal diameter measured by quantitative coronary angiography twelve weeks after the initial revascularization procedure. 

NIH/NIA Grant: R01 AG16332-01A1, 1999- 2000

Prevention Of Events With Angiotensin (PEACE)

Principal Investigator:  Madeline Rice, Ph.D.
Co-Investigator:  Sarah E. Fowler, Ph.D.

The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial is a randomized placebo controlled, multi-center multi-national trial initiated in November 1995 by the National Heart, Lung, and Blood Institute (NHLBI). The primary objective of the trial is to test whether the addition of the angiotensin converting enzyme (ACE) inhibitor, trandolapril, to standard therapy will reduce the incidence of cardiovascular mortality, non-fatal myocardial infarction, or the occurrence of a coronary artery bypass graft surgery (CABG) or percutaneous transluminal coronary angiography (PTCA) in patients with documented coronary artery disease and preserved left ventricular function. Over one hundred and eighty-five clinical centers in the United States, Puerto Rico, Canada, and Italy completed recruiting 8,290 patients for the study in June 2000. Follow-up ended on December 31, 2003 with an average follow-up of over 4 years. The George Washington University Biostatistics Center serves as the Clinical and Statistical Coordinating Center for this trial.

Prospective Investigation Of Pulmonary Embolism Diagnosis (PIOPEDII)

Principal Investigator:  Sarah E. Fowler, Ph.D.
The Biostatistics Center served as the Data Coordinating Center (DCC) for a multi-center study of patients with suspected pulmonary embolism (PE) in order to determine the sensitivity, specificity, positive predictive value, and negative predictive value of contrast enhanced spiral computed tomography (spiral CT) for the diagnosis of acute PE. The Prospective Investigation Of Pulmonary Embolism Diagnosis (PIOPED II) involved an established group of investigators at nine institutions in addition to the DCC. Spiral CT is a minimally invasive diagnostic test. Appropriate use of spiral CT in a diagnostic strategy could reduce or eliminate the need for more invasive tests such as ventilation/perfusion lung scans, compression ultrasound of the lower extremities, and digital subtraction angiography. Data will be collected on 824 patients with suspected PE who will be followed for 6 months. The DCC coordinated distribution of scan images to readers throughout the clinical centers for final interpretation and conduct analyses of study results. 

Funded by NIH/NHLBI R01 HL63942-01, 2000-2004

Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED III)

Principal Investigator:  Sarah E. Fowler, Ph.D.
The Prospective Investigation of Pulmonary Embolism Diagnosis III (PIOPED III) will estimate the diagnostic accuracy of gadolinium-enhanced magnetic resonance angiography of the pulmonary arteries (Gd-MRA) and Gd-MRA combined with gadolinium-enhanced magnetic resonance venography (MRV) for the diagnosis of acute pulmonary embolism (PE). Diagnostic accuracy will be expressed as the sensitivity, specificity, likelihood ratio for a positive test and likelihood ratio for a negative test. The reference test consists of the most definitive from among combinations of tests comprising standard of care for diagnosing PE: spiral CT/CTV angiogram/venogram, ventilation/perfusion lung scan, pulmonary angiogram, and compression US, d-Dimer, and standardized clinical assessment. 

The study will enroll 1256 patients to determine the extent to which Gd-MRA or Gd-MRA/MRV can serve as a diagnostic test in patients with clinically suspected PE, and thereby eliminate the need for iodinated contrast material or ionizing radiation in patients who have a relative contraindication to one of them. This is important because 24% of patients with suspected acute PE have a relative contraindication to diagnostic procedures that involve ionizing radiation or iodinated contrast material. 

Possible results of PIOPED III are that Gd-MRA or the combination Gd-MRA/MRV, can be used as: 1) a definitive diagnostic test in patients with suspected acute PE; 2) a definitive test to diagnose (but not exclude) PE; 3) a test to exclude (but not diagnose) PE; and 4) a definitive diagnostic test to diagnose PE in central pulmonary arteries, requiring additional tests to exclude PE in segmental or subsegmental arteries. 

The Biostatistics Center serves as the Data Coordinating Center (DCC) for the study. In addition to data collection, data management, and statistical analysis, the DCC coordinates distribution of scan images to readers throughout the clinical centers for final interpretation. 

The study is funded by the NIH/NHLBI through the cooperative agreement mechanism. (5U01-HL077155-01A1, 2005-2009)

rhIGF-1 Genentech Epidemiological Project (IGEP)

Principal Investigator:  Patricia A. Cleary, M.S.

The Biostatistics Center served as the Methodological and Biostatistical Coordinating Center (MBCC) for the rhIGF-1 Genentech Epidemiological Project (IGEP). The IGEP consisted of 6 separate observational epidemiological studies. The studies were selected to provide complementary safety information to clinical trials conducted by Genentech. The trials are designed to determine the efficacy and safety of rhIGF-1 therapy in patients with insulin-dependent diabetes mellitus and non-insulin dependent diabetes mellitus (NIDDM) receiving standard diabetes therapy. Demonstrating safety in clinical trials lasting twelve months with approximately 1,500 patients exposed to rhIGF-1 is limited to the more common events of acute onset. IGEP was designed to provide evidence on the safety of rhIGF-I in the short-term for less common events. 

Safety considerations and complications of diabetes with rhIGF-1 treatment differ between IDDM and NIDDM. Hypoglycemia is a more frequent complication of IDDM. Cardiovascular disease, in part because of its association with age, is frequently observed in NIDDM. Microvascular complications, retinopathy, neuropathy and nephropathy, are common to both. Events other than the complications of diabetes may apply jointly to IDDM and NIDDM. 

The rhIGF-1 treated cohort was assembled from the randomized controlled trials and their open-label extensions. These consisted of two subcohorts of patients with IDDM and those with NIDDM, treated with either insulin or oral agents. The non- experimental studies within the IGEP utilized the following data bases for reference purposes: 

1. Diabetes Control and Complications Trial (DCCT) 
2. Epidemiology of Diabetes Interventions and Complications 
3. Kaiser Permanente Diabetic Registry 
4. Wisconsin Epidemiological Study of Diabetic Retinopathy 
5. St. Thomas Hospital Diabetic Registry 
6. rhIGF-I Open Label Studies in IDDM and NIDDM 

The Biostatistics Center served as the Coordinating Center for the IGEP until the clinical trial was stopped in 1997. Contract funded by Genentech 1997

Routine Antenatal Diagnostic Imaging with Ultrasound (RADIUS)

Principal Investigator:  Raymond P. Bain, Ph.D.

The Biostatistics Center served as coordinating center for the trial of Routine Antenatal Diagnostic Imaging with Ultrasound (RADIUS); an office-based, multi-center clinical trial of ultrasound use in low risk pregnancies. RADIUS was a randomized clinical trial designed to evaluate the efficacy of routine prenatal ultrasound use on perinatal outcome in obstetrical participants at low risk for perinatal problems. Over a 3.5 year period in 109 primary care sites in 5 geographic regions of the US, RADIUS randomized a total of 15,530 low-risk obstetrical patients. Participants were randomized to one of two groups: selective use of ultrasound on the basis of clinical judgment or two routine antenatal ultrasounds which were scheduled at 16 to 22 and 31 to 35 week gestation. Pregnancy outcome was abstracted from antenatal medical records and inpatient hospital records. RADIUS concluded that screening ultrasound did not improve perinatal outcome as compared with the selective use of ultrasonography on the basis of clinical judgment (The New England Journal of Medicine 1993;329:821-827). 

Funded by NIH/NICHD (U01-HD-19897), 1987-1993

Sarcoidosis Genetic Analysis (SAGA)

Principal Investigator:  Kathryn Hirst, Ph.D.
Principal Investigator:  Sarah E. Fowler, Ph.D.

Sarcoidosis is a systemic granulomatous disease of unknown etiology that likely involves some environmental agent in a genetically susceptible host. The National Heart, Lung, and Blood Institute (NHLBI) sponsored Sarcoidosis Genetic Analysis (SAGA) consortium will identify sarcoidosis susceptibility genes and to determine how these genes and environmental risk factors interact to cause sarcoidosis. The 10-site multi-center consortium will recruit a sample of sarcoidosis families for analysis. The study enrolled 338 African American sarcoidosis-affected sibling pairs and a percentage of their parents and unaffected siblings for a total of 1038 subjects. The study collected phenotypic data on sibling pairs with sarcoidosis and, for each family member enrolled, collected demographic and environmental data and a blood sample for genetic analysis. The study scanned the genome for linked chromosomal regions using affected sibling pair linkage analysis; evaluated candidate genes in those regions with evidence for linkage using transmission disequilibrium testing; and collected data on environmental exposures to test for possible interactions of susceptibility genes with exogenous risk factors. The Biostatistics Center served as the coordinating center for the study. 

NIH/NHLBI Cooperative Agreement: U01-HL60263-01A1, 1999 - 2004

Sites Testing Osteoporosis Prevention/Intervention Treatments (STOP/IT)

Principal Investigator:  Sarah E. Fowler, Ph.D.

Sites Testing Osteoporosis Prevention/Intervention Treatments(STOP/IT) was a cooperative agreement funded by the National Institute on Aging (NIA). Sarah Fowler was the Principal Investigator and Kathryn Hirst was Co-investigator. The STOP/IT project investigated the impact of four different interventions on the rate of bone loss in the elderly. The four trials randomized 1119 subjects and followed them for up to three years on interventions of hormone replacement therapy, vitamin D, calcium supplements, weight bearing exercise, or testosterone. In addition to longitudinal measurement of bone mineral density using dual-energy x-ray absorptiometry, effects on mobility and activities of daily living are also examined. Three of the STOP/IT clinical centers also conducted a two-year post intervention follow-up study. The coordinating center was responsible for: creating a cooperative effort among the independent trials; for accumulation, management, and analysis of the central common data set; and for reporting to the Data Safety Monitoring Board. Investigators met as a Steering Committee to decide the contents of the common data set, quality control issues affecting laboratory and bone density values, and statistical analysis and manuscript preparation. 

NIH/NIA Cooperative Agreement, AG10373, 1999-2000

Statistical Methods for Cancer Clinical Trials

Principal Investigator:  Gordon K.K. Lan, Ph.D.

The objective of the project was to develop sequential statistical methods for the data monitoring of complex clinical trials in cancer. In many of these clinical trials, the principal outcomes include immediate responses that can be completely measured soon after a patient enters the study; or in many others, time to an event; responses recorded periodically over time, or events that recur over time. Sequential monitoring of responses of these types in large clinical trials usually fit into a unified framework. 

NIH/NCI Grant 5-RO1-CA55098, 1991-1995

Statistical Methods for Longitudinal Studies in Cancer

Principal Investigator:  James Rochon, Ph.D.

In this research, we proposed to address the issue of adjusting for confounders observed post-randomization in randomized clinical trials. Examples of these confounders included patient "compliance" measured through pill counts and other biochemical markers, the occurrence of co-morbid events, the use of concomitant and "rescue" medications, withdrawal from the assigned therapy, and so on. Since the confounder is observed following randomization, it can be considered as an outcome measure and analyzed accordingly. Previous research has begun from this premise and demonstrated how to adjust inferences on the primary endpoint for the influence of these confounding variables. In this study, we proposed to extend previously developed methodologies in several important directions: 

(1) development of a methodology to perform inference on a primary response variable adjusting for a survival confounding measure in repeated measures experiments; 
(2) development of a methodology in longitudinal data to adjust for informative censoring and other missing value problems; 
(3) perform a simulation study of the proposed estimation and hypothesis testing procedures; 
(4) development of procedures for analyzing bivariate repeated measure data; and, 
(5) development of a general methodology for performing sample size calculations for discrete and continuous repeated measures studies. 

Grant from NIH/NCI, 1-R01-CA70286- 01, 1996-1999

Statistical Methods In Cancer Clinical Trials

Co-Investigator:  John M. Lachin, Sc.D.
Co-Investigator:  Oliver M. Bautista, Ph.D.
Co-Investigator:  Gordon K.K. Lan, Ph.D.

Drs. Lachin and Bautista , in collaboration with Dr. K.K. Gordon Lan, former faculty member of the Center, undertook research into various statistical methods related to the analysis of clinical trials in cancer, and to trials in general. The principal focus of the research was to develop methods for the analysis of event count data, the analysis of longitudinal data, the properties of group sequential procedures, especially with application to these areas. Other matters of general interest such as rank analyses with informative censoring and the intention-to-treat principle have also been addressed. 

For the analysis of count data, that is common in the assessment of adverse events in clinical trials, methods have been developed that allow the estimation of the mean rate, and the variance of the mixing distribution, for an over-dispersed Poisson process without the need to specify the form of the mixing distribution. We also extend these results to Poisson regression models with distribution-free estimates of the over-dispersion variance component. We have also shown that a process of these statistics, computed sequentially, can be characterized as Brownian motion. 

For the analysis of longitudinal data, we have likewise relaxed the usual assumption of a random effect that is normally distributed and have described the properties of such analyses when computed sequentially over time. For distribution-free multivariate analyses of repeated measures, we have also described the joint distribution of a sequence of K-df chi-square tests. 

We have described the power of group sequential procedures in general and the factors that affect the power of such sequential tests. We have also shown that if the boundary is crossed but the trial is not terminated, then the previously spent type I error may be retrieved with negligible effect on the final type I error of the sequential test and with minimal effect on power. 

Grant from NIH/NCI 5-R01-CA55098 1997-2000

Study of Plasmapheresis in Severe Lupus Nephritis

Principal Investigator:  John M. Lachin, Sc.D.

The Lupus Nephritis Collaborative Study was a randomized, controlled, multicenter clinical trial to evaluate the effectiveness of plasmapheresis therapy in subjects with severe lupus nephritis. The study was launched in 1981 and was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Lupus nephritis is an autoimmune disease which leads to potentially severe renal disease (lupus nephritis) for which the standard therapy is steroids (prednisone) plus immunosuppressive drug therapy (cytoxan). Patients were randomized to receive either standard drug therapy versus drug therapy plus plasmapheresis. The principal outcome was significant renal impairment, renal transplant or dialysis or death. The study was terminated after 80 subjects had been enrolled due to lack of effectiveness. Long-term follow-up indicated that plasmapheresis had no beneficial long-term effects on survival (LNCSG, NEJM, 1992). All total, 9 papers have been published by the LNCS group. 

NIH/NIDDK Grant 2-R01-AM22769, 1981-1988

Targeting Inflammation Using Salsalate In Type 2 Diabetes (TINSAL-T2D)

Principal Investigator:  Kathleen Jablonski, Ph.D.
The Biostatistics Center serves as the Coordinating Center for the Targeting Inflammation Using Salsalate for Type 2 Diabetes Study (TINSAL-T2D). This study is a multi-center, randomized, double-masked, placebo-controlled, parallel-group clinical treatment trial. The primary objective of the study is to determine whether salicylates represent a new pharmacological option for diabetes management. This new study is in the first of two stages. The primary objective of stage one is to select a dose of salsalate that is both well-tolerated and demonstrates a trend toward improvement in glycemic control. The implementation of the second stage is predicated on the successful selection of a dose in the first stage. If no dose meets the criteria for continuation to Stage 2, the study will end after Stage 1. The primary objective of Stage 2 of the study will be to evaluate: the effects of salsalate on glycemic control in diabetes; the tolerability of salsalate use in patients with type 2 diabetes (T2D); and the effects of salsalate on measures of inflammation, the metabolic syndrome, and cardiac risk. Funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Cooperative Agreement 1-U01-DK074556-01, 2006-2009

The Womens Health Study

Principal Investigator:  Sarah E. Fowler, Ph.D.
A hospital-based case-control study of 20,000 women evaluated the associations between IUD use in relation to pelvic inflammatory disease and other OB/GYN conditions. The study found that IUD users were at significantly greater risk of pelvic inflammatory disease (OBGYN, 1981) and were 10 times more likely to experience a second trimester fetal loss if the IUD was not removed in the first trimester (OBGYN, 1981). 

NIH/NICHD Contract N01-HD-5-2852, 1975-1982

Type 1 Diabetes TrialNet Coordinating Center (TRIALNET)

Principal Investigator:  John M. Lachin, Sc.D.
Co-Investigator:  Naji Younes, Ph.D.
Co-Investigator:  Heidi Krause-Steinrauf, M.S.

The Type 1 Diabetes TrialNet is jointly funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), and National Institute of Child Health and Development(NICHD) with additional support from the Juvenile Diabetes Research Foundation International (JDRFI). The Biostatistics Center serves as the Coordinating Center for the project. The overall purpose of Trialnet is to conduct clinical research and clinical trials in the preservation of insulin-generating islet cells in those newly diagnosed with type 1 diabetes mellitus (T1DM), and in the etiology and prevention of the onset of diabetes in individuals at high risk for developing diabetes. 

In 2003, it was estimated that worldwide about 194 million individuals had diabetes mellitus. Type 1 diabetes accounts for 5% to 10% of all diagnosed cases of diabetes. In the US alone, approximately 20.8 million individuals, or 7.0% of the total population have diabetes. About one in every 400 to 600 children and adolescents has type 1 diabetes. The onset of type 1 diabetes mellitus is one step in a chain of events that begins at the moment of conception. Genetic polymorphisms, principally HLA haplotypes, have been identified that confer an increased risk of developing diabetes, or are protective. Genetic defects render an individual susceptible to an aberrant immunologic response to one of possibly many environmental insults. Following the environmental trigger, the T-cells begin an assault on the insulin-producing beta or islet cells of the pancreas. This autoimmune response is manifest by the appearance of antibodies and the subsequent loss of first phase insulin response. Thereafter beta cell function declines. This makes it feasible to conduct studies of the genetics of type 1 diabetes and immune tolerance, the role of environmental pathogens, the characterization of autoimmunity and immune tolerance, evaluation of the risk of developing diabetes, and various interventions aimed at immune tolerance or preservation of beta cell function. 

TrialNet is conducting a nationwide program of screening of first degree relatives of subjects with T1DM to identify individuals at exceptionally high risk of diabetes who have measurable levels of antibodies to insulin products and islet cells which indicate that the autoimmune process of rejection has been initiated. Subjects with auto-immune pre-diabetes are followed to evaluate factors associated with development of diabetes. Such subjects will also be enrolled in studies of agents to prevent diabetes onset. TrialNet is also conducting studies of the use of immunosuppression or immunomodulation to preserve beta cell function in subjects newly diagnosed with T1DM. A study of dietary intervention to prevent the onset of autoimmunity in newborns is also being conducted, as well as methodologic studies related to the evaluation of the metabolic and immunologic status of subjects with diabetes or at risk of diabetes. 

TrialNet consists of 14 Clinical Centers in the United States and Canada, one in Australia and 3 in Europe. Each Clinical Center has a network of Affiliate sites, numbering in the hundreds. In 2006, 15 Major Affiliate sites were designated in North America. The study is chaired by Jay Skyler, MD of the University of Miami. The study is supported by a Central Pharmacy, an insulin autoantibody laboratory, an islet cell antibody laboratory, a class II major histocompatibility and DNA extraction lab, a Beta Cell function laboratory, Central Virology Laboratory and Central Biochemistry Laboratory - all funded by subcontracts through the GWU Coordinating Center. 

Funded by NIH/NIDDK Cooperative Agreement U01-DK061055, 2001- 2008. 

A description of current ongoing and completed studies follows: 

Natural History Study (2004 - ) This study is screening first degree relatives of subjects with type 1 diabetes to identify subjects with insulin or islet cell autoimmunity who are then further evaluated with metabolic tests to attempt to determine the risk of developing type 1 diabetes over the coming 5 years. Subjects with autoimmunity are then eligible to enroll in a long-term follow-up study aimed at identifying risk factors for diabetes onset and the precise quantification of the 5 year diabetes risk. Such subjects may also be eligible to enroll in studies aimed at the prevention of diabetes onset, or if diabetes is diagnosed, in studies aimed at preservation of Beta-cell function in subjects newly diagnosed with diabetes. Clinical centers in North America, Europe and Australasia, and their affiliates, are screening 10 to 20 thousand or more such subjects annually. 

Mycophenolate Mofetil Daclizumab Clinical Trial (2004 - ) This randomized, double-blind, placebo controlled clinical trial enrolled a total of 126 subjects at 13 participating sites (11 in North America, 2 in Europe). The study aims to compare Mycophenolate mofetil (MMF) alone and in combination with Daclizumab (DZB) against placebo in preserving beta cell function, as measured by stimulated C- peptide, in subjects newly diagnosed with type 1 diabetes. All subjects will be on treatment for two years, followed by at least one year of post-treatment follow-up. The first subject enrolled in the study began treatment in July 2004, and the last subjects enrolled will complete the treatment period in December 2008. 

Mixed Meal Tolerance Test vs Glucagon Stimulation Test (2004-2005) The primary objective of this study was to evaluate the reproducibility and tolerability in two tests measuring C- peptide as a measure of Beta cell function. In the Mixed Meal Tolerance Test (MMTT), the stimulus is provided via ingestion of a liquid meal (Sustacal/Boost) when in the fasting state, with timed measurement of C-peptide levels over the subsequent 2 hours (sometimes 4 hours). In the Glucagon Stimulation Test (GST) the stimulus is an injection of glucagon with timed measurements over the subsequent 10 minutes. 166 participants were enrolled in 14 North American and 2 international centers, of whom 148 underwent at least one test. The first visit took place on September, 2004 and the last visit took place In December 2005. 

T Cell Validation Study (2005 - 2007) Type 1 diabetes is a consequence of prolonged autoimmunity mediated by progressive T-cell destruction of the insulin secreting Beta-cells or islet cells of the pancreas. Although it is known that T-cell mediated autoimmunity is the underlying pathogenesis of type 1 diabetes, there has been modest progress in the development of reliable and valid assays of T-cell activity. The purpose of this study is to evaluate four different T-cell assays in 5 different laboratories with respect to their ability to discriminate subjects with diabetes versus normal controls, and to assess the qualitative and quantitative reproducibility of each assay. 

Effects of Rituximab on the Progression of Type 1 Diabetes in New Onset Subjects (2006 - ) The Anti-CD20 study is a multicenter, two-arm, randomized, double-masked, placebo-controlled clinical trial to assess whether Beta-cell function, as measured by stimulated C- peptide, among subjects receiving rituximab differs significantly from that for placebo subjects assessed at one year of follow-up. Sixty-six participants will be randomized, in a 2:1 ratio, to receive rituximab (anti-CD20 monoclonal antibody) at a dose of 375mg/m2 or matching placebo administered weekly for a period of 4 weeks. Study activities initiated April 2006. Twelve sites (US and international combined) are conducting the study. Enrollment was closed in July of 2007. 

Nutritional Intervention to Prevent (NIP) Type 1 Diabetes Pilot Trial (2006 - ) This is a multicenter, randomized, placebo controlled, double masked study to evaluate whether dietary supplementation with docosahexaenoic acid (DHA) starting prior to or immediately after birth will prevent development of insulin or islet cell autoimmunity in children at genetic risk of Type 1 Diabetes. This clinical trial pilot is being conducted at 9 sites in the United States. Subjects enter through one of two pathways. The first pathway enrolls pregnant women whose infant has a first degree relative with T1D while in their third trimester of pregnancy. The mother is randomized to receive either placebo or DHA capsules throughout her pregnancy. The infant continues in the study if they are determined to be eligible based on HLA typing after birth. The second pathway enrolls infants who have a first degree relative with T1D up to age six months of age. These infants will either receive DHA or placebo via formula feedings. In the case of a nursing mother, the infant will receive DHA or placebo via breast milk as the mother will take either DHA or placebo capsules. A total of 90 subjects will be enrolled in one year's time and followed for a year after which the feasibility of conducting a large scale trial will be assessed. 

Oral Insulin for the Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes (2007 - ) The Oral Insulin trial is a multicenter, randomized, double-masked, placebo-controlled clinical trial to assess whether oral insulin administration will delay or prevent the onset of T1DM to subjects at risk for the disease by virtue of the presence of insulin or islet cell autoimmunity but without glucose intolerance. This trial is conducted under a maximum information design in which subjects will be followed until the required amount of statistical information is obtained so as to provide 85% power to detect a 40% reduction in the risk of type 1 diabetes onset, or a relative hazard of 0.6. It is projected that approximately 300 subjects followed for up to 8 years may be required. Participants will be randomized, in a 1:1 ratio, to receive daily doses of insulin capsule (7.5 mg of recombinant human insulin) or matching placebo for the duration of the trial. Trial activities initiated February 1, 2007. Approximately 100 sites (US and international combined) will conduct the trial.


Principal Investigator:  Patricia A. Cleary, M.S.

This study involves a study of the device, SCOUT DS System, that employs fluorescence spectroscopy to non-invasively measure advanced glycation endproducts (AGEs) in the skin of an individual's forearm as an indicator of cumulative hyperglycemic exposure shown to predict the development of type 2 diabetes. AGEs are macroprotein complexes formed by the Maillard reaction of reducing sugars with free amino groups on proteins, amino acids, or lipids. Although they increase naturally with age, their formation is accelerated with chronic hyperglycemia and oxidative stress. AGEs are associated with almost all long-term complications of diabetes, and increased levels have been observed in the collagen of those with diabetes. In the Diabetes Control and Complications Trial, AGEs were a better marker of progression to micro-vascular complications than was A1C (Monnier et al., 1999). Several AGEs form fluorescent molecular cross-links. Increased fluorescence has been observed in the skin, retina, and kidney of individuals with diabetes (Forbes et al., 2005)Conventional AGE assays require a skin biopsy and are time intensive. Skin fluorescence provides a summary measure of skin AGEs and may be a strong indicator of diabetes complications. Funded through a subagreement with the VeraLight Corporation, 2009-2012.

Women's Angiographic Vitamin And Estrogen Trial (WAVE)

Principal Investigator:  Naji Younes, Ph.D.

 This study was a randomized, controlled, factorial clinical trial to evaluate the use of selected interventions in reducing the progression of coronary atherosclerosis in women. Approximately four hundred-twenty eligible women were randomized into the clinical trial. The trial utilized a factorial design to test the effect of a regimen of hormonal replacement therapy (an estrogen, and a progestin, when appropriate) and a combination of the antioxidants vitamins C and E, on the progression of atherosclerotic lesions in the coronary arteries. This was accomplished with a multi-disciplined team of investigators from 7 Clinical Centers, a Statistical Coordinating Center (SCC), the National Heart, Lung, and Blood Institute (NHLBI) project office, one central serum chemistry laboratory, a central angiographic reading center and a central pharmacy have been assembled. 

Contract funded by NIH/NHLBI, N01-HV-68165, 1996- 2001