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23andMe (United States)

360DIGITMG

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Accudata Solution

ADVENTHEALTH

AEGIS SCHOOL OF DATA SCIENCE AND CYBER SECURITY

AFRICAN INSTITUTE FOR MATHEMATICAL SCIENCES

African Institute of Science and Technology

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Air Force Medical University

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Al Azhar University

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Albany Stratton Va Medical Center

Albert Einstein College of Medicine

Alere (United Kingdom)

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Allegheny Health Network ESOPHAGEAL INSTITUTE

ALLUCENT

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AMERICAN FEDERATION FOR AGING RESEARCH

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ANDHRA UNIVERSITY

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ANKARA UNIVERSITY

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Arbor Research Collaborative for Health

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Assistance Publique – Hôpitaux de Paris

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BioMarin (United States)

Biomedical Research Foundation of the Academy of Athens

BIOMEDICAL RESEARCH INSTITUTE OF SOUTHERN CALIFORNIA

BIOTEAM

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BLEKINGE INSTITUTE OF TECHNOLOGY

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346346

National Institute of Diabetes and Digestive and Kidney Diseases

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Eunice Kennedy Shriver National Institute of Child Health and Human Development

National Institute on Deafness and Other Communication Disorders

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Nidcr

Niddk/Kuh

National Heart Lung and Blood Institute

United States National Library of Medicine

National Institute of Neurological Disorders and Stroke

National Institute on Minority Health and Health Disparities

Nhgri

FOUNDATION FOR THE NATIONAL INSTITUTES OF HEALTH

Cash Prize

Non-monetary

Both cash prize & non-monetary

Stress urinary incontinence (SUI) is one of two major subtypes of urinary incontinence, a common and costly condition that significantly impairs quality of life of women of all ages. Surgery is one of the most common treatments for SUI. Urodynamic studies (UDS), which assess physiological variables during bladder storage and emptying, are often performed preoperatively to confirm and characterize the clinical features of the condition or to guide decisions about modifications in treatment. Despite common use of UDS, these studies are uncomfortable and costly, increase the risk of urinary tract infection, and their ability to improve surgical outcomes was unkown.

In response to the lack of evidence concerning the utility of UDS, the Value of Urodynamic Evaluation (ValUE) study, a multi-center noninferiority trial was  conducted to compare outcomes among women with SUI who underwent a basic office evaluation without UDS (evaluation-only group) with those among women with SUI who underwent UDS in addition to the office evaluation (urodynamic-testing group) before their planned surgery. Participants with SUI were enrolled from 11 centers nationwide and randomly assigned to a study group. Women in the urodynamic-testing group underwent noninstrumented uroflowmetry with a comfortably full bladder, filling cystometry with Valsalva leak-point pressures, and a pressure-flow study. After interpretation of the urodynamic tests, study physicians again completed the same comprehensive checklist of clinical diagnoses without viewing their previous entries. The primary outcome measure included the Urogential Distress Inventory (UDI), an objective measure that assesses symptoms of incontinence, and the Patient Global Index—Improvement (PGI-I), a patient-reported measure of perceived improvement following treatment. Both measures were assessed at 12 months.
 
Results showed no significant between-group differences in secondary measures of incontinence severity, quality of life, patient satisfaction, rates of positive provocative stress tests, voiding dysfunction, or adverse events. The study concluded that preoperative office evaluation alone was not inferior to evaluation with UDS on outcomes at one year for women with uncomplicated SUI.

The Modification of Diet in Renal Disease (MDRD) study consisted of two randomized clinical trials that investigated whether protein restriction and control of blood pressure had an effect on the progression of chronic kidney disease (CKD). The study tested two hypotheses—that (1) a reduction in dietary protein and phosphorous intake and (2) the maintenance of blood pressure at a level below that usually recommended safely and effectively delays the progression of CKD.
 
In study 1, 585 patients with glomerular filtration rates (GFR) of 25-55 ml/min/1.73 m2 of body-surface area were randomly assigned to a usual-protein diet or a low-protein diet (1.3 or 0.58 g of protein per kilogram of body weight per day) and to a usual- or a low-blood-pressure group (mean arterial pressure, 107 or 92 mm Hg). In study 2, 255 patients with GFR of 13 to 24 ml/min/1.73 m2 were randomly assigned to the low-protein diet (0.58 g per kilogram per day) or a very-low-protein diet (0.28 g per kilogram per day) with a keto acid-amino acid supplement, and a usual- or a low-blood-pressure group (same values as those in study 1). The length of follow-up varied from 18-to-45-months, with monthly evaluations of the patients. The primary outcome was the change in GFR rate over time. The study found that among patients with moderate renal insufficiency, the slower decline in renal function that started four months after the introduction of a low-protein diet suggests a small benefit of this dietary intervention. Among patients with more severe renal insufficiency, a very-low-protein diet, as compared with a low-protein diet, did not significantly slow the progression of renal disease.

The Interstitial Cystitis Data Base (ICDB) cohort study was a prospective, multicenter clinical study of patients with Interstitial Cystitis (IC). The study gathered data to investigate the treated history of IC and identify patient subgroups with specific symptoms, physical findings, histopathologic findings from bladder biopsies, and treatment responses. Data was collected on patients at baseline and longitudinally concerning demographic and diagnostic information, medical history, dietary intake, urinary symptoms, and treatments and their outcomes. Additionally, bladder tissue specimens were stored in a specimen bank.  Initial analyses on patient data supported the clinical observation that IC is a chronic symptom complex and showed that no current treatments had a significant impact on symptoms over time.

The Interstitial Cystitis Clinical Trials Group (ICCTG) RCT1 was a pilot clinical trial using a 2x2 factorial study design with double masked drug treatment to evaluate the feasibility of oral pentosan polysulfate (PPS) and oral hydroxyzine in patients with interstitial cystitis (IC).  IC is a bladder syndrome characterized as painful, debilitating and chronic, with no widely accepted effective treatment. Characteristic symptoms include pain with bladder filling, and marked urinary frequency (to relieve pain). The presentation of symptoms can be quite variable among patients, suggesting that IC is a multi-factorial syndrome with several proposed etiologies, some of which may be interrelated.
Subjects with IC were randomized over 18 months and followed for 24 weeks. The primary endpoint was a patient reported global response assessment (GRA) of overall symptoms. Secondary endpoints included symptom indexes and patient reports of urinary pain, urgency and frequency.  The low global response rates for PPS and hydroxyzine suggest that neither provided benefit for the majority of patients with IC.

The ICCTG RCT2 study was a randomized, placebo-controlled, two-arm clinical trial that investigated the efficacy and safety of intravesical Bacillus Calmette-Guerin (BCG) therapy in treating patients with treatment refractory Interstitial Cystitis (IC). IC is a bladder syndrome characterized as painful, debilitating and chronic, with no widely accepted effective treatment. Characteristic symptoms include pain with bladder filling, and marked urinary frequency (to relieve pain). The presentation of symptoms can be quite variable among patients, suggesting that IC is a multi-factorial syndrome with several proposed etiologies, some of which may be interrelated.

Subjects with IC were randomized to 6 weekly double-blinded intravesical instillations of either BCG or placebo, and then followed for a total of 34 weeks. The primary outcome was a patient reported global response assessment at week 34, supplemented with medications for IC during weeks 31 to 34 recorded in a diary. Although the safety profile for BCG was acceptable, the therapy did not show significant benefit compared to placebo.

The NIDDK Liver Transplantation Database was established to prospectively investigate questions related to the experience of patients evaluated for and undergoing liver transplantation. The LTD contains data for 1563 patients referred and evaluated for orthotopic liver transplantation (OLT) at three large liver transplant centers in the United States; of these patients, 916 underwent transplantation and were followed for 1 to 5 years. 

All patients referred for OLT were screened for eligibility to be entered in the database, which required informed consent, no prior liver transplant, and availability to be followed. For each participant, standardized data was collected on demographics, medical history, preoperative and post-transplant symptoms and quality of life, post-transplant complications, and mortality. Liver biopsies and serum samples were also obtained pre- and post-transplantation at intervals specified in the study protocol. 

Following primary data collection, which occurred from April 1990 to June 1994, the Liver Transplantation Database Follow Up (LTD2) study was conducted to prospectively generate detailed survival data from a large multicenter cohort of liver transplant recipients. This study observed the long-term outcomes of transplantation to examine adverse effects, assess risk factors, and determine long-term mortality rates and causes of death post-transplant. 

Follow-up data was obtained for 798 transplant patients from 1998 to 2003 at 3 clinical centers. Cause of death was captured in the early (≤ 1 year) and late (> 1 year and > 5 years) post-transplant periods. Patient-related risk factors were analyzed for overall deaths as well as for each major cause of death in the late post-transplant period. Adverse events, including complications of transplantation and recurrence or development of disease, were monitored. 

The follow-up study identified common etiologies and risk factors that contributed to the morality of liver transplant patients at various stages post-transplantation. Results showed that hepatic etiologies were the most frequent cause of death in the late post-transplant setting. In addition to malignancy and cardiovascular disease, renal failure was found to be an important and escalating cause of death in the late post-transplant setting. Ancillary studies have also been performed on LTD data to evaluate pathology reliability and cost of liver transplantation, as well as examine various characteristics or biomarkers of collected serum.

The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was established to develop and implement studies to test whether imaging techniques can provide accurate and reproducible markers of progression of renal disease in patients with polycystic kidney disease. Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function; however, standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to reliably measure renal cyst volumes. The CRISP cohort study longitudinally observed ADPKD individuals using high-resolution magnetic resonance (MR) imaging to determine if change in renal and cyst volumes can be detected over a short period of time, and if they correlate with decline in renal function early in disease.

Patients who were diagnosed with ADPKD and had a creatinine clearance of at least 70 mL/min were enrolled. Standardization studies were conducted at each participating clinical center. After, in the full-scale protocol, participants underwent standardized MR renal imaging, comprehensive clinical evaluation, evaluation of renal iothalamate clearance, and determination of 24-hour urinary albumin and electrolyte excretion. Stereology was used from T1-weighted images to quantify renal volume, and region-growing thresholding was used from T2-weighted images to determine cyst volume.

The CRISP cohort was also analyzed by molecular analysis. Given the high level of unclassified variants (UCV) in patients with ADPKD, the purpose of the molecular analysis was to systematically classify UCVs in the PKD1 and PKD2 genes. 

The current data package contains data through the CRISP 3 cycle as well as CRISP allele frequency data.

MRI images for CRISP participants are not included in the package, but are available upon request.

Chronic prostatitis is a disabling condition of unknown origin affecting men of all ages and ethnic groups. Most have chronic pelvic pain associated with urinary frequency and urgency; however, they do not have demonstrable urinary or prostatic infections that can be detected by conventional microbiological techniques. In response to the growing concerns about the diagnosis and treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), the Chronic Prostatitis Collaborative Research Network (CPCRN), which consists of six clinical centers and one data coordinating center, was established to study this syndrome in order to improve diagnosis and treatment. 

The CPCRN conducted a prospective observational cohort study designed to characterize CP/CPPS, examine symptoms and quality of life in affected men, and assess the economic impact of the condition. Men of any age with symptoms of discomfort or pain in the pelvic region for at least 3 of the 6 months prior were eligible for enrollment. The CPCRN cohort study consisted of a baseline screening phase and a longitudinal follow-up phase. During the baseline screening phase, eligibility criteria were assessed, and baseline data and biospecimens (including serum, prostatic fluid, and semen) were collected. Information on symptoms and quality of life, demographic and lifestyle factors, medical history, prior treatments and procedures, and health resource utilization was collected. 

The study found that CP/CPPS is a multifactorial problem affecting men of all ages and demographics. The condition is characterized by substantial variation in symptoms within and among subjects. There is no evidence that the disorder worsens significantly during 2 years of follow-up, and for about a third of men with long-standing symptoms there may be moderate to marked improvement during this period. Men with chronic prostatitis experience impairment in the mental and physical domains of general health related quality of life, and many have benefited only minimally from empirical, goal-directed therapy. The CPCRN has conducted numerous clinical trials to investigate the safety and efficacy of numerous treatments for CP/CPPS, for which more details are available on the NIDDK Repository website.

Increases in childhood obesity have been accompanied by an increased prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents. Research has shown the importance of adequate treatment and management on the vascular disease progression of T2DM in adults, but research on the treatment and clinical course of T2DM in youth has been limited. the TODAY (Treatment Options for Type 2 Diabetes in Adolescents & Youth) study, was a randomized clinical trial of treatment for adolescents diagnosed with T2DM.

The TODAY study tested the hypothesis that an aggressive approach to reducing insulin resistance early in the course of T2DM would prolong glycemic control and improve associated risk factors. The trial consisted of three treatment arms: metformin alone, metformin with rosiglitazone, and metformin with an intensive lifestyle intervention program (called the TODAY Lifestyle Program or TLP). Individuals between 10 and 17 years old with a diagnosis of T2DM for less than two years, a body mass index (BMI) ≥ 85th percentile, and an absence of diabetes-related autoimmunity were eligible for the study. Upon enrollment, participants entered a run-in period of 2 to 6 months, with the goals of weaning them from non-study diabetes medications, initiating treatment with metformin, providing standard diabetes education, and documenting adherence to the medication regimen. Participants were required to attain glycemic control, defined as a glycated hemoglobin level of less than 8% and measured monthly for at least 2 months, with metformin alone before proceeding. Following successful completion of the run-in period, participants were randomized to treatment with metformin and either placebo or rosiglitazone as appropriate. For those assigned to treatment with the TLP, the program was delivered in a series of in-person visits and focused on weight loss through family-based changes in eating and activity behaviors. The primary outcome measure compared between groups was time to treatment failure, defined as a persistently elevated glycated hemoglobin level (≥8%) over a period of 6 months or persistent metabolic decompensation (defined as either the inability to wean the participant from insulin within 3 months after its initiation for decompensation or the occurrence of a second episode of decompensation within 3 months after discontinuation of insulin).

Results showed rates of failure of 51.7% (120 of 232 participants) for metformin alone, 38.6% (90 of 233) for metformin plus rosiglitazone, and 46.6% (109 of 234) for metformin plus lifestyle intervention. The study found that metformin with the addition of rosiglitazone, but not the intervention program, was superior to metformin alone.

The Complementary and Alternative Medicine for Urological Symptoms (CAMUS) study was a double-blind, placebo-controlled randomized clinical trial that investigated the efficacy of a widely available phytotherapy, saw palmetto extract, at up to 3 times the standard dose on lower urinary tract symptoms attributed to benign prostatic hyperplasia  (BPH) in men. Although saw palmetto fruit extract is widely used for treating lower urinary tract symptoms attributed to BPH, a well-design National Institutes of Health supported clinical trial (Avins A et al. JAMA) failed to a benefit of this treatment compared to placebo. The CAMUS study enrolled males with a peak urinary flow rate of at least 4 mL/s and an American Urological Associate Symptom Index (AUASI) score of between 8 and 24 at screening visits. Participants were randomly assigned equally to receive one, two, and then three 320 mg gelcaps daily containing a standardized saw palmetto fruit extract with dose escalations at 24 and 48 weeks; or an identical number of placebo gelcaps escalated similarly. The primary outcome was the change in AUASI score from baseline to 72 weeks. Participants were closely monitored for adverse events. The study concluded that saw palmetto extract used at up to 3 times the standard daily dose had no greater effect than placebo on improving lower urinary symptoms or other outcomes related to BPH.

The NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC) and cell line repository was created in 2002 by the National Institute of Diabetes, Digestive and Kidney diseases (NIDDK) to advance knowledge on the inflammatory bowel diseases, specifically Crohn’s Disease and Ulcerative Colitis. The Consortium consists of six genetic research centers (GRC) and a data coordinating center (DCC) that prospectively recruits a combination of cases, controls, and trios to gather a large collection of samples and linked phenotype information. Phenotyping is performed using a standardized protocol, and lymphoblastoid cell lines are established for each subject. The resulting DNA samples are used to conduct genetic linkage and association studies. The IBDGC is involved with independent genetic research studies and actively works with members of the IBD and genetic communities on collaborative projects.

Autosomal dominant polycystic kidney disease (ADPKD) impacts 1 in 400 to 1 in 1000 live births and accounts for about 4.6% of the kidney replacement population in the US. Hypertension is the most common manifestation and an important risk factor for its progression to end stage renal disease (ESRD) and cardiovascular morbidity and mortality.

The HALT Progression of Polycystic Kidney Disease (HALT PKD) studies were two simultaneous multicenter clinical trials designed to test the efficacy of interruption of the renin-angiotensin-aldosterone system (RAAS) on the progression of cystic disease and the decline in renal function in ADPKD. Specifically, the studies assessed the effects of ACE-I/ARB combination therapy as compared to ACE-I monotherapy in hypertensive ADPKD subjects.

The two studies varied on eligibility criteria (particularly kidney function), blood pressure treatment, and primary outcome measure. Study A investigates treatment effects on individuals with early ADPKD and implements a standard (120-130/70-80 mm Hg) vs. low (95-110/60-75 mmHg) blood pressure control target for both treatment arms in a 2x2 design. Study B investigates treatment effects on individuals with moderately advanced ADPKD in the setting of standard blood pressure control (110-130/80 mm Hg). Participants enrolled in study A were followed for at least five years, while those enrolled in study B were followed for five to eight years, with the average length of follow-up being six and a half years.

The complete HALT PKD data package is available for request.

MRI images for HALT PKD participants are not included in the package, but are available upon request.

The Maryland Genetics of Interstitial Cystitis Study (MaGIC) collected information on several hundred families with two or more blood relatives with interstitial cystitis (IC) to investigate the genetic basis of the condition. The study sought to find genetic variants that are more prevalent in family members who have interstitial cystitis than in those who do not have the disease. Participants who had IC and at least one blood relative with the condition were enrolled. Information was collected via interview by phone, mail, or website.

The Diabetes Prevention Trial—Type 1 Diabetes (DPT-1) consisted of two randomized clinical trials to determine whether insulin could prevent or delay the onset of overt diabetes in relatives of patients with diabetes. One study investigated the effects of parenteral insulin in relatives with a projected five-year risk of diabetes higher than 50 percent, while the other looked at the effects of oral insulin in relatives with a projected five-year risk of 26 to 50 percent.
 
First and second-degree relatives were screened for islet-cell antibody (ICA) titer ≥ 10 and then staged to assess risk of diabetes. Those with a high risk were eligible for the parenteral insulin trial, and those with a low risk were eligible for the oral insulin trial. In the parenteral insulin trial, subjects in the intervention group received parenteral insulin subcutaneous injections twice daily, plus annual intravenous infusions; the control group received no treatment. In the oral insulin trial, subjects were assigned to receive capsules of either oral insulin or matched placebo. For both trials, participants were seen every 6 months, and at those visits an oral glucose tolerance (OGT) test was performed to assess glycemic status, the primary study end point. Other assessments included intravenous glucose tolerance tests and mixed-meal tolerance tests performed at baseline, as well as at various points during the study. Results showed that neither parenteral nor oral insulin succeeded in delaying or preventing the development of diabetes in high-risk relatives of current diabetes patients. Long-term follow-up to detect any effects on the course of diabetes was initiated.

The Diabetes Prevention Program (DPP) was a multicenter trial examining the ability of an intensive lifestyle program or treatment with metformin to prevent or delay the development of type 2 diabetes in high-risk individuals with prediabetes. The DPP study showed that both interventions reduced the incidence of diabetes in participants, compared with placebo; the lifestyle intervention proved more effective than metformin in preventing the onset of diabetes. The Diabetes Prevention Program Outcomes Study (DPPOS) is the long-term follow-up of the original DPP study. The DPPOS sought to evaluate the effects of the interventions on the further development of diabetes and diabetes complications, including retinopathy, microangiopathy, and cardiovascular disease.

All active DPP participants were eligible for continued follow-up, and 88% of DPP participants enrolled in DPPOS (910 participants from the lifestyle, 924 from the metformin, and 932 from the original placebo groups). On the basis of the benefits from the intensive lifestyle intervention in the DPP, all three groups were offered group-implemented lifestyle intervention. Placebo was discontinued in the placebo group, metformin treatment was continued in the original metformin group, with participants unmasked to assignment, and the original lifestyle intervention group was offered additional lifestyle support. Comprehensive annual and semi-annual assessments similar to those done in the DPP study continued in DPPOS and included physical measurements, medical history updates, adverse event assessment, medication adherence and dispensing, questionnaires, and an annual oral glucose tolerance test (OGTT). OGTTs were discontinued after a confirmed diagnosis of diabetes.

DPPOS found that prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years; the cumulative incidence of diabetes remained lowest in the lifestyle group.

Data collected after the final DPP Bridge visits in 2002 through February 2020 are available from the Repository.

Treatment of chronic hepatitis C in adults has evolved from alpha interferon (IFNα) alone to the combination of PEG-IFNα with ribavirin (RV). Recommendations for treatment for HCV infection in children have been derived from trials in adults, although the efficacy and safety of these therapies may be different in children. The Pediatric Study of Hepatitis C (PEDS-C) was conducted as a randomized, controlled trial to investigate the safety and efficacy of PEG-IFNα with and without RV in children and adolescents with chronic hepatitis C. The primary objective of the PEDS-C study was to determine if the addition of RV to PEG-IFNα maximized outcome of therapy of children with chronic hepatitis C. 

Children and adolescents ages 5 to 18 years with documented chronic HCV infection were enrolled in the study. All participants were randomly assigned in a 1:1 ratio to receive either PEG-IFNα and RV or PEG-IFNα and placebo. PEG-IFNα was administered in a dose of 180 µg/1.73m2 body surface area subcutaneously once weekly to all subjects, and ribavirin was administered in a dose of 15 mg/kg orally twice daily to the appropriate treatment group. Patients without detectable HCV RNA at 24 weeks were continued on treatment for another 24 weeks, while those with detectable HCV RNA at 24 weeks were considered treatment failures. The primary outcome measure was the proportion of subjects with a sustained virologic response, defined as non-detectable HCV RNA in plasma (<10 IU/ml) at least 24 weeks after stopping treatment. The secondary outcome measure was safety, assessed by vital signs, laboratory tests, and adverse events.

Results showed that therapy with PEG-IFNα plus RV was superior to PEG-IFNα plus placebo regardless of age, alanine aminotransferase (ALT) levels, and histologic severity. Additionally, there was little change in side effect profile with the addition of RV to PEG-IFNα. The study concluded that the combination of PEG-IFNα and RV is superior to PEG-IFNα alone as therapy for chronic hepatitis C in children and adolescents in both safety and efficacy.

The FHN Daily Trial was a randomized controlled trial which recruited subjects from dialysis units associated with designated Clinical Centers in the U.S. and Canada and followed for 1 year. Subjects were randomized to either conventional hemodialysis delivered for at least 2.5 hours (typically 3 to 4 hours), 3 days per week (120 patients), or to more frequent hemodialysis delivered for 1.5 - 2.75 hours, 6 days per week (125 patients). The study had two co-primary outcomes: 1) a composite of mortality with the change over 12 months in left ventricular mass by magnetic resonance imaging, and 2) a composite of mortality with the change over 12 months in the SF-36 RAND physical health composite (PHC) quality of life scale.

Note: The available data do not contain digital raw ECG recordings. Please review the Data Dictionary for a listing of available datasets and variables.

Acute liver failure (ALF) is a condition in which liver function rapidly deteriorates. ALF often affects young people and causes serious, and sometimes fatal, complications. Treatment of the disease is dependent upon its cause, which can be numerous factors. Because recovery from this disease is random, there is no way to predict how a patient will respond to treatment. Sometimes a liver transplant is required in order for a patient to make a full recovery. The mission of the Pediatric Acute Liver Failure (PALF) study is to develop methods to predict whether a child will require a life-saving procedure in order to recover from the illness.

Clinical, epidemiological, and outcome data on PALF patients will be collected and analyzed. The study group will also use the data to identify unrecognized mechanisms of liver injury that cause PALF. Acute liver failure leads to hepatic encephalopathy and cerebral edema, so patients will be invited to participate in neurocognitive testing to determine whether long-term neurocognitive function has been compromised. The prediction methods will vary and be influenced by age, diagnosis, multi-system organ failure, degree of encephalopathy, and coagulopathy level.

This multicenter, randomized, double-blind, placebo-controlled trial was designed to determine whether daily antimicrobial prophylaxis is superior to placebo in preventing recurrence of urinary tract infection (UTI) in children with vesicoureteral reflux (VUR). Patients were randomly assigned to treatment for 2 years with daily antimicrobial prophylaxis (trimethoprim-sulfamethoxazole) or placebo. The study was designed to recruit 600 children (approximately 300 in each treatment group. The protocol encouraged prompt evaluation of children with UTI symptoms and early therapy of culture-proven UTIs. It was expected that approximately 10% of children would have to discontinue study medication due to allergic reactions. Assuming a 20% placebo event rate and 10% non-adherence rate, the study had 83% power to detect an absolute 10% event rate in the antimicrobial prophylaxis group. If the placebo event rate was instead 25%, power was 97% to detect an absolute 10% event rate in the treated group, even if non-adherence were as high as 15%. The primary analysis is intention-to-treat with missing outcome data analyzed as UTI.

Teen-LABS conducted coordinated clinical, epidemiological, and behavioral research focused on adolescent bariatric surgery. The study developed common clinical protocols and a bariatric surgery database for the purpose of collecting information from participating clinical centers that performed bariatric surgery on teenagers. Outside of investigating surgical outcomes, Teen-LABS sought to better understand the etiology, pathophysiology, and behavioral aspects of severe obesity in youth as well as how severe obesity impacts humans over time. Participants were recruited from six clinical centers and underwent bariatric surgery. Pre- and post-surgery data and biospecimens were obtained at pre-determined points.

The African American Study of Kidney Disease and Hypertension study (AASK Trial) was a multi-center, randomized clinical trial that investigated the effects of blood pressure (BP) control and the use of specific antihypertensive regimens on the progression of chronic kidney disease (CKD). The study was designed to address the high incidence of CKD in African Americans with hypertension. A two by three factorial study design, including two levels of BP control as defined by mean arterial pressure (MAP) and three different anti-hypertensive regimens, was used. Participants were randomized into two levels of BP control groups, either a goal MAP < 92 mmHg or a goal MAP between 102-107 mmHg inclusive.. The antihypertensive drugs used for treatment were amlodipine, a calcium channel blocker; ramipril, an angiotensin-converting enzyme inhibitor; and metoprolol, a β-blocker. The trial was double-blind (drug administration only). The change in glomerular filtration rate (GFR) as determined by iothalamate clearance was measured as the primary outcome to test the regimens’ efficacy in slowing the rate of decline of kidney function.
 
The study showed that the angiotensin-converting enzyme inhibitor ramipril was more effective than the beta blocker metoprolol or the dihydropyridine calcium channel blocker amlodipine in slowing the rate of GFR decline. The results suggest that reduction in blood pressure to levels below those currently advocated for cardiovascular risk reduction does not provide readily identifiable benefits to African Americans with hypertensive nephrosclerosis.

The Family Investigation of Nephropathy and Diabetes (FIND) was a multicenter observational study designed to identify genetic genetic determinants of diabetic kidney disease. Study participants were recruited from 11 centers and in many ethnic groups throughout the United States for a genome-wide association study (GWAS). Two additional strategies were also used to localize susceptibility genes: a family-based linkage study and a case-control study using mapping by admixture linkage disequilibrium (MALD). In the family-based study, participants with diabetic nephropathy were recruited with their parents and selected siblings. Linkage analyses were conducted to identify chromosomal regions containing genes that influence the development of diabetic nephropathy and related quantitative traits.  Subsequently, a GWAS was carried out.

Two types of MALD studies were done. The first was a case-control study of unrelated individuals of Mexican American heritage in which both cases and controls had diabetes, but only the case had nephropathy. The second was a case-control study of African American patients with nephropathy (cases) and their spouses (controls) unaffected by diabetes and nephropathy; offspring were genotyped when available to provide haplotype data. Through the family and MALD studies, the FIND study identified several genes that contribute to diabetic nephropathy, albuminuria, and glomerular filtration rate (GFR), including ApoL1.

Note: Native American participants have been excluded due to consent to not share data.

The Genetics of Kidneys in Diabetes (GoKinD) study was an initiative that aimed to identify genes that are involved in diabetic nephropathy. A large number of individuals with type 1 diabetes were screened to identify two subsets, one with clear-cut kidney disease and another with normal renal status despite long-term diabetes. Those who met additional entry criteria and consented to participate were enrolled. When possible, both parents also were enrolled to form family trios. DNA, serum, plasma, and urine samples and clinical information were collected from participants. A repository of genetic and clinical information was created for use in genetic analysis to investigate the genetic risk factors of the renal disease of Type 1 diabetes, with the ultimate aim of determining pathways for intervention to prevent diabetic kidney disease and allow targeting of preventive therapies.

GWAS data must be requested through dbGAP.

The National Institutes of Health–sponsored TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) trials determine whether this generic and inexpensive drug is safe, tolerated, and efficacious in diabetes.  Stage 1 was a dose-ranging study whereas stage 2 of TINSAL-T2D is a larger study to assess the magnitude and durability of glycemic efficacy over 1 year, tolerability, and an array of safety variables relevant to patients with diabetes.

This trial evaluated glycemic effects of salicylate compared with placebo as add-on therapy for patients with inadequately treated, established T2DM.  Salicylate is one of the oldest drugs in clinical practice, with documented use of relevant plant extracts for treating pain and inflammation dating back at least 3500 years.  Nevertheless, its medicinal properties and mechanisms of action remain incompletely understood.  When salicylate is acetylated by chemists, it yields aspirin.   However, pure salicylate lacks an acetyl group and, thus, must have a different mechanism of action. Salicylate has not been tested previously for efficacy and safety under what regulatory agencies now consider to be current standard practice in clinical trials.

The Silymarin Trial for Hepatitis C and NASH (SyNCH) is a randomized, double-masked, placebo-controlled phase II study that assessed the safety and efficacy of a standardized orally administered silymarin preparation (Legalon®) for the treatment of patients with chronic hepatitis C virus (HCV) who failed conventional antiviral therapy. The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. In light of inconclusive past clinical trials, the SyNCH study aimed to determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV). In the phase I trial, an initial dose-ranging study was performed to identify silymarin doses for further study. Two doses, 3 and 5 times higher than the customary dose, were selected for the phase II trial based on this early testing.

The study enrolled participants with chronic HCV infection and serum alanine aminotransferase (ALT) levels of at least 65 U/L who were previously unsuccessfully treated with interferon-based therapy were enrolled. Participants were randomly assigned to 1 of 3 groups: 420-mg silymarin, 700-mg silymarin, or matching placebo gelatin capsules administered 3 times daily for 24 weeks, a standard duration of treatment for which effective therapies for HCV have regularly demonstrated improvement in disease activity. The primary outcome measure for efficacy was serum ALT level of 45 U/L or less (approximate normal range) or attainment of at least 50% decline of ALT level to less than 65 U/L after the 24-week treatment period. 
Results showed that after 24 weeks of treatment, only 2 participants in each treatment group met the primary outcome measure: 3.8% for placebo, 4.0% for 420-mg silymarin, and 3.8% for 700-mg silymarin. Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy.

The Comprehensive Dialysis Study (CDS) is a special data collection study in which physical activity, health-related quality of life, and work/disability data were requested from patients identified as initiating maintenance dialysis during 2005 to 2007. The CDS study aimed to understand factors contributing to physical, functional, and nutritional health status among patients starting dialysis. The study was coordinated in part by the United States Renal Data System (USRDS), which maintains an extensive database that facilitates biomedical and economic research on end-stage renal disease (ESRD) in the U.S. population. In a subset of participants, dietary intake and nutritional status were also evaluated. The study represents one of few cohorts in which laboratory proxies of nutrition and inflammatory status were measured simultaneously. The study successfully gathered information and samples from participants and generated baseline characteristics for patients undergoing maintenance dialysis. Information reported by CDS participants was linked with patient-specific modality history, mortality, hospitalization, and cost information in USRDS files.

Among women with urinary incontinence, 50 to 80% are identified as having stress urinary incontinence (SUI), or involuntary leakage of urine resulting from physical exertion, sneezing, or coughing. The Burch colposuspension and the autologous rectus fascial sling are two surgical procedures frequently used to treat SUI. Both procedures are believed to have similar “cure” rates, yet have not been compared directly to each other in a large, randomized clinical trial. The Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr) is a multicenter, randomized study that was conducted to compare the efficacy and safety of the sling and Burch procedures. Complications, quality of life, sexual function, patient satisfaction, costs, and the need for additional treatments or surgery were also compared for the two procedures as secondary objectives. 

Women with documented symptoms of SUI for at least 3 months and a positive standardized urinary stress test who were planning to undergo surgery as treatment were enrolled and randomly assigned in the operating room to either a sling or Burch procedure. Key elements of the two surgical procedures were standardized among all clinical centers and participating surgeons. Data were collected preoperatively and postoperatively and included information on demographics, risk factors for urinary incontinence, clinical characteristics of urinary incontinence, findings on physical examination, and urodynamic evaluation. The two primary outcome measures consisted of composite measures of success of treatment in both overall urinary incontinence and specific stress incontinence. 

Results showed that the pubovaginal fascial sling had significantly higher rates of success for both overall and stress-specific incontinence than did the Burch colposuspension in women with predominant SI at 24 months. Additionally, the frequency of surgical retreatment for SI was greater in the Burch group than in the sling group, although these higher success rates were offset by increased morbidity in the sling group.  

Data from the E-SISTEr 5 year follow-up are now included in the data package.

Urinary incontinence affects up to 50% of women, resulting in substantial medical, social, and economic burdens. Among U.S. women with urinary incontinence, 15 to 80% have a component of stress incontinence, which results in leakage of urine during physical exertion, sneezing, and coughing. Of these women, 4 to 10% undergo surgery.

TOMUS is a 2-arm, unmasked, multi-center randomized controlled trial that compared two types of mid-urethral slings used for treatment of stress incontinence: the retropubic mid-urethral mesh sling (RMUS) and the transobturator mid-urethral sling (TMUS). RMUS procedures are less invasive than the fascial sling procedures that were reference standards at the start of the study. Specifically, a synthetic tape is passed transvaginally at the midurethral level through the retropubic space. TMUS procedures were developed to minimize the potential for bladder and bowel injuries associated with the retropubic sling, since the sling is passed through the obturator canal, avoiding the pelvic organs in the retropubic space. 

Eligible women 21 years of age or older who were planning to undergo surgery for the treatment of stress incontinence were invited to participate in TOMUS. Randomization was performed after anesthesia was administered. Women were randomly assigned with the use of a permuted-block randomization schedule, with stratification according to clinical site. After the surgery, information regarding the treatment assignment was not kept from the patient. Subjects were followed up at 12 and 24 months after the surgery.

ETOMUS: Women completing 2-year participation in a randomized equivalence trial who had not undergone surgical re-treatment for stress urinary incontinence were invited to participate in a 5-year observational cohort.

Type 1 diabetes (T1D) is a common childhood disease caused by islet cell autoimmunity.  Reports suggest omega-3 fatty acids may decrease the risk of T1D by suppressing the inflammatory immune responses that initiate the process of islet autoimmunity.  Various epidemiological studies and observations have concluded that the intake of omega-3 fatty acids is associated with a decreased risk of the development of T1D in children with an increased genetic risk for the disease.  

The TrialNet 06 study hypothesized that islet autoimmunity could be prevented in infants, with an increased risk for T1D, through the consumption of DHA, an omega-3 fatty acid.  Participants were enrolled during pregnancy or after birth, and randomized into the treatment or control group.  During the study, subjects in the treatment group received a vegetarian DHA substance while those in the control group received a placebo.  Treatments were administered daily for at least 36 months from the date of birth or the date of randomization.  Participants were regularly tested for DHA and inflammatory cytokine levels.  Additionally, TrialNet 06 was used as a pilot trial in order to determine the feasibility of a full-scale DHA supplementation study.

This multicenter, double-masked, randomized, controlled trial evaluated whether treatment of with a target antigen (glutamic acid decarboxylase) could modulate aggressive autoimmunity effects in subjects recently diagnosed with type 1 diabetes mellitus. Subjects were randomized via a 1:1:1 ratio into one of three treatment groups: three injections of 20 μg GAD-alum, two injections of GAD-alum and one of aluminum hydroxide alone (placebo), or three injections of aluminum hydroxide. These subcutaneous injections were completed at baseline, four weeks, and twelve weeks. All subjects received intensive diabetes management with the goal of achieving excellent glycemic control. Stimulated C-peptide levels were measured at the year 1 visit via a mixed meal tolerance test (MMTT). Subjects continued follow up for a second year including the performance of a MMTT every 6 months.

Acute kidney injury is a common complication of acute illness, affecting approximately 2 to 7% of hospitalized patients and more than 35% of critically ill patients. While renal-replacement therapy is the main treatment method for patients with acute kidney injury, the optimal timing for the initiation, method, and dosing of therapy is uncertain. Given this uncertainty, the Acute Renal Failure Trial Network (ATN) study was established to determine whether more intensive renal replacement therapy decreases mortality among critically ill patients with acute kidney injury. 

The study was a multicenter, prospective, randomized trial of two strategies for renal-replacement therapy in patients with acute kidney injury. Participants were randomized to receive intensive (i.e., intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml/kg of body weight/hour) or less intensive renal-replacement therapy (i.e., the corresponding treatments were provided three times per week and at 20 ml/kg/hour). The assigned renal-replacement therapy was provided for up to 28 days after randomization or until recovery of kidney function, discharge from acute care, withdrawal of life-sustaining therapy, or death. The primary outcome measure was death from any cause by day 60. Recovery of kidney function (defined as lack of need for continuing dialysis support, with a minimum creatinine clearance of 20 ml/minute), duration of renal-replacement therapy, lengths of stay in the intensive care unit (ICU) and hospital, and days free of nonrenal organ failure were also assessed. 

Results showed that the primary outcome measure, death from any cause by day 60, did not differ between the two groups. Additionally, recovery of renal function and reduction in the rate of nonrenal organ showed no improvement with intensive renal support. The study found no added benefit from an intensive (high-dose) treatment strategy as compared with the more conventional, less-intensive treatment strategy.

The Chronic Renal Insufficiency Cohort (CRIC) Study is an observational study that examined risk factors for progression of chronic renal insufficiency (CRI) and cardiovascular disease (CVD) among CRI patients. The study enrolled adults aged 21 to 74 years with a broad spectrum of renal disease severity, half of whom were diagnosed with diabetes mellitus. Subjects underwent extensive clinical evaluation at baseline and at annual clinic visits and via telephone at 6 month intervals. Data on quality of life, dietary assessment, physical activity, health behaviors, depression, cognitive function, health care resource utilization, as well as blood and urine specimens were collected. Measures of kidney function and occurrence of new and worsening CVD  are the primary outcomes, among others.

Data from the recruitment and follow-up phases through Phase 3. Additionally, the data package includes variables related to APOL1, Echocardiogram, Electrocardiogram, and censored composite and individual outcomes. The data package includes data through 2024.

Retinal images for CRIC participants are not included in the package, but are available upon request.

In response to a lack of basic descriptive epidemiology of urologic symptoms in the general populationthe Boston Area Community Health (BACH) Survey was established by the NIDDK to survey residents in the Boston metropolitan area about their urologic symptoms and how those symptoms affect their daily lives. The BACH Survey was designed to estimate the prevalence of urologic symptoms typical of  interstitial cystitis (IC), urinary incontinence, benign prostatic hyperplasia, prostatitis, hypogonadism, and impaired sexual function by race/ethnicity, age, sex, and socioeconomic status (SES). The survey created a random community-based sample of racially and ethnically diverse men and women across a broad age range, between 30 and 79 years.  The cohort consisted of 5502 participants, approximately equally divided between African American, Hispanic, and Caucasian individuals.   A substantial proportion of the originally recruited cohort was followed-up.

The investigators conducted a two-hour, in-home, bilingual field interview of all eligible participants, in which they examined symptoms and asked questions about lifestyle, physical activity, alcohol use, nutrition, demographics, and morbidity. They also conducted a detailed inventory of medications, both prescribed and over-the-counter, and took two non-fasting blood samples for hormone, cholesterol, and lipid levels. While the initial BACH study focused on urologic symptoms and conditions as its main outcomes of interest, two follow-up and a number of sub-studies were subsequently initiated on the BACH cohort with a focus on other health conditions in addition to urologic symptoms.

The BACH study contributed greatly to knowledge of the prevalence of urologic conditions, which was shown to be greater than previously estimated. The study succeeded in creating a large, racially-diverse sample to provide cross sectional, longitudinal data to explore urologic questions. This data has been used by researchers to identify gender, racial/ethnic, and socioeconomic disparities in a number of health conditions and is available for future studies.

The BARC study was a retrospective study that analyzed the results of a large cohort of patients with biliary atresia from US institutions with expertise in management of children with liver disease. The study consisted of a comprehensive retrospective chart review of clinical data and outcomes for all patients with biliary atresia undergoing HPE between January 1, 1997 and December 31, 2000 at 9 clinical centers. All children included in the study were followed for 2 years or until loss of the native liver as a result of transplantation or death. The data showed that there was no standard approach to the diagnosis of biliary atresia and that postsurgical management varied considerably among the BARC centers; nevertheless, the outcomes at age 2 years for the 9 centers were comparable to the best outcome data published from other countries and in large single-center reports. The study also showed that total bilirubin in early follow-up after HPE was highly predictive of outcome.

Data from the P001 and P002 protocols are now available.

The RAND Interstitial Cystitis Epidemiology Study (RICE) is an observational study that sought to develop a case definition for Bladder Pain Syndrome (BPS)/Interstitial Cystitis (IC) with known sensitivity and specificity and to estimate the prevalence of the condition, which at the time had never been done using a large-population model. BPS/IC, which is clinically diagnosed based on patient-reported symptoms, is a poorly understood condition that can cause significant disability.

 An expert panel developed a case definitions of BPS/IC based on a review of medical literature. This definition was tested on 599 adult women diagnosed with BPS/IC or other conditions characterized by pelvic symptoms. Testing revealed that no single epidemiological definition demonstrated both high sensitivity and high specificity, so two definitions were developed: one of high sensitivity/low specificity and one of low sensitivity/high specificity.
Using these two definitions, researchers then screened 96,995 US households to identify women who had bladder symptoms. Those with symptoms underwent a secondary, more intensive screening and were asked to provide more information regarding symptoms, medical history, medical treatments, impact on daily life, physical and mental health, and demographic information.  Multivariate modeling was used to construct population and non-response weights. Weighted data was used to calculate prevalence estimates for both definitions and estimate the number of women affected.

The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. Therefore, this multicenter, double-blind, randomized, controlled trial evaluated the effect of abatacept in subjects with recently diagnosed type 1 diabetes mellitus. Subjects were randomly assigned in a 2:1 ratio to receive either the experimental treatment of 30 minute intravenous infusion of 10 mg/kg of CTLA-4 Ig (abatacept) or an intravenous saline solution (placebo). The treatments were administered on days 1, 14, 28, and then every 28 days for a total of 27 doses over 700 days. All subjects received intensive diabetes management with the goal of achieving excellent glycemic control. 2 hour mixed meal tolerance tests (MMTT) were performed at 3, 6, 12 and 18 months. Four hour MMTTs were performed at baseline and at 24 months. Safety and efficacy were assessed over a two year follow-up period.

TrialNet is a network of 19 clinical centers worldwide that conducts research on the study, prevention, and early treatment of type 1 diabetes (T1D).  The TrialNet Pathway To Prevention (TN01) is a screening and monitoring study that was established to provide a source of subjects for enrollment into prevention trials. In addition, the prospectively followed cohort is used to gain new insights into the natural history of pre-type 1 diabetes in patients with increased risk for the disease. The primary aim of the study is to identify subjects for TrialNet prevention and investigation trials, but can also be used for assessing the predictive value of existing and novel risk markers of T1D, and for examining the demographic, immunologic, and metabolic characteristics of individuals at risk for developing T1D.

Participants who are unaffected by T1D but who had a family member with TID and hence increased risk for developing the disease are eligible for enrollment. Screened subjects are tested for pancreatic autoantibodies (glutamic acid decarboxylase, insulin, ICA-512) using a blood screening test. Participants with at least one positive tests for any of the antibodies are eligible for confirmatory autoantibody measurements, and metabolic testing including oral glucose tolerance tests (OGTTs). Subjects under age 18 are re-screened annually, and subjects with some risk for disease can be enrolled in prevention trials or followed prospectively.  

Data collected on patients recruited through 2020 are available from the Repository.

The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial (HALT-C) was a randomized clinical trial of long-term use of peginterferon alfa-2a in patients with chronic hepatitis C. The study investigated whether long-term antiviral therapy could prevent progressive liver disease—including cirrhosis, liver failure, hepatocellular carcinoma, and death—in chronic hepatitis C participants. Participants with chronic hepatitis C and advanced fibrosis who failed to respond to prior treatment with peginterferon and ribavirin were enrolled in the study. The participants, who were stratified according to stage of fibrosis, were randomly assigned to receive either peginterferon or no therapy for 3.5 years. The primary outcome measure was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points. Results showed that the level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly with treatment, but there was no significant difference between the groups in the rate of disease progression.

Some of the patients with hepatitis C-related advanced liver disease developed hepatocellular carcinoma (HCC), and there is an existing matched set of samples from these patients and controls. Please see the HCC Documents detailing the description of this set of samples and guidelines for its use in validating serum biomarkers. Investigators interested in using this set should make sure to refer to it specifically in their requests.

Standard treatment for primary focal segmental glomerulosclerosis (FSGS) includes administration of corticosteroids and immunosuppressive therapy, with the goals of achieving complete remission of proteinuria and preservation of renal function.  When standard treatments fail to induce remission, a number of agents are used as renoprotective therapy to delay progression of chronic kidney disease (CKD) to end stage renal disease (ESRD); however, there is a need for the development of new therapies that are safe and effective for patients with FSGS, particularly those for whom standard therapy fails. The Novel Therapies for Resistant FSGS (FONT II) trial was a randomized, multicenter Phase I/II clinical trial designed to investigate the potential efficacy of novel therapies for resistant FSGS. Two different therapies, adalimumab (a human anti-TNF-α antibody) and galactose, were evaluated against standard conservative therapy for resistant FSGS, which consists of the combination of lisinopril, losartan, and atorvastatin. Additional aims of the study included identification of one or more novel agents as candidates for evaluation in a future Phase III trial and creation of an infrastructure for the timely completion of clinical trials in patients with rare glomerular diseases such as FSGS. 

Individuals with primary FSGS confirmed by renal biopsy who failed to respond to prior immunosuppressive therapy were eligible for the study. Participants were required to complete a run-in period in which they were taken off all immunosuppressive medications, including corticosteroids, for 30 days. Participants who achieved an estimated GFR ≥ 30 mL/min/1.73 m2 at the end of the run-in period were randomized to treatment with adalimumab, galactose, or standard conservative therapy. The primary outcome measure, evaluated at 6 months, was a composite of two end points, a reduction of proteinuria by 50% from the baseline value and an estimated GFR (eGFR) that was either ≥ 75% of the value at time of randomization or that was persistently ≥ 75 mL/min/1.73 m2 in those whose renal function was ≥ 75 mL/min/1.73 m2. Adverse effect profile, patient satisfaction score using the TSQM questionnaire, percent change in proteinuria (evaluated as a continuous variable) and change in or time to doubling of eGFR were also assessed as secondary outcome measures.

In patients undergoing hemodialysis for end-stage renal disease, a large number of fistulas fail to mature adequately to support the hemodialysis blood circuit and cannot be used for dialysis. Currently, hemodialysis access using fistulas is hindered by a lack of predictors of and therapies for arteriovenous fistula (AVF) failure.  The Hemodialysis Fistula Maturation Study was a prospective, multicenter observational study that was established by the Hemodialysis Fistula Maturation Consortium (HFMC) to identify the clinical and biological factors associated with AVF maturation outcomes. The primary objectives of the study included improving prediction of AVF maturation and exploring the mechanism of AVF failure by examining the relationship between clinical usability and anatomy, biology, clinical attributes, and processes of care.

The study enrolled patients nearing or with end-stage renal disease who are undergoing AVF creation for hemodialysis. Data were collected pre-operatively, peri-operatively, and post-operatively. Medical history, demographics, and physical examination information were collected prior to surgery at baseline. Participants undergone preoperative ultrasound arterial and venous mapping, flow-mediated and nitroglycerin-mediated brachial artery dilation, arterial pulse wave velocity, and venous distensibility; additionally, ultrasounds will be administered at 1 day, 2 weeks, 6 weeks, and prior to fistula intervention and initial cannulation. Information were collected peri-operatively on surgical personnel, surgical procedures, and clinical observations. Outcome data on AVF usability and other dialysis-related data were collected post-operatively. In addition to these measurements, tissue and blood specimens were collected for analyses of histology, morphometry, immunohistochemistry, and gene expression.

Type 1 diabetes (T1D) is an autoimmune disease. This means that the immune system (the part of the body which helps fight infections) mistakenly attacks and destroys the cells that produce insulin (islet cells found in the pancreas). As these cells are destroyed, the body's ability to produce insulin decreases. There is evidence suggesting that repeated oral administration of an autoantigen (the same protein that the immune system is reacting to) may introduce a protective immunity and cause the immune system to stop its attack. An earlier, large scale study was done to see if oral insulin could delay or prevent the development of T1D in relatives at risk for developing T1D. The overall results showed that for the entire study population, oral insulin did not delay or prevent T1D.

However, an analysis that was done after the conclusion of the trial suggested a potential beneficial effect in a subgroup of participants. The participants who seemed to benefit from oral insulin had higher levels of insulin autoantibodies which were directed against insulin itself (called mIAA). Eligible participants were randomized to receive either oral insulin (7.5 mg of recombinant human insulin crystals) or placebo daily.

All participants randomized into TrialNet 07 were seen at a study site for a follow-up evaluation, three and six months after randomization, and every six months thereafter. Participants were contacted by phone between six monthly clinic visits to assess changes in diabetes status, medication compliance, and adverse events. These phone contacts occurred approximately three months from the date of the previous clinic visit. At the study visits, participants underwent assessments of their insulin production, immunologic status, and overall health.

The CIT consortium conducted a total of 9 studies across North America (CIT02 through CIT08) and the Nordic region (CIT01). CIT08 was a long-term follow-up study for interested participants at the North American sites. The target population is individuals with type 1 diabetes, normal kidney function, and intractable hypoglycemia. All studies treated participants with up to 3 separate infusions of islets. Subjects in CIT07, a single arm Phase 3 license-enabling study, received induction and maintenance immunosuppression in an open-label fashion consisting of rabbit anti-thymocyte globulin (ATG; basiliximab instead of ATG for the 2nd and 3rd transplants, if applicable), etanercept, sirolimus and low-dose tacrolimus.

The CIT consortium conducted a total of 9 studies across North America (CIT02 through CIT08) and the Nordic region (CIT01). CIT08 was a long-term follow-up study for interested participants at the North American sites. The target population was individuals with type 1 diabetes, normal kidney function, and intractable hypoglycemia. All studies treated participants with up to 3 separate infusions of islets. The CIT02 protocol focused on treating islets pre-transplant, and subjects were randomized to receive islets prepared with either Lisofylline or Exenatide. For induction and maintenance immunosuppression, the subjects received rabbit anti-thymocyte globulin (ATG; basiliximab instead of ATG for the 2nd and 3rd transplants, if applicable), etanercept, sirolimus, and tacrolimus in an open-label fashion.

The CIT consortium conducted a total of 9 studies across North America (CIT02 through CIT08) and the Nordic region (CIT01). CIT08 was a long-term follow-up study for interested participants at the North American sites. The target population was individuals with type 1 diabetes, normal kidney function, and intractable hypoglycemia. All studies treated participants with up to 3 separate infusions of islets. The focus of CIT03 was to evaluate the investigational agent, deoxyspergualin. Subjects in CIT03 received rabbit anti-thymocyte globulin (ATG; basiliximab instead of ATG for the 2nd and 3rd transplants, if applicable), deoxyspergualin, etanercept, sirolimus, and low-dose tacrolimus in an open-label fashion.

The CIT consortium conducted a total of 9 studies across North America (CIT02 through CIT08) and the Nordic region (CIT01). CIT08 was a long-term follow-up study for interested participants at the North American sites. The target population was individuals with type 1 diabetes, normal kidney function, and intractable hypoglycemia. All studies treated participants with up to 3 separate infusions of islets. The focus of CIT04 was to evaluate the effectiveness of an IS regimen that included belatacept. For immunosuppression, CIT04 subjects received belatacept, basiliximab, and mycophenolate mofetil in an open-label fashion.

The CIT consortium conducted a total of 9 studies across North America (CIT02 through CIT08) and the Nordic region (CIT01). CIT08 was a long-term follow-up study for interested participants at the North American sites. The target population was individuals with type 1 diabetes, normal kidney function, and intractable hypoglycemia. All studies treated participants with up to 3 separate infusions of islets. Subjects in CIT05 received, in an open label-fashion, the anti-CD20 agent rituximab in combination with rabbit anti-thymocyte globulin (ATG; daclizumab or basiliximab instead of ATG for the 2nd and 3rd transplants, if applicable) for induction and sirolimus alone for maintenance, a calcineurin-inhibitor free regimen.

The CIT consortium conducted a total of 9 studies across North America (CIT02 through CIT08) and the Nordic region (CIT01). CIT08 was a long-term follow-up study for interested participants at the North American sites. The target population was individuals with type 1 diabetes, normal kidney function, and intractable hypoglycemia. All studies treated participants with up to 3 separate infusions of islets. Unlike the other studies, subjects in CIT06 had previously received a kidney transplant and were receiving maintenance immunosuppression. CIT06 was a single arm Phase 3 license-supporting study. At the time of islet transplant, subjects in CIT06 received induction therapy in an open-label fashion with rabbit anti-thymocyte globulin (ATG, 5 doses; daclizumab or basiliximab instead of ATG for the 2nd and 3rd transplants, if applicable) and etanercept. Subjects remained on their calcineurin-based maintenance immunosuppression regimen already in place for their renal allograft.

Biliary atresia is a condition in which the common hepatic bile duct becomes blocked, preventing bile drainage from the liver. Biliary atresia occurs in infants and requires portoenterostomy, a surgical procedure, in order to re-establish bile flow from the liver to the small intestine. Despite the surgical intervention, about half of the children will need a liver transplant before the age of five. The aim of the START study was to determine whether corticosteroid treatment after portoenterostomy would improve bile drainage and reduce the need for liver transplantation, compared to surgery alone. 

The START study participants were recruited from the PROBE study and randomized into either the corticosteroid or placebo group within 72 hours after the portoenterostomy procedure. Participants were given their assigned treatments daily over the course of 13 weeks. After the treatment period, participants underwent follow-up testing and assessments until age 24 months.

This is a multi-center project to establish a prospective database of clinical information and a repository of blood and tissue samples from children with diagnoses of neonatal liver diseases, such as biliary atresia and neonatal hepatitis in order to perform research in these liver problems. Children were screened and enrolled at presentation at the participating pediatric liver sites. Participants diagnosed with biliary atresia were followed intensively for the first year, at 18 months of age, then annually up to 20 years of age, liver transplantation, or resolution of the underlying liver disease. Other subjects diagnosed with cholestasis were followed on the same schedule; if there was complete (clinical and biochemical) resolution of their underlying liver disease off all therapy, there was one follow up visit within one year (preferably scheduled at the time of the next planned follow up visit or at 12 months of age, whichever was later) for data collection and to obtain blood samples. The development of a serum and tissue bank of specimens from children with various neonatal cholestatic disorders are for use by future investigations into the etiology and pathogenesis of hepatobiliary injury in the infant.

The data package available for request includes analysis datasets from multiple publications including combined data from the <a href=https://repository.niddk.nih.gov/studies/basic/>BASIC</a>, <a href=https://repository.niddk.nih.gov/studies/logic/>LOGIC</a>, and <a href=https://repository.niddk.nih.gov/studies/start/>START</a> studies.

Cholestasis, a rare condition involving a reduction or obstruction of bile flow from the liver to the small intestine, can cause significant growth problems, liver complications, the need for liver transplantation, and death. The four rare genetic disorders Alagille syndrome (ALGS), alpha-1 antitrypsin (a-1AT) deficiency, bile acid synthesis defects, and progressive familial intrahepatic cholestasis (PFIC) account for approximately 20% to 30% of all infant cases of cholestasis. Current knowledge concerning the etiology and outcomes of these diseases is limited. The Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC) study is a longitudinal cohort study that was established by the Childhood Liver Disease Research and Education Network (ChiLDReN) to investigate the natural history and progression of these four genetic disorders.  

Children and adults ages 6 months through 25 years who have been diagnosed with ALGS, a-1AT deficiency, bile acid synthesis defects, and PFIC are enrolled. Individuals who are siblings of a-A1T participants and have underlying disease with no evidence of liver involvement may also be enrolled. Participants will complete a baseline visit and give annual follow-up visits. Study visits involve review of clinical information, family history, and any treatments and their outcomes. A physical exam, laboratory tests, and radiologic and imaging evaluations will also be performed. In addition to these standard of care evaluations, participants will undergo neurodevelopment evaluations, DEXA scanning, hearing exams, and liver histology studies. The primary outcome measure is the evaluation of disease progression for each condition, which includes assessment of growth failure, worsening liver functions, developmental complications of portal high blood pressure, liver transplantation, and death. Jaundice, listing for liver transplantation, calculated pediatric end-stage liver disease (PELD) score or model for end-stage liver disease (MELD) score, health-related quality of life, growth, bone mineral density, and presence of hearing loss are assessed as secondary outcome measures. 

The data package now includes analysis datasets from multiple publications.

Cystic fibrosis is an inherited condition in which cell secretions are thick and sticky, instead of thin and slippery. The secretions obstruct passageways and ducts, leading to severe internal damage. Patients with cystic fibrosis sometimes develop advanced liver disease (CFLD). Hepatic cirrhosis can occur with CFLD, as a result of the inflammation and scarring caused by clogged bile ducts.

The Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in Cystic Fibrosis Liver Disease (CFLD PUSH) study was a prospective longitudinal study that aimed to determine the utility of abdominal ultrasound to predict the development of cirrhosis in patients with cystic fibrosis as indicated by a nodular liver on ultrasound. Participants underwent abdominal ultrasound at enrollment and based on the outcome, were placed in one of four groups. Within a 10-year period, participants underwent other specimen collection procedures in addition to abdominal ultrasound. This study also monitored the effects of cystic fibrosis on associated pulmonary and nutritional issues.

The HEALTHY study is a randomized prevention trial that investigated the effectiveness of an integrated intervention in middle schools that aimed to moderate risk for type 2 diabetes in children. The trial was conducted at 7 field centers in 42 middle schools, randomly assigned to intervention or control. Student recruitment and baseline data collection occurred during in the first semester of 6th grade (2006); the intervention was implemented the following semester (2007) and continued through 8th grade (2007-2009). For schools that received intervention, the program consisted of four integrated components targeting nutrition, physical education, behavior change initiatives, and educational communications activities that were designed to impact the environment and lifestyle choices of middle school children. The intervention was implemented either school-wide or grade-wide, so all students were exposed; those who provided appropriate informed consent participated in data collection and evaluation. The primary outcome measure was the combined prevalence of overweight and obesity (BMI ≥ 85th percentile). The study found that the combined prevalence of overweight and obesity decreased in both intervention and control schools, with no significant difference between school groups. However, the intervention did result in significantly greater reductions in various indexes of adiposity, including obesity.

Detailed information about the HEALTHY study, including the protocol, intervention materials, and publications, is available at www.healthystudy.org.

For diabetics with gastroparesis, unpredictable gastric emptying rates and uncertainties in nutrient absorption can lead to difficulties in managing glycemia. The utility of continuous glucose monitoring (CGM), which quantifies real time glucose excursions, in planning periprandial insulin dosing for diabetic patients with gastroparesis has not been explored. The Safety, Feasibility, and Potential Efficacy of Continuous Glucose Monitoring and Insulin Pump Therapy in Diabetic Gastroparesis (GLUMIT-DG) study is a multicenter, uncontrolled clinical trial that was established by the Gastroparesis Clinical Research Consortium (GpCRC) to assess the safety and utility of CGM in guiding insulin pump therapy in patients with type 1 and type 2 diabetes and gastroparesis. 

Individuals with symptoms of gastroparesis, a Gastroparesis Cardinal Symptom Index (GCSI) score of 18, and diabetes for at least 2 years are enrolled in the study. Participants are treated using a combination of CGM and insulin pump therapy. The primary outcome measure, the frequency of mild and moderate (glucose level < 70 mg/dL) and severe hypoglycemic episodes while undergoing therapy, is assessed at 12 and 24-week follow-up visits. CGM data are related to finger stick levels and HbA1c values to test comparability of CGM and finger stick values. The efficacy of CGM-guided insulin pump therapy on symptoms of gastroparesis, quality of life, satiety, gastric myoelectrical activity, and autonomic function are also evaluated as a secondary outcome measures.

The purpose of this study is to find out if very tight blood glucose control from the onset of Type 1 Diabetes can preserve beta cell function. Study subjects will be randomly assigned to receive either standard diabetes management or intensive diabetes management, which involves several days of closed loop therapy followed by home use of a continuous glucose monitor and insulin pump.

Obesity is one of the key risk factors in the development of type 2 diabetes.  Research has shown that excess body mass is linked to insulin resistance and loss of beta-cell function, which are precursors of type 2 diabetes. Clinical studies indicate medication and weight loss attained through lifestyle changes are both effective at slowing the progression of the disease by mitigating the effects of obesity on beta-cell function. The Beta Cell Restoration Through Fat Mitigation (BetaFat) Study was created to determine if weight loss through gastric banding surgery would be more effective than metformin medication at sustaining or improving beta-cell function in individuals with prediabetes or early type 2 diabetes, who are also mildly to moderately obese. 

BetaFat, a component of the Restoring Insulin Secretion (RISE) Consortium, was a two-arm, unblinded clinical trial. Study participants were recruited at the University of Southern California and randomized into two intervention groups.  One group received gastric banding surgery and the other group was treated with metformin. Patients underwent assessments at baseline and at predetermined intervals during the 24-month study period. Beta-cell function, insulin sensitivity, and blood glucose levels were regularly evaluated during the study period. Participants were also monitored for adverse effects to the interventions.

The Medical Therapy of Prostatic Symptoms (MTOPS) study was a multi-center, randomized, double-blind placebo controlled clinical trial that tested whether the oral drugs finasteride (Proscar) and doxazosin (Cardura), alone or in combination, could delay or prevent the worsening of symptoms in men with benign prostatic hyperplasia (BPH). Doxazosin is an α-adrenergic receptor agonist (α-blocker) that reduces muscle tone of the prostate and bladder neck, and finasteride is a 5-α-reductase inhibitor that reduces prostate volume by inducing epithelial atrophy. The MTOPS study hypothesized that these two classes of drugs may act synergistically to delay or prevent the clinical progression of BPH.
 
Participants were randomly assigned, in a double-blind fashion, to one of the following 4 treatment groups: placebo, doxazosin, finasteride, or combination therapy. The primary outcome measure was time to overall clinical progression of BPH, defined as either a confirmed 4 point or greater increase from baseline in the American Urological Association (AUA) symptom score, acute urinary retention, incontinence, renal insufficiency, or recurrent urinary tract infection. The progression of BPH was also assessed using digital rectal examination, serum PSA measurement, urinalysis, transrectal ultrasound, biopsies, urinary flow, and change in the AUA score. 
The study found that combination therapy with doxazosin and finasteride was more effective than either therapy alone in the preventing the clinical progression of BPH.

The Chronic Prostatitis Collaborative Research Network (CPCRN), which consists of six clinical centers and one data coordinating center, was established to study all aspects of chronic prostatitis with the hope of improving diagnosis and treatment. Because the cause of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is unknown, affected men receive many empirical therapies. The two most common treatments prescribed by physicians are antimicrobial agents (including quinolones such as ciprofloxacin) and α-adrenergic receptor antagonists (such as tamsulosin), although there is little objective evidence to support their use. Based on these common clinical practices, the CPCRN conducted a randomized, two-by-two factorial design double-bind, clinical trial (CPCRN RCT#1) to evaluate whether ciprofloxacin or tamsulosin reduces symptoms of long-standing CP/CPPS of at least moderate severity. 

Men with CP/CPPS from 11 clinical centers were enrolled and randomly assigned in equal proportions to receive placebo; ciprofloxacin alone, 500 mg twice daily; tamsulosin alone, 0.4 mg once daily; or a combination of both drugs. Patients were treated for 6 weeks, at which time the primary endpoint was assessed. Symptoms at 9 and 12 weeks after randomization (3 and 6 weeks after completion of treatment) were also assessed to evaluate longer-term treatment response. The primary outcome measure was the change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score from baseline to 6 weeks. Secondary outcome meaures included changes in the pain, voiding, and quality-of-life subscales of the NIH-CPSI; physical and mental summary scores on the Medical Outcomes Study 12-Item Short-Form Health Survey; and a 7-point patient-reported global response assessment. All adverse events were monitored and analyzed.

The study found that neither ciprofloxacin nor tamsulosin significantly reduced the NIH-CPSI total score over 6 weeks compared with placebo. Moreover, neither treatment showed a significant benefit among a wide range of secondary outcomes related to symptoms and quality of life. Findings do not support the use of these agents as empirical therapy for men with long-standing CP/CPPS and at least moderate symptoms.

The Type 1 Diabetes Genetics Consortium (T1DGC) was an international, multicenter program organized to promote research to identify genes and alleles that determine an individual's risk for type 1 diabetes. The program had two primary goals: (1) to identify genomic regions and candidate genes whose variants modify an individual’s risk of type 1 diabetes and help explain the clustering of the disease in families and (2) to make research data available to and establish resources that can be used by the research community. The T1DGC assembled a resource of affected sib-pair families, parent-child trios, and case-control collections with banks of DNA, serum, plasma, and EBV-transformed cell lines. In addition to T1DGC-recruited ASP families, the T1DGC recruited trio families from ethnic groups with lower prevalence of type 1 diabetes. The T1DGC also welcomed the inclusion of earlier ascertained case-control collections (from the UK, Denmark, etc.). Research with T1DGC data has included genome-wide linkage scans, evaluation of the human major histocompatibility complexes, examination of published candidate genes for type 1 diabetes, and examination of autoimmune disease genes and those affecting β-cell function in type 2 diabetes.

In 2007, the T1DGC incorporated over 7,000 cases from the UK (the JDRF/WT case series, aka GRID). GRID samples are available here, and data from dbGaP, the European Genome-phenome Archive (EGA) and data and documentation at the JDRF/WT DIL.

The Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) was a consortium of 9 U.S. liver transplant centers performing adult-to-adult living donor liver transplant (AALDLT) with the primary goal of examining outcomes of AALDLT versus deceased donor liver transplant (DDLT).  AALDLT is a relatively new procedure increasingly used at major transplantation centers. Relatively small numbers of cases are performed at any one center and approaches to the patient and donor are too diverse across centers to provide reliable and generalizable information on donor and recipient outcomes from individual centers. Therefore, the consortium was organized to accrue and follow sufficient numbers of patients being considered for and undergoing AALDLT to provide generalizable results from adequately powered studies.

The Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL) consisted of both retrospective and prospective studies of AALDLT. Legacy data from the A2ALL retrospective cohort is housed in the NIDDK Data Repository. The A2ALL retrospective cohort comprised 819 adult patients, each with a potential living donor, evaluated between January 1, 1998 and February 28, 2003. The retrospective study was designed to gain initial insights into outcomes associated with liver transplant procedures, with data drawn from existing medical records and patient materials. It was hypothesized that pursuit of a living liver allograft leads to decreased pre-transplant morbidity and mortality and better long term outcomes for patients starting from the point at which listed patients have a potential donor evaluated (at least a history and physical examination). The study analyzed numerous variables to determine the factors influencing allograft survival in recipients.
 
The A2ALL study showed evidence that AALDLT is a viable option for liver replacement with outcomes that improve with center experience. Donor characteristics associated with survival included younger age and cold ischemia time of the right lobe graft. 

MRI and CT Scan images from subjects enrolled in A2ALL are not included in the data package, but are available upon request.

The Acute Liver Failure Study Group (ALFSG) was a clinical research network that collected data and biospecimens from participants with acute liver failure (ALF) and acute liver injury (ALI). ALF is defined as a severe form of acute liver injury characterized by rapid onset over days and weeks in the absence of underlying cirrhosis, leading to abnormal coagulation with prolongation of the prothrombin time (INR ≥ 1.5) in the presence of altered mentation. ALI is defined as a severe acute liver injury with an INR ≥ 2.0 and no encephalopathy (altered mental functioning, drowsiness, or coma). Outcomes vary, but nearly 29% die while another 22% undergo liver transplantation, and the remaining recover fully in general. A unique feature of ALF and ALI is that there are a variety of causes, all of which share similar clinical features (coagulopathy, encephalopathy, susceptibility to infection, and bleeding) regardless of cause. The most frequent causes are acetaminophen overdose, drug-induced liver injury, autoimmune hepatitis, and viral hepatitis B, but less common causes include acute fatty liver of pregnancy, ischemia/shock, Wilson disease, heat stroke, and metastatic cancer. 

ALFSG conducted a Multi-Center Trial to Study Adult Acute Liver Failure (AALF) with ALF and ALI participants and those less severe that had coagulopathy but not the threshold of encephalopathy, a pilot study with a subset of AALF participants using rotational thromboelastography as a dynamic measure of coagulation, and a clinical trial with a subset of AALF participants using 13C labeled methacetin breath testing to determine outcomes in ALF patients being considered for transplantation.

Previous studies have shown an aggregation of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) (including esophagastric junctional adenocarcinoma [EGJAC]) in families, a syndrome that has been termed Familial Barrett’s esophagus (FBE). This aggregation, which suggests a biological relationship between BE and EAC, may be caused by common environmental exposures in family members, a genetic predisposition to disease, or both. For complex diseases such as BE and cancer, genetic influences may be more evident in pedigrees that have 3 or more affecteds. Thus, the Familial Barrett’s Esophagus study was established by the Familial Barrett’s Esophagus Consortium (FBEC) to determine whether cancers develop at an earlier age in multiplex Familial Barrett’s Esophagus (FBE) kindreds, defined as 3 or more members affected by Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC). Ultimately, the study aims to identify putative susceptibility genes for BE and its associated cancers. 

 Individuals with BE, EAC, or EGJAC were recruited at 8 academic care centers participating in the FBEC. After providing informed consent, participants were enrolled and given a self-administered FBE questionnaire. Information was collected on gastroesophageal reflux symptoms; risk factors such as age, gender, race, and self-reported obesity measures; and family history of BE, EAC, stomach and throat cancer (which may be incorrect ways of reporting esophageal cancer). Probands, defined as the first known affected member in a family, had the opportunity to discuss and clarify family history with their relatives before mailing back the questionnaire. Pedigrees were constructed from the questionnaire.  Differences in the age of diagnosis and other variables of interest, such as gender, obesity, race, acid regurgitation, heartburn, smoking and alcohol consumption, were assessed between the three family groups (non-familial, duplex and multiplex). Only probands and kindreds with a confirmed diagnosis were included in the analysis.

The study found that EAC is diagnosed at a significantly earlier age in multiplex FBE kindreds when compared to duplex and non-familial kindreds. Findings suggest that individuals who are members of multiplex FBE pedigree may be considered for screening at an earlier age than the general population. Following that earlier age of disease onset is considered an indicator of genetic susceptibility to disease, these results support a genetic basis for FBE. Future investigations into the genetic basis of FBE are needed and should focus on FBE kindreds with 3 or more members affected with defined BE and EAC phenotypes.

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological diagnosis in which more than 5% of hepatocytes demonstrate macrovesicular steatosis in an individual without significant history of alcohol intake. NAFLD has become the most common cause of chronic liver disease in children in the United States, and encompasses a range of severity from bland steatosis to nonalcoholic steatohepatitis (NASH) that may ultimately result in advanced fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD was selected as the histologic entry criterion for this study because of a lack of knowledge about the natural history in the pediatric subset. Treatment approaches to NAFLD in adults and children target reduction in insulin resistance and oxidative stress. Based on pediatric pilot data demonstrating potential efficacy of metformin or vitamin E, the NASH Clinical Research Network (NASH CRN), initiated a phase 3, multicenter, randomized, double-blinded, placebo-controlled trial evaluating vitamin E or metformin for the Treatment of NAFLD in Children (TONIC). The purpose of this study was to determine if therapeutic modification of insulin resistance or oxidative stress leads to improvement in serum or histologic indicators of liver injury or quality of life. 173 eligible patients were randomized in permuted blocks of treatments stratified by clinical center. Patients were assigned in a 1:1:1 ratio to 1 of 3 groups for 96 weeks of treatment, either (1) oral metformin (500 mg twice daily) and vitamin E placebo twice daily, (2) vitamin E (400 IU twice daily) and metformin placebo twice daily, or (3) vitamin E placebo and metformin placebo, each twice daily. 

The complete TONIC data is now available.

Type 1 diabetes (T1D) is a chronic, slowly progressive autoimmune disease characterized by the destruction of β-cells in the pancreas. Results from previous studies of T1D have suggested that an intervention that prolongs β-cell function would be expected to improve metabolic control and reduce complications in patients.  The Preservation of Pancreatic Production of Insulin Through Immunosuppression (TN02 MMF/DZB) trial was established by TrialNet, a network of 18 clinical centers that conducts research on T1D, to investigate the effects of immunosuppressive agents on the progression of β-cell destruction in patients with recent-onset T1D. The study was a randomized, multicenter, placebo-controlled clinical trial that sought to determine the efficacy of mycophenolate mofetil (MMF) alone or in combination with daclizumab (DZB) in preserving β-cell function.

Eligible patients aged 8-45 years with evidence of β-cell function who were affected with autoimmune T1D for less than 3 months were enrolled. Participants were randomized to receive MMF alone (with DZB placebo), MMF and DZB in combination, or control (MMF placebo and DZB placebo). Study visits were conducted to evaluate safety, including assessment of diabetes care, adverse events, and laboratory measurements to assess medication side effects. Participants were followed for 2 years. The primary outcome measure was the geometric mean difference between active- and placebo-treated subjects of the area under the stimulated C-peptide curve over the first 2 hours of a 4-hour mixed meal glucose tolerance test conducted at the 2-year visit. Secondary outcome measures included differences in A1C hemoglobin levels, insulin dose, hypoglycemic episodes, rates of infection, and adverse events over time. 

Results showed comparable rates of diminishing C-peptide levels between the MMF and MMF and DZB treatment groups and the control group. The study found no treatment benefit from either MMF alone or from the combination of MMF and DZB on the preservation of β-cell function in patients with recent-onset T1D.

Canakinumab is a fully human anti-interleukin-1β (anti-IL-1β) monoclonal antibody, designed to bind to human IL-1β and to functionally neutralize the bioactivity of this pro-inflammatory cytokine. In this phase II clinical trial, subjects were randomized to receive either monthly subcutaneous injections of 2.0 mg/kg canakinumab or placebo for 12 months. All subjects received standard intensive diabetes treatment with insulin and dietary management. Diabetes control was evaluated by measuring glycosylated hemoglobin (HbA1c) every three months. Insulin production was measured by a series of mixed meal glucose tolerance tests (MMTT) conducted regularly during the study. Subjects were followed for one year of treatment, plus one to three years of follow-up.

Gastroparesis, a syndrome in which patients experience delayed gastric emptying, is characterized by symptoms such as nausea, vomiting, bloating, abdominal pain, and early satiety. Management of gastroparesis is limited by few effective treatments, many of which function by accelerating gastric emptying. Based on the hypothesis that some symptoms of gastroparesis arise because of neuropathic changes in enteric and sensory nerves, tricyclic antidepressants (TCAs) in low doses have been used as neuromodulators to treat refractory symptoms of nausea, vomiting, and abdominal pain, but there is little evidence to support this use. The Nortriptyline for Idiopathic Gastroparesis (NORIG) study is a multicenter, randomized, clinical trial that was designed by the Gastroparesis Clinical Research Consortium (GpCRC) to test whether treatment with nortriptyline, a TCA with reduced anticholinergic side effects, results in symptomatic improvement in patients with idiopathic gastroparesis. 

Individuals between the ages of 21 and 68 years old with moderate to severe symptoms of idiopathic gastroparesis for at least 6 months were enrolled. Participants were randomized to treatment with either nortiptyline or placebo. In both groups, dosing was escalated at 3-week intervals (10, 25, 50, 75 mg) up to 75 mg at 12 weeks. At follow-up study visits, which occurred every 3 weeks, symptom questionnaires were administered to assess gastrointestinal and psychological symptoms, quality of life, and TCA side effects. Electrogastrography (EGG) satiety tests and electrocardiography tests were also performed. Treatment was continued for 15 weeks, at which time study medication dose was tapered to zero with a final assessment at 18 weeks.  The primary outcome measure was a decrease from the patient’s baseline Gastroparesis Cardinal Symptom Index (GCSI) score of at least 50% on two consecutive 3 week GCSI assessments over 15 weeks of treatment. Secondary outcome measures included physiological assessments during satiety testing, clinical and psychological symptom scores, and adverse event rates.

Overall symptomatic improvement, as defined by the primary outcome measure, did not differ between the treatment groups: 23% on nortriptyline versus 21% on placebo. Additionally, treatment with nortriptyline showed no improvement in nausea, fullness/satiety, bloating, or quality of life measures. These findings suggest that TCAs may not be effective in the treatment of idiopathic gastroparesis.

Characteristics associated with the phenotype of frailty include fatigue and reduced physiologic capacity in neurologic control, mechanical performance, and energy metabolism. Studies have shown that there is an increased risk of frailty in chronic disease populations, including patients with chronic kidney disease undergoing hemodialysis. Currently, little is known about the prevalence or the contributing factors of frailty among patients with this condition. The ACTIVE/ADIPOSE (a Cohort Study to Investigate the Value of Exercise in ESRD/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD) study is a prospective, multicenter observational study designed to characterize the prevalence and progression of frailty among patients undergoing hemodialysis for end-stage renal disease (ESRD). 

Patients at least 18 years of age who were on hemodialysis for at least three months were enrolled in the study. Participants were assessed using the validated Fried frailty index, which defines frailty as the presence of 3 or more criteria, including recent unintentional weight loss, reported exhaustion, low grip strength, slow walk speed, and low physical activity. Information was collected on participants’ demographics, medical history, activity status, and mood, and physical performance was assessed via tests of grip strength, walk speed, and body composition. Additionally, blood draws were conducted semi-annually for evaluation of nutrition, inflammation, and cardiac markers. All participants were followed for two years. Logistic regression models were used to estimate the association of nutrition, cardiovascular, and rehabilitation parameters with patient frailty. 

Analyses showed that peripheral vascular disease and cardiac diseases, such as dysrhythmia, atrial fibrillation, tachycardia, pericarditis, and cardiac arrest, were associated with higher odds for frailty. In contrast, black race and higher serum albumin concentration were associated with lower odds for frailty. Among patients who met the Fried definition of frailty, 78% scored as frail on walk speed and 56% scored as frail on grip strength, the two measures of physical performance. The association of these sociodemographic and clinical risk factors with wasting in this cohort provides evidence for the prevalence of frailty in hemodialysis patients.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network was established to focus on a broader approach to the study of Interstitial Cystitis (IC)/Painful Bladder Syndrome (PBS) in men and women, and Chronic Prostatitis (CP)/Chronic Pelvic Pain Syndrome (CPPS) in men. Participants with some form or symptoms of IC or CP were asked to join the Trans-MAPP Epidemiology and Phenotyping (EP) Study. Participants with no Urologic Pelvic Pain Syndromes as well as participants with specific conditions (Fibromyalgia (FM), Irritable Bowel Syndrome (IBS), Chronic Fatigue Syndrome (CFS)) were recruited for the Trans-MAPP Control Study. These participants were a reference/control group for the Trans-MAPP EP Study.

Full study data are available for request.

MRI images for MAPP I participants are not included in the package, but are available upon request.

Aprepitant is an FDA-approved medication for the treatment of nausea following chemotherapy or surgery. Aprepitant is also used by some doctors to reduce nausea and vomiting in patients with gastroparesis, although the drug is not approved for this use. The Aprepitant for the Relief of Nausea in Patients with Chronic Nausea and Vomiting of Presumed Gastric Origin (APRON) study is a multicenter, randomized, placebo-controlled clinical trial designed to test the safety and efficacy of aprepitant in reducing symptoms among patients with gastroparesis. 

Patients at least 18 years of age who have experienced symptoms of chronic nausea and vomiting related to gastroparesis for at least 6 months are eligible for the study. Participants are randomized to treatment with either aprepitant (125 mg/day) or placebo for 4 weeks. Nausea symptoms are measured daily on a 0 to 100 mm visual analog scale (VAS) for one week at baseline and for four weeks after randomization. The primary outcome measure is improvement in VAS scores from baseline to through the course of treatment, as defined by a 25 mm or more reduction in mean VAS or attaining a mean VAS during the treatment period of < 25 mm. Improvement in other gastrointestinal symptoms, including symptoms of fullness, hunger, bloating, and abdominal pain, will be measured using the Gastroparesis Cardinal Symptom Index Daily Diary (GCSIDD), an overall relief of symptom questionnaire, and patient perception of improvement. Safety will be determined through satiety tests, electrogastrography for measuring of EGG dysrhythmias, and monitoring of side effects.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of the disease, which results in cirrhosis, liver failure, and death in a substantial proportion of patients. Treatment approaches to NAFLD in adults and children target reduction in insulin resistance and oxidative stress. Several agents have been found to be promising as therapy of NAFLD in small clinical trials, but none have been proven to alter its natural history or outcome, and none are approved for general use in this disorder.  The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) was established by the NIDDK in 2002 to investigate the natural history, pathogenesis, and therapy of NAFLD and NASH in both children and adults. The Farnesoid X Receptor (FXR) Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis (NASH) Treatment (FLINT) trial was a multicenter, randomized, placebo-controlled clinical trial conducted by the NASH CRN to investigate the safety and efficacy of treatment of obeticholic acid compared to placebo in adults with nonalcoholic fatty liver disease.

Individuals with histologic evidence of NASH, based on a liver biopsy and a disease activity score (NAS) of at least 4 (with a score of at least 1 in each component of the NAS 8-point scale), were enrolled and randomized to treatment with either obeticholic acid (25 mg) or placebo for 72 weeks. Each participant received a baseline oral glucose tolerance test and a baseline MRI scan to determine liver fat content. Additionally, information was collected on demographics, alcohol consumption, and medication use. The primary outcome measure was improvement in the NAS score by at least 2 points with no worsening of liver fibrosis and was assessed by liver biopsy at 72 weeks. Secondary outcome measures included change in NASH diagnosis (from determinate or indeterminate to not-NASH), fibrosis score, hepatocellular ballooning score, hepatic fat fraction, serum aminotransferase and gamma-glutamyl transpeptidase (GGT) levels, fasting glucose levels, and health related quality of life scores.

A planned interim analysis of end-of-treatment liver biopsies from 58% (164/283) of enrolled patient demonstrated that the primary endpoint had been reached and the statistical significance crossed the preset boundry set for efficacy (p ≤ 0.0031). Accordingly, further liver biopsies were not performed. Additionally, because of the observation of disproportionate lipid abnormalities among patients receiving OCA and in the context of the study having met its primary endpoint, further treatment with OCA and placebo was discontinued and remaining patients completed a 24-week follow-up off treatment.

Urge incontinence, the involuntary urine loss associated with a strong desire to void, is one of several types of urinary incontinence (UI) and has one of the greatest impacts on quality of life. Common treatments for urge incontinence include behavioral training and antimuscarinic medications, but long-term adherence with medication therapy can be difficult to achieve. The Behavior Enhances Drug Reduction of Incontinence (BE-DRI) study was a multicenter, randomized clinical trial that combined behavioral training and pharmacological treatment with the goal of improving patient outcomes. The primary aim of this randomized clinical trial was to determine whether combining antimuscarinic drug therapy with supervised behavioral training, compared to drug therapy alone, improves the ability of women with urge incontinence to achieve clinically important reductions in incontinence episodes and to sustain these improvements after discontinuing medication. 

Participants with urge incontinence (defined as urge symptom index > stress symptom index on the Medical, Epidemiological, and Social Aspects of Aging Questionnaire) were enrolled in the study and randomly assigned either to drug therapy alone or combined behavioral and drug therapy. Drug therapy was tolterodine tartrate at a dose of 4 mg per day. Combination therapy included drug and behavioral training, which consisted of teaching pelvic floor muscle control and exercises, delayed voiding to increase voiding interval, individualized fluid management, and strategies to diminish urgency, suppress bladder contractions, and prevent both stress and urge incontinence. Treatment was discontinued for both groups after 10 weeks. The primary outcome measure, assessed at 8 months, was no receipt of drugs or other therapy for urge incontinence and a 70% or greater reduction in frequency of incontinence episodes. Secondary outcome measures included reduction in incontinence, self-reported satisfaction and improvement, and scores on validated questionnaires measuring symptom distress and health-related quality of life.

Results showed that the rate of successful discontinuation of therapy at 8 months was the same in the combination therapy and drug therapy alone groups, although a higher proportion of participants who received combination therapy than drug therapy alone achieved a 70% or greater reduction in incontinence at 10 weeks. The study concluded that the addition of behavioral training to drug therapy may reduce incontinence frequency during active treatment but does not improve the ability to discontinue drug therapy and maintain improvement in urinary incontinence.

Epidemiological studies suggest that obesity is a strong risk factor for urinary incontinence (UI), and preliminary studies have suggested that weight loss may have a beneficial effect on urinary incontinence in obese women. The Program to Reduce Incontinence by Diet and Exercise (PRIDE) study was a multi-center (2 sites) randomized clinical trial conducted to examine the long term effects of a weight loss intervention on urinary incontinence in overweight and obese women. 

A total of 338 women with at least UI episodes per week and a body-mass index (BMI) between 25 and 50 were enrolled in the study. Participants were randomly assigned to an intensive 6-month behavioral weight-loss program (intervention group) or to a structured four-session education program (control group) and followed for 18 months. Following completion of the 6-month weight loss intervention, participants in the intervention group underwent a second randomization to a motivationally focused weight loss maintenance program or a standard skills-based maintenance approach. The secondary randomization allowed the comparison of two approaches to weight loss maintenance. Urinary incontinence was assessed with a 7-day voiding diary. Assessments were completed at 6, 12, and 18 months, and information was collected on height, weight, demographics, and medical history, including urinary  incontinence history. The primary outcome measure was the percentage change in the number of urinary incontinence episodes reported in the 7-day voiding diary at 6 months after randomization. Secondary outcome measures included the change in number of episodes of urge and stress urinary incontinence, participant satisfaction with incontinence treatment, and a standardized pad test to measure 24-hour involuntary urine loss. Longer term effects of the behavioral weight-loss program on UI were assessed at 12 and 18 months. 

Results showed that the comprehensive behavioral weight-loss program resulted in a significantly greater reduction in the frequency of self-reported UI episodes (mean weekly number of incontinence episodes) at 6 months as compared with the structured education program. Additionally, decreased stress incontinence episode frequency was maintained at 12 months with a trend toward continued reduction in total incontinence episode frequency. At 18 months, there were no statistically significant differences in the reduction of weekly incontinence episode frequency for stress or total urinary incontinence between the groups, despite a substantial difference in greater weight loss and participant satisfaction with improvements in UI in the intervention group. The study concluded that the behavioral weight loss intervention was more effective than an educational control program in decreasing stress-related UI through 12 months, although the benefits at 18 months were more limited.

The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes in patients with end-stage renal disease (ESRD). The Clopidogrel Prevention of Early AV Fistula Thrombosis (FISTULA) study was one of two major clinical trials conducted under the DAC.  The study was a randomized, double-blind, placebo-controlled trial of clopidogrel administered following fistula creation in a large group of patients with advanced chronic kidney disease or ESRD. The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters; however, early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. The FISTULA study aimed to investigate the ability of platelet inhibition to prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access.

Participants with chronic kidney disease or ESRD who underwent creation of a new native arteriovenous (AV) fistula were randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery.  The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. The study found that clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis.

The Hemodialysis (HEMO) Study was a multi-center, randomized clinical trial designed to test whether the mortality and morbidity of hemodialysis (HD) patients can be reduced by modifying the dialysis procedure for the removal of toxins from the blood. The study examined two factors, the dose of dialysis delivered and the size of the molecules removed, to determine the effect on the survival or morbidity among hemodialysis patients. A two-by-two factorial design was used to assign 1846 patients randomly to either a standard or high dose of dialysis and to either a dialyzer with a low-flux or high-flux membrane for dialysis three times a week. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment. The relative risk of death was not significantly different in the high-dose group compared to the standard-dose group, or the high-flux group as compared with the low-flux group. The main secondary outcomes, including first hospitalization, did not differ significantly for either the dose groups or the flux groups. Patients undergoing hemodialysis three times a week appear to have no major benefit from either a higher dialysis dose than that recommended by current U.S. guidelines or from the use of a high-flux membrane.

It has been proposed that the chronic, long-term ingestion of analgesics leads to specific renal pathology and renal failure. Previous studies suggested that the non–contrast-enhanced computerized tomography (CT) scan is a highly reliable tool for the diagnosis of analgesic-associated renal disease. The National Analgesic Nephropathy Study (NANS) is a case control study that was established to examine the association between heavy analgesic use and renal insufficiency and to investigate the ability of the CT scan to detect heavy analgesic use in the US population with end-stage renal disease (ESRD).

Patients with ESRD without a clear nonanalgesic cause for renal failure who had begun dialysis within the previous 3 months were enrolled in the study. A non-contract enhanced CT scan was performed using a standardized protocol. Three parameters—size, indentations, and calcifications—were used to identify patients who might have analgesic-induced kidney disease. Additionally, an interview was conducted to obtain information from patients concerning analgesic use, pre-dialysis signs and symptoms of renal disease, medical history, and demographics. 

The study concluded that findings of small indented calcified kidneys (SICK) did not occur with sufficient frequency in US patients with ESRD and heavy analgesic exposure to render the non-contrast-enhanced CT scan a sensitive tool to identify such individuals. Although the conclusion concerning the lack of diagnostic value of the CT scan is clear, the study did not address the overall relationship between analgesics and the progression of renal disease. Results showed an association between heavy analgesic ingestion and findings of SICK in incident US patients with ESRD, which seemed to be accounted for mostly by phenacetin-containing products; however, future studies are needed to learn whether there is an association in the US population between currently available analgesics and ESRD and whether the ingestion of NSAID or cyclooxygenase-2 inhibitors contribute to the development of ESRD.

The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes in patients with end-stage renal disease (ESRD). The Aggrenox Prevention of Access Stenosis Study (GRAFT) was one of two major clinical trials conducted under the DAC.  Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The GRAFT study was a double-blind, placebo-controlled randomized clinical trial designed to test whether treatment with Aggrenox (dipyridamole and low-dose aspirin) prolonged the primary unassisted patency of newly placed grafts. Participants undergoing placement of a new AV graft for hemodialysis were randomly assigned to receive treatment with Aggrenox or placebo immediately following access surgery. The primary outcome measure was loss of primary unassisted patency, defined as the time from access placement until thrombosis or requirement for intervention to maintain or restore patency. Major secondary outcome measures included cumulative access failure and death. The GRAFT study found that treatment with Aggrenox had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts.

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