Ethical challenges experienced by clinical research nurses:: A qualitative study.

BACKGROUND:: Clinical investigation is a growing field employing increasing numbers of nurses. This has created a new specialty practice defined by aspects unique to nursing in a clinical research context: the objectives (to implement research protocols and advance science), setting (research facilities), and nature of the nurse-participant relationship. The clinical research nurse role may give rise to feelings of ethical conflict between aspects of protocol implementation and the duty of patient advocacy, a primary nursing responsibility. Little is known about whether research nurses experience unique ethical challenges distinct from those experienced by nurses in traditional patient-care settings. RESEARCH OBJECTIVES:: The purpose of the study was to describe the nature of ethical challenges experienced by clinical research nurses within the context of their practice. RESEARCH DESIGN:: The study utilized a qualitative descriptive design with individual interviews. PARTICIPANTS AND RESEARCH CONTEXT:: Participating nurses (N = 12) self-identified as having experienced ethical challenges during screening. The majority were Caucasian (90%), female (83%), and worked in outpatient settings (67%). Approximately 50% had > 10 years of research experience. ETHICAL CONSIDERATIONS:: The human subjects review board approved the study. Written informed consent was obtained. FINDINGS:: Predominant themes were revealed: (1) the inability to provide a probable good, or/do no harm, and (2) dual obligations (identity as a nurse vs a research nurse). The following patterns and subthemes emerged: conflicted allegiances between protocol implementation, needs of the participant, desire to advance science, and tension between the nurse-patient therapeutic relationship versus the research relationship. DISCUSSION:: Participants described ethical challenges specific to the research role. The issues are central to the nurse-participant relationship, patient advocacy, the nurse's role in implementing protocols, and/or advancing science. CONCLUSION:: Ethical challenges related to the specialized role of clinical research nurses were identified. More research is warranted to fully understand their nature and frequency and to identify support systems for resolution.

Development of a plain-language library of educational resources for research participants.

There is a paucity of educational resources for potential clinical trial participants, particularly resources in plain language, attentive to health literacy principles and translated into native languages. The New England Research Subject Advocacy Group was formed to explore common issues, interests, and concerns related to the experience of participation in clinical research and research participant safety. Specifically, the group sought to increase community awareness and trust through the development and distribution of publicly accessible informational resources. In support of these aims, the group developed a robust library of high-quality, plain-language educational materials covering topics in health research, research participation, and common research procedures, and translated the majority of the materials into an additional 15 languages. These resources have been downloaded over 130,000 times. After English, the most common languages downloaded are Vietnamese, Spanish, and Korean.

Insulin secretion and sensitivity in healthy adults with low vitamin D are not affected by high-dose ergocalciferol administration: a randomized controlled trial.

BACKGROUND: Epidemiologic data suggest that low serum 25-hydroxyvitamin D [25(OH)D] increases insulin resistance and the risk of type 2 diabetes. Few interventional trials have assessed the effect of vitamin D on insulin metabolism, and published results are discordant. OBJECTIVE: The goal of this study was to perform a detailed assessment of the effect of ergocalciferol administration on glucose and insulin metabolism in healthy people with low total 25(OH)D(total). DESIGN: This was a 12-wk, double-blinded, randomized controlled trial. We enrolled 90 healthy volunteers aged 18-45 y with serum 25(OH)D ≤20 ng/mL (by immunoassay) and administered 50,000 IU ergocalciferol/wk or placebo for 12 wk. Primary endpoints were change in first-phase insulin response and insulin sensitivity as measured by intravenous glucose tolerance test. Secondary endpoints included change in homeostasis model assessment of insulin resistance; fasting glucose, insulin, and lipids; body mass index (BMI); and blood pressure. RESULTS: On-study 25(OH)D(total) was assessed by liquid chromatography-tandem mass spectrometry. In the treated group, 25(OH)D(total) rose from 18 ± 7 to 43 ± 12 ng/mL (P < 0.001) with no change in the placebo group. Despite this increase, at 12 wk, there were no between-group differences in either insulin response or insulin sensitivity; nor were there differences in any measured secondary endpoints. There was no evidence of effect modification by sex, race, glucose tolerance status, baseline 25(OH)D(total), or BMI. CONCLUSION: In healthy persons with low 25(OH)D(total), ergocalciferol administration for 12 wk normalizes 25(OH)D(total) but does not improve insulin secretion, insulin sensitivity, or other markers of metabolic health.

A distributed model: redefining a robust research subject advocacy program at the Harvard Clinical and Translational Science Center.

The Harvard Clinical and Translational Science Center ("Harvard Catalyst") Research Subject Advocacy (RSA) Program has reengineered subject advocacy, distributing the delivery of advocacy functions through a multi-institutional, central platform rather than vesting these roles and responsibilities in a single individual functioning as a subject advocate. The program is process-oriented and output-driven, drawing on the strengths of participating institutions to engage local stakeholders both in the protection of research subjects and in advocacy for subjects' rights. The program engages stakeholder communities in the collaborative development and distributed delivery of accessible and applicable educational programming and resources. The Harvard Catalyst RSA Program identifies, develops, and supports the sharing and distribution of expertise, education, and resources for the benefit of all institutions, with a particular focus on the frontline: research subjects, researchers, research coordinators, and research nurses.

Continuing improvement in type 2 diabetes care through performance-based evaluations.

AIMS: The timely evidence-based care of type 2 diabetes mellitus (T2DM) is imperative for achieving and maintaining glycemic control, reducing complications, and changing the paradigm of this epidemic. Based largely on results from earlier performance improvement (PI) activities, we conducted a continuing medical education (CME)-certified PI activity to foster improved adherence to guideline recommendations and current evidence for the care of patients with T2DM. METHODS: Participants engaged in a 3-stage process of self-assessment, goal setting, and reassessment. RESULTS: A total of 64 clinicians completed the entire PI process, abstracting data from 1600 patient charts before and after a period of self-improvement. After the intervention, clinicians were more likely to assess patients for disease-related complications and provide counseling on proper nutrition, exercise, and smoking cessation. Patients with A1C, blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) values above goal (defined as A1C ≥7, BP ≥130/80 mm Hg, and LDL-C >100 g/dL) were more likely to receive treatment modifications compared with baseline clinician performance. Significant changes observed in patient outcomes included improved mean A1C values (baseline 7.5% vs postintervention 7.3%; P = .027), decreased likelihood of BP at or above 130/80 mm Hg (baseline 37% vs postintervention 30%; P < .001), and decreased likelihood of LDL-C above 100 g/dL (baseline 33% vs postintervention, 27%; P < .001). CONCLUSIONS: Significant changes in clinician performance of key quality measures were reported in patients with T2DM after a PI CME activity improved adherence to evidence-based recommendations of care.

A randomized controlled trial of cognitive behavioral therapy for adherence and depression (CBT-AD) in patients with uncontrolled type 2 diabetes.

OBJECTIVE: To test cognitive behavioral therapy for adherence and depression (CBT-AD) in type 2 diabetes. We hypothesized that CBT-AD would improve adherence; depression; and, secondarily, hemoglobin A1c (A1C). RESEARCH DESIGN AND METHODS: Eighty-seven adults with unipolar depression and uncontrolled type 2 diabetes received enhanced treatment as usual (ETAU), including medication adherence, self-monitoring of blood glucose (SMBG), and lifestyle counseling; a provider letter documented psychiatric diagnoses. Those randomized to the intervention arm also received 9-11 sessions of CBT-AD. RESULTS: Immediately after acute treatment (4 months), adjusting for baseline, CBT-AD had 20.7 percentage points greater oral medication adherence on electronic pill cap (95% CI -31.14 to -10.22, P = 0.000); 30.2 percentage points greater SMBG adherence through glucometer downloads (95% CI -42.95 to -17.37, P = 0.000); 6.44 points lower depression scores on the Montgomery-Asberg Depression Rating Scale (95% CI 2.33-10.56, P = 0.002); 0.74 points lower on the Clinical Global Impression (95% CI 0.16-1.32, P = 0.01); and 0.72 units lower A1C (95% CI 0.29-1.15, P = 0.001) relative to ETAU. Analyses of 4-, 8-, and 12-month follow-up time points indicated that CBT-AD maintained 24.3 percentage points higher medication adherence (95% CI -38.2 to -10.3, P = 0.001); 16.9 percentage points greater SMBG adherence (95% CI -33.3 to -0.5, P = 0.043); and 0.63 units lower A1C (95% CI 0.06-1.2, P = 0.03) after acute treatment ended. For depression, there was some evidence of continued improvement posttreatment, but no between-group differences. CONCLUSIONS: CBT-AD is an effective intervention for adherence, depression, and glycemic control, with enduring and clinically meaningful benefits for diabetes self-management and glycemic control in adults with type 2 diabetes and depression.

Pathways to quality inpatient management of hyperglycemia and diabetes: a call to action.

Currently patients with diabetes comprise up to 25-30% of the census of adult wards and critical care units in our hospitals. Although evidence suggests that avoidance of hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL) is beneficial for positive outcomes in the hospitalized patient, much of this evidence remains controversial and at times somewhat contradictory. We have recently formed a consortium for Planning Research in Inpatient Diabetes (PRIDE) with the goal of promoting clinical research in the area of management of hyperglycemia and diabetes in the hospital. In this article, we outline eight aspects of inpatient glucose management in which randomized clinical trials are needed. We refer to four as system-based issues and four as patient-based issues. We urge further progress in the science of inpatient diabetes management. We hope this call to action is supported by the American Diabetes Association, The Endocrine Society, the American Association of Clinical Endocrinologists, the American Heart Association, the European Association for the Study of Diabetes, the International Diabetes Federation, and the Society of Hospital Medicine. Appropriate federal research funding in this area will help ensure high-quality investigations, the results of which will advance the field. Future clinical trials will allow practitioners to develop optimal approaches for the management of hyperglycemia in the hospitalized patient and lessen the economic and human burden of poor glycemic control and its associated complications and comorbidities in the inpatient setting.

Validity of medication adherence self-reports in adults with type 2 diabetes.

OBJECTIVE: To assess the validity of self-report measures of diabetes medication adherence and evaluate the effect of depression on the validity of these reports. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes, treated with oral medications, completed a set of medication adherence self-reports that varied response scales and time frames, were administered structured clinical interviews for depression, and provided blood samples for HbA(1c) as part of a screening for an intervention study. A subsample of participants with HbA(1c) ≥7.0% and clinically significant depression received Medication Event Monitoring System (MEMS) bottle caps to record adherence. Analyses examined relationships between adherence measures and HbA(1c) and, in the subsample, MEMS. Moderated linear regression evaluated whether depression severity modified relationships with HbA(1c). RESULTS: Participant (n = 170, 57% men, 81% white, mean HbA(1c) 8.3% [SD, 1.7]) adherence self-reports were significantly (r = -0.18 to -0.28; P < 0.03) associated with lower HbA(1c). In the subsample (n = 88), all self-reports were significantly (r = 0.35 to 0.55; P ≤ 0.001) associated with MEMS-measured adherence. Depression significantly moderated the relationship between three of six self-reports and HbA(1c); at high levels of depression, associations with HbA(1c) became nonsignificant. CONCLUSIONS: Results support the validity of easily administered self-reports for diabetes medication adherence. One-month, percentage-based ratings of adherence had the strongest associations with MEMS and HbA(1c); those requiring the report of missed doses had weaker associations. One-week self-ratings and measures that require respondents to record the number of missed doses appear to be vulnerable to bias from depression severity.

Impact of inpatient diabetes management, education, and improved discharge transition on glycemic control 12 months after discharge.

AIM: To determine whether inpatient diabetes management and education with improved transition to outpatient care (IDMET) improves glycemic control after hospital discharge in patients with uncontrolled type 2 diabetes (T2DM). METHODS: Adult inpatients with T2DM and HbA1c > 7.5% (58 mmol/mol) admitted for reasons other than diabetes to an academic medical center were randomly assigned to either IDMET or usual care (UC). Linear mixed models estimated treatment-dependent differences in the change in HbA1c (measured at 3, 6, and 12 months) from baseline to 1-year follow-up. RESULTS: Thirty-one subjects had mean age 55 ± 12.6 years, with mean HbA1c of 9.7 ± 1.6% (82 ± 18 mmol/mol). Mean inpatient glucose was lower in the IDMET than in the UC group (176 ± 66 versus 195 ± 74 mg/dl [9.7 versus 10.8 mmol/l], P = 0.001). In the year after discharge, the average HbA1c reduction was greater in the IDMET group compared with the UC group by 0.6% (SE 0.5%, [7 (SE 5)mmol/mol], P = 0.3). Among patients newly discharged on insulin, the average HbA1c reduction was greater in the in the IDMET group than in the UC group by 2.4% (SE 1.0%, [25 (SE 11)mmol/mol], P = 0.04). CONCLUSIONS: Inpatient diabetes management (IDMET) substantially improved glycemic control 1 year after discharge in patients newly discharged on insulin; patients previously treated with insulin did not benefit.

Improvement in outcomes of clinical islet transplantation: 1999-2010.

OBJECTIVE: To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. RESEARCH DESIGN AND METHODS: A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999-2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years. RESULTS: Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003-2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA(1c) and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). CONCLUSIONS: The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient.

Effectiveness of a computerized insulin order template in general medical inpatients with type 2 diabetes: a cluster randomized trial.

OBJECTIVE: To determine whether an electronic order template for basal-bolus insulin ordering improves mean blood glucose in hospitalized general medical patients with hyperglycemia and type 2 diabetes. RESEARCH DESIGN AND METHODS: We randomly assigned internal medicine resident teams on acute general medical floors to the use of an electronic insulin order template or usual insulin ordering. We measured diabetes care parameters for 1 month on all patients with type 2 diabetes and blood glucose <60 mg/dl or >180 mg/dl treated by these physicians. RESULTS: Intervention group patients (n = 65) had mean glucose of 195 ± 66 mg/dl. Control group patients (n = 63) had mean glucose of 224 ± 57 mg/dl (P = 0.004). In the intervention group, there was no increase in hypoglycemia. CONCLUSIONS: Access to a computer insulin order template was associated with improved mean glucose levels without increasing hypoglycemia in patients with type 2 diabetes.

Cognitive Behavioral Therapy for Adherence and Depression (CBT-AD) in Type 2 Diabetes.

Depression is one of the most common psychological problems among individuals diabetes, and it is associated with worse treatment adherence and clinical outcomes. As part of a program of treatment research aimed at integrating interventions for depression and treatment nonadherence, five depressed patients with suboptimally controlled type 2 diabetes were treated with 10-12 sessions of individual cognitive behavioral therapy for adherence and depression (CBT-AD) in a case-series design. The intervention was delivered in a hospital setting by a collaborative team consisting of a psychologist, a nurse educator, and a dietitian. Post-treatment, all participants demonstrated a decrease in depression severity and demonstrated improvements in diabetes self-care. Four of the five demonstrated improved glycemic control. These preliminary results provide evidence for the acceptability, feasibility, and potential utility of CBT-AD for patients with type 2 diabetes and depression.

Predictive factors for in-stent late loss and coronary lesion progression in patients with type 2 diabetes mellitus randomized to rosiglitazone or placebo.

BACKGROUND: Type 2 diabetics (DM2) are at increased risk for restenosis as well as nonculprit coronary artery lesion (NCCL) progression. Rosiglitazone (RSG) favorably modifies many of the altered biologic processes in DM2, although recent reports have questioned its safety. We conducted a double-blind randomized trial to assess the effects of RSG versus placebo on in-stent late lumen loss (LL) and angiographic progression of NCCL. METHODS: A total of 65 DM2 were randomized to RSG (4 mg/d) (n = 32) or placebo (n = 33) at the time of stenting and underwent clinical and laboratory analysis at 1 and 4 months and 8-month angiography (n = 46 patients). Rapid angiographic progression (RAP) was defined as > or =20% diameter reduction of preexisting NCCL by quantitative coronary angiography, or a new narrowing > or =30%. RESULTS: Mean LL in RSG (n = 33 lesions) was not different from that of placebo (0.62 +/- 0.59 vs 0.70 +/- 0.67, P = NS). Seven (13.5%) of 52 NCCLs have RAP in RSG versus 9 (16.1%) of 56 in placebo (P = NS). High-sensitivity C-reactive protein (hs-CRP) was the only predictor of RAP. Patients with a 120-day hs-CRP > or =75th percentile had an OR of 7.35 (95% CI 2.35-23) for RAP versus those below. Although RSG treatment also lowered log (hs-CRP) at 4 months (RSG 0.10 +/- 0.37 vs placebo 0.26 +/- 0.49, P = .06), it did not decrease the likelihood of plaque progression while also raising LDL and N-terminal brain naturetic peptide. CONCLUSIONS: Rosiglitazone appears not to lower LL or reduce angiographic progression of NCCL in DM2 and had complex effects on markers of cardiac risk.

Point-of-care glucose and hemoglobin A1c in emergency department patients without known diabetes: implications for opportunistic screening.

OBJECTIVES: The objectives were to evaluate the correlation between random glucose and hemoglobin A1c (HbA1c) in emergency department (ED) patients without known diabetes and to determine the ability of diabetes screening in the ED to predict outpatient diabetes. METHODS: This was a cross-sectional study at an urban academic ED. The authors enrolled consecutive adult patients without known diabetes during eight 24-hour periods. Point-of-care (POC) random capillary glucose and HbA1c levels were tested, as well as laboratory HbA1c in a subset of patients. Participants with HbA1c > or = 6.1% were scheduled for oral glucose tolerance test (OGTT). RESULTS: The 265 enrolled patients were 47% female and 80% white, with a median age of 42 years. Median glucose and HbA1c levels were 93 mg/dL (interquartile range [IQR] = 82-108) and 5.8% (IQR = 5.5-6.2), respectively. The correlation between POC and laboratory HbA1c was r = 0.96, with mean difference 0.33% (95% confidence interval [CI] = 0.27% to 0.39%). Glucose threshold > or = 120 mg/dL had 89% specificity and 26% sensitivity for predicting the 76 (29%) patients with abnormal HbA1c; > or = 140 mg/dL had 98% specificity and 14% sensitivity. The correlation between random glucose and HbA1c was moderate (r = 0.60) and was affected by age, gender, prandial status, corticosteroid use, and current injury. Only 38% of participants with abnormal HbA1c returned for OGTTs; 38% had diabetes, 34% had impaired fasting glucose/impaired glucose tolerance, and 28% had normal glucose tolerance. CONCLUSIONS: ED patients have a high prevalence of undiagnosed diabetes. Although screening with POC random glucose and HbA1c is promising, improvement in follow-up with confirmatory testing and initiation of treatment is needed before opportunistic ED screening can be recommended.

Prevalence of elevated hemoglobin A1c among patients admitted to the hospital without a diagnosis of diabetes.

CONTEXT: One in four hospitalized patients has diagnosed diabetes. The prevalence of unrecognized, or undiagnosed, diabetes among hospitalized patients is not well established. OBJECTIVE: Our objective was to determine the prevalence of unrecognized probable diabetes in this patient population determined by elevated hemoglobin A1c (HbA1c) level. DESIGN: We conducted a prospective observational cohort trial with retrospective follow-up of patients with elevated HbA1c levels and no diagnosis of diabetes. HbA1c levels were obtained for all patients. SETTING: The study was conducted at an acute care general hospital. PATIENTS: Patients included 695 adult, nonobstetric patients admitted on 11 d in 2006. MAIN OUTCOME MEASURES: Outcome measures included rate of unrecognized probable diabetes, defined as admission HbA1c of more than 6.1% and no diagnosis of diabetes or treatment with antidiabetic medications before or during their admission and rate of unrecognized diabetes 1 yr after discharge. RESULTS: Eighteen percent of hospitalized patients had elevated HbA1c levels without a diagnosis of diabetes. Random glucose levels poorly predicted elevated HbA1c levels (area under receiver operating characteristic curve, 0.60). Neither diagnosed diabetes nor HbA1c level was associated with length of stay or costs (P>0.1 for all comparisons). Only 15% of patients with elevated HbA1c levels who continued to receive care within the system studied had diabetes diagnosed in the year after the index admission. CONCLUSIONS: Nearly one in five adult patients admitted to a large general hospital had unrecognized probable diabetes, based on elevated HbA1c levels. Random glucose levels during the hospital stay were poorly predictive of this condition. Few hospitalized patients with elevated HbA1c levels were diagnosed within the year after admission.

Pathology of an islet transplant 2 years after transplantation: evidence for a nonimmunological loss.

BACKGROUND: We report the immunological and pathological findings of a 52-year-old woman, who died two years after the second of two islet transplants performed using the Edmonton protocol. After each islet transplant, she gradually lost insulin independence while maintaining low levels of C-peptide secretion. METHODS: A complete autopsy was performed including pathological and immunohistochemical analysis of hepatic allogeneic islets and native pancreatic islets to identify rejection or autoimmunity. Elispots assays for allogeneic sensitization and autoantibody assays for autoimmunity were performed antemortem after her islet transplantations to test in vitro for evidence of allogeneic sensitization or autoimmunity. RESULTS: The cause of death was a hypertensive stroke. Small numbers of islets without inflammation were identified within portal venules and stained with insulin. The atrophic pancreas contained small numbers of islets, which stained for insulin, and lacked any inflammation within or adjacent to the islets. In vitro assays for alloantibodies were negative, and Elispots assays failed to identify allogeneic sensitization. In vitro assays for diabetic associated autoantibodies did not identify autoimmune resensitization. The allografted kidney showed only early changes of recurrent diabetic nephropathy, and no evidence of rejection. CONCLUSIONS: In summary, no evidence was found to support an immunological basis (either allo or autoimmunity) for the slow loss of intrahepatic islets, which may, therefore, be related to nonimmunological anatomic and physiological abnormalities of islets infused into the portal veins or to drug toxicity.

Measuring psychological insulin resistance: barriers to insulin use.

PURPOSE: The purpose of this study is to explore the attitudes that contribute to psychological insulin resistance (PIR) in insulin-naive patients with type 2 diabetes and to identify predictors of PIR. METHODS: A prospective study using 2 self-report surveys and incorporating demographic and health variables was conducted to determine the prevalence of PIR among a sample of 100 adult, insulin-naive patients with type 2 diabetes at an outpatient diabetes center in a university-affiliated teaching hospital. RESULTS: Thirty-three percent of patients with type 2 diabetes were unwilling to take insulin. The most commonly expressed negative attitudes were concern regarding hypoglycemia, permanent need for insulin therapy, less flexibility, and feelings of failure. Less than 40% expressed fear of self-injection or thought that injections were painful. However, compared with willing subjects, unwilling subjects were more likely to fear injections and thought injections would be painful, life would be less flexible, and taking insulin meant health would deteriorate (P< .005 for all comparisons). Poorer general health and higher depression scores also correlated with PIR. CONCLUSIONS: The results of the surveys, which were generally consistent, identified several remediable misconceptions regarding insulin therapy and suggest targets for educational interventions.

Value of risk stratification to increase the predictive validity of HbA1c in screening for undiagnosed diabetes in the US population.

BACKGROUND: Opportunistic screening using hemoglobin A1c (HbA1c) may improve detection of undiagnosed diabetes but remains controversial. OBJECTIVE: To evaluate the predictive validity of HbA1c as a screening test for undiagnosed diabetes in a risk-stratified sample of the US population. DESIGN: Weighted cross-sectional analysis of diabetes risk factors, HbA1c, and fasting plasma glucose (FPG) in National Health and Nutrition Examination Survey (NHANES), 1999-2004. SUBJECTS: Six thousand seven hundred and twenty-three NHANES participants from morning examination session, aged > or = 18 years and without prior physician-diagnosed diabetes. MEASUREMENTS: HbA1c and undiagnosed diabetes defined by FPG > or = 7.0 mmol/l (126 mg/dl). RESULTS: The estimated prevalence of undiagnosed diabetes in the US population was 2.8% (5.5 million people). HbA1c had strong correlation with undiagnosed diabetes, with an area under the receiver-operating characteristic curve of 0.93. Independent predictors of undiagnosed diabetes were older age, male sex, black race, hypertension, elevated waist circumference, elevated triglycerides, and low high-density lipoprotein cholesterol. We derived a risk score for undiagnosed diabetes and stratified participants into low (0.44% prevalence), moderate (4.1% prevalence), and high (11.1% prevalence) risk subgroups. In moderate and high risk groups, a threshold HbA1c value > or = 6.1% identified patients requiring confirmatory FPG; HbA1c < or = 5.4% identified patients for whom diabetes could be reliably excluded. Intermediate HbA1c (5.5-6.0%) may exclude diabetes in moderate, but not high risk groups). CONCLUSIONS: Risk stratification improves the predictive validity of HbA1c in screening for undiagnosed diabetes in the US population. Although opportunistic screening with HbA1c would improve detection of undiagnosed diabetes, cost-effectiveness studies are needed before implementation of specific screening strategies using HbA1c.