Quantitative retrospective natural history modeling for orphan drug development.

The natural history of most rare diseases is incompletely understood and usually relies on studies with low level of evidence. Consistent with the goals for future research of rare disease research set by the International Rare Diseases Research Consortium in 2017, the purpose of this paper is to review the recently developed method of quantitative retrospective natural history modeling (QUARNAM) and to illustrate its usefulness through didactically selected analyses examples in an overall population of 849 patients worldwide with seven (ultra-) rare neurogenetic disorders. A quantitative understanding of the natural history of the disease is fundamental for the development of specific interventions and counseling afflicted families. QUARNAM has a similar relationship to a published case study as a meta-analysis has to an individual published study. QUARNAM relies on sophisticated statistical analyses of published case reports focusing on four research questions: How long does it take to make the diagnosis? How long do patients live? Which factors predict disease severity (eg, genotypes, signs/symptoms, biomarkers)? Where can patients be recruited for studies? Useful statistical techniques include Kaplan-Meier estimates, cluster analysis, regression techniques, binary decisions trees, word clouds, and geographic mapping. In comparison to other natural history study methods (prospective studies or retrospective studies such as chart reviews), QUARNAM can provide fast information on hard clinical endpoints (ie, survival, diagnostic delay) with a lower effort. The choice of method for a particular drug development program may be driven by the research question and may encompass combinatory approaches.

Disease awareness or subtle product placement? Orphan diseases featured in the television series "House, M.D." - a cross-sectional analysis.

BACKGROUND: Approximately 7% of the general population is affected by an orphan disease, which, in the United States, is defined as affecting fewer than 1 in 1500 people. Disease awareness is often low and time-to-diagnosis delayed. Different legislations worldwide have created incentives for pharmaceutical companies to develop drugs for orphan diseases. A journalistic article in Bloomberg Businessweek has claimed that pharmaceutical companies have tried marketing orphan drugs by placing a specific disease into the popular television series "House, M.D." which features diagnostic journeys and was produced between 2004 and 2012. This study aimed to describe the presentation of orphan diseases in the television series "House, M.D.", to test in an exploratory fashion the hypothesis that treatable orphan conditions are overrepresented in "House, M.D." and to discuss whether such marketing practices may or may not be ethical. METHODS: A list of all medical cases depicted in the television series "House, M.D." was obtained and classified as orphan or non-orphan according to the Orphanet database. The ratios of orphan diseases among all diseases, such with an orphan drug designation and such with an orphan drug approval by the FDA were then compared with conservative approximations of real world conditions (chi-squared tests for equality of proportions). STROBE criteria were respected. RESULTS: Out of a total of n = 181 different medical diagnoses, n = 42 (23.2%) were orphan diseases. The difference in percentages in between "House, M.D." and reality was not statistically significant for orphan diseases overall (p = 0.96), yet was statistically significantly higher for both orphan diseases with one or more orphan drug designations (p = 0.0192) and such with one or more approved orphan drugs (p < 0.0001). CONCLUSIONS: Orphan diseases with a designated and/or approved orphan drug were overrepresented in the television series "House, M.D." with statistical significance while orphan diseases overall were not. This may be explained by (so far) undocumented efforts of pharmaceutical companies to place their orphan drugs in the television series, as described in the article in Bloomberg Businessweek. Further research is needed into marketing practices in popular and emerging media formats.

Clinical characteristics of 248 patients with Krabbe disease: quantitative natural history modeling based on published cases.

PURPOSE: Krabbe disease (OMIM 245200) is an orphan neurometabolic disorder caused by a deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Hard clinical endpoints and biomarker-phenotype correlations are useful for future clinical trials. METHODS: We performed a quantitative analysis of published cases (N = 248) with Krabbe disease, stratified by age at disease onset: early infantile (age 0-6 months), late infantile (age 7-36 months), juvenile/adolescent (age 37-180 months), and adult onset (>180 months). Main outcome measures were age of disease onset and survival. Cerebrospinal fluid (CSF) protein concentrations were explored as a potential predictor of survival. STROBE criteria were respected. RESULTS: Median age of onset was 4 months (early infantile), 14 months (late infantile), 48 months (juvenile), and 384 months (adult). Age of disease onset and therefore disease subtype determined survival rates. CSF protein concentrations predicted age at onset and survival rates in Krabbe disease. Patients with a CSF protein content ≤61.5 mg/dl survived significantly longer than patients with CSF protein values above this threshold. CONCLUSION: We define the estimated survival in published Krabbe disease cases and demonstrate an association of CSF protein concentration with disease severity. These data inform patient care and clinical trials.

Critical appraisal of genotype assessment in molybdenum cofactor deficiency.

INTRODUCTION: Molybdenum cofactor deficiency (MoCD) is an ultra-orphan, life-threatening disease. Substrate substitution therapy has successfully been performed in single cases of MoCD type A and clinical trials are underway for drug registration. We present an innovative approach for classification of genotype severity to test the hypothesis that milder sequence variants in MoCD result in a less severe disease phenotype quantitated by patient survival. METHODS: All available worldwide published cases with clinical and genetic data were included (n = 40). We stratified the already published disease causing sequence variants as mild or severe with the use of in silico prediction programs, where possible and assessed the possible impact of the variants on the expression of the gene or function of the expressed protein. In a compound heterozygous situation the mildest sequence variant determined the genotype. Subsequently, clinical manifestations and outcomes of both groups were compared. RESULTS: Patients with a severe genotype showed a median survival of 15 months and had a lower probability of survival compared to patients with mild genotypes who were all alive at last reported follow-up (p = 0.0203, Log-rank test). DISCUSSION: The severity of the genotype assessed by in silico prediction and further classification explained survival in molybdenum cofactor deficiency and may therefore be considered a confounder for the outcome of therapeutic clinical trials requiring adjustment in the clinical trial design or analysis. These results should further be investigated by future in vitro or in vivo functional studies. Caution should be taken with this approach for the classification of variants in molecular genetic diagnostics or genetic counseling.

Perioperative Fluid Utilization Variability and Association With Outcomes: Considerations for Enhanced Recovery Efforts in Sample US Surgical Populations.

OBJECTIVES: To study current perioperative fluid administration and associated outcomes in common surgical cohorts in the United States. BACKGROUND: An element of enhanced recovery care protocols, optimized perioperative fluid administration may be associated with improved outcomes; however, there is currently no consensus in the United States on fluid use or the effects on outcomes of this use. METHODS: The study included all inpatients receiving colon, rectal, or primary hip or knee surgery, 18 years of age or older, who were discharged from a hospital between January 1, 2008 and June, 30 2012 in the Premier Research Database. Patient outcomes and intravenous fluid utilization on the day of surgery were summarized for each surgical cohort. Regression models were developed to evaluate associations of high or low day-of-surgery fluids with the likelihood of increased hospital length of stay (LOS), total costs, or postoperative ileus. RESULTS: The study showed significant associations between high fluid volume given on the day of surgery with both increased LOS (odds ratio 1.10-1.40) and increased total costs (odds ratio 1.10-1.50). High fluid utilization was associated with increased presence of postoperative ileus for both rectal and colon surgery patients. Low fluid utilization was also associated with worse outcomes. CONCLUSIONS: According to results from this review of current practice in US hospitals, fluid optimization would likely lead to decreased variability and improved outcomes.

Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency.

PURPOSE: Experimental treatment with substrate replacement was successfully performed in single cases with molybdenum cofactor deficiency type A. The objective of this study was to quantitate the yet undefined natural history in untreated patients to ultimately benefit knowledge in experimental treatments in the future. METHODS: Systematic analysis of published cases with molybdenum cofactor deficiency. The main outcome measures were survival, initial cardinal disease features at onset, and diagnostic delay. RESULTS: The median survival for the overall population was 36 months. Initial cardinal disease features at onset were seizures (72%) as well as feeding difficulties (26%) and hypotonia (11%). In addition, developmental delay (9%), hemiplegia (2%), lens dislocation (2%), and hyperreflexia (1%) were reported. The median age at onset of the disease was the first day of life; the median age at diagnosis was 4.5 months. The median time to diagnosis (diagnostic delay) was 89 days. CONCLUSION: Molybdenum cofactor deficiency has its onset during the neonatal period and infancy. There is considerable diagnostic delay. Although seizures were the most frequent initial cardinal sign, molybdenum cofactor deficiency should be considered as a differential diagnosis in patients presenting with hypotonia, developmental delay, or feeding difficulties. The survival data will inform further natural-history and therapeutic studies.

Adequacy of oral health information for patients with diabetes.

OBJECTIVE: We investigated the perception of dental hygienists regarding their adequacy of providing diabetics with diabetes-related oral health preventive education. METHODS: A one-page questionnaire printed on both sides was mailed to 2,237 licensed registered dental hygienists with a South Carolina (SC) mailing address. In addition to the dental hygienists' background and practice characteristics, their perception of adequacy for educating patients with diabetes on various diabetes-related oral health topics and reasons for inadequate coverage of materials were queried in the survey. RESULTS: After two follow-up mailings, 995 completed and usable surveys were returned. An average of 93.6 percent of respondents indicated that they adequately covered topics of oral hygiene and general oral health issues. However, about 60 percent of respondents reported not covering all essential materials related to oral health when educating diabetic patients. The three most common reasons were: a) insufficient time (60.1 percent); b) patient disinterest (41.2 percent); and c) insufficient information on oral care and diabetes (39.7 percent). Respondents reporting insufficient information were less likely to adequately address the effect of periodontal disease on diabetes (P < 0.001), effect of uncontrolled diabetes on periodontal disease (P < 0.001), and dry mouth management (P = 0.03). CONCLUSION: This study indicates that SC dental hygienists do not routinely provide patient education on diabetes-related oral health and healthy lifestyle topics. Lack of time, patient disinterest, and insufficient information were the three main reasons for respondents not covering these essentials. A practical method for improving dental hygienists' comprehensive service to patients with diabetes is to offer them more continuing education on diabetes and oral health to supplement their knowledge, skills, and confidence to educate this growing population.

Racial disparities in trends for cardiovascular disease and procedures among hospitalized diabetic patients.

METHODS: To determine if racial differences exist for trends in diabetes-related cardiovascular disease (CVD) hospitalization rates, we analyzed data from an inpatient hospital discharge database maintained by the South Carolina Office of Research and Statistics. All hospitalizations involving a diagnosis of diabetes were collected from 1996 through 2003. International Classification of Diseases codes were used to determine diagnosis for diabetes, acute myocardial infraction (AMI), stroke, and other CVD outcomes. Multiple linear regression was performed to model the age-standardized rates during the study period. An interaction parameter for race and discharge year was used in the models to determine if the trend slopes varied between African Americans and Caucasians. RESULTS: The diabetes-related hospitalization rates for AMI and stroke declined for both race groups. Although the stroke rates for African Americans were consistently higher than those for Caucasians, the African American trend declined more sharply (P=.027). AMI rates showed sharper declines among Caucasians (P<.001). Rates of CVD procedures (percutaneous transluminal coronary angioplasty and coronary artery bypass graft) were two to three times greater among Caucasians. Cardiomyopathy rates were significantly greater among African Americans and showed a larger increasing trend (P<.001), and findings for congestive heart failure trends were similar (P<.001). CONCLUSIONS: Diabetes-related CVD rates and trends vary considerably by race. Rates of AMI and stroke declined in African Americans and Caucasians from 1996 through 2003, while other CVD rates increased. Further research is needed to understand the underlying components of these disparities.

Differences in All-Cause Health Care Utilization and Costs in a Type 2 Diabetes Mellitus Population with and Without a History of Cardiovascular Disease.

BACKGROUND: Multiple studies have reported that type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular diseases (CVD), and presence of T2DM and CVD increases risk of death. There is growing interest in examining the effects of antidiabetic treatments on the reduction of cardiovascular events in T2DM adults with a history of CVD and thus at higher risk of cardiovascular events. OBJECTIVE: To estimate the incremental all-cause health care utilization and costs among adults with T2DM and a history of CVD compared with adults without a history of CVD, using a national linked electronic medical records (EMR) and claims database. METHODS: Adults aged ≥ 18 years with evidence of at least 1 T2DM-related diagnosis code or antidiabetic medication (date of earliest occurrence was defined as the index date) in calendar year 2012 were identified. The population was divided into 2 cohorts (with and without a history of CVD) and followed until the end of their enrollment coverage, death, or 12 months, whichever came first. Multivariable generalized linear models were used to assess differences in health care utilization and per patient per month (PPPM) total costs (plan- and patient-paid amount for health care services) between the 2 groups during the post-index year, while adjusting for an a priori list of demographic and clinical characteristics. RESULTS: A total of 138,018 adults with T2DM was identified, of which 16,547 (12%) had a history of CVD. The unadjusted resource utilization (outpatient: 27.5 vs. 17.8; emergency room [ER]: 0.8 vs. 0.4; inpatient: 0.4 vs. 0.2 days; and total unique drug prescriptions: 10.1 vs. 8.3) and PPPM total health care costs ($2,655.1 vs. $1,435.0) were significantly higher in T2DM adults with a history of CVD versus T2DM adults without a history of CVD. The adjusted models revealed that T2DM adults with a history of CVD had a 31% higher number of ER visits (rate ratio [RR] = 1.31, 95% CI = 1.25-1.37); 27% more inpatient visits (RR = 1.27, 95% CI = 1.21-1.34); 15% longer mean inpatient length of stay (RR = 1.15, 95% CI = 1.06-1.25); and 11% more outpatient visits (RR = 1.11, 95% CI = 1.09-1.13) compared with T2DM adults without a history of CVD. Furthermore, the difference in total PPPM health care cost was found to be 16% ($200) higher in adults with a history of CVD (RR = 1.16, 95% CI = 1.13-1.19). PPPM costs associated with outpatient and ER visits were approximately 21% and 19% higher among adults with a history of CVD, respectively (P < 0.0001), while costs for inpatient visits were similar between the 2 groups. In addition, a subgroup analysis revealed that adjusted differences in PPPM total cost was larger in the younger age group (56% higher cost in those aged < 45 years) and diminished in the older age group (only 2% higher in those aged ≥ 65 years). CONCLUSIONS: Study findings showed that resource utilization and costs remains significantly higher in T2DM patients with a history of CVD compared with patients without a history of CVD even after controlling for significant patient comorbid and demographic characteristics. Also, younger age groups had higher differences in outcomes compared with older age groups. This study underscores the importance of cost-effective interventions that may reduce economic burden in this T2DM population with a history of CVD. DISCLOSURES: This study was funded by Boehringer Ingelheim. At the time of this study, Mehta and Mountford were employed by IQVIA, which received funding from Boehringer Ingelheim to conduct this study. Mountford is employed by Allergan, which has no connection with this study. Ghosh, Sander, and Kuti are employed by Boehringer Ingelheim. Study concept and design were contributed by Mountford, Mehta, and Ghosh, along with Sander and Kuti. Mountford and Mehta collected the data, and data interpretation was performed by all the authors. The manuscript was written by Sander and Kuti, along with the other authors, and revised by Mehta and Gosh, along with the other authors.

Concordance between self-reported heights and weights and current and ideal body images in young adult African American men and women.

Satisfaction with overweight and obesity purportedly contribute to greater weight gain in African American women than men, yet relatively little data on perceived (PBI) and ideal body image (IBI) are available for young adult African Americans. In this survey, 509 self-identified African American freshmen in 2003 and 669 in 2006 at a historically Black university completed a survey that included self-reported height, weight and IBI. In 2003 and 2006, 42.2%-48.8% of men and women were overweight (body mass index [BMI] 25.0-29.9 kg/m2) or obese (BMI > or = 30). In both surveys, >75% of overweight women and >90% obese women selected a smaller IBI. In contrast, a greater proportion of overweight men was satisfied (approximately 50%) than the proportion who had larger than IBI (<40%). Among students with a normal BMI (<25), men were more likely than women to report being smaller than ideal (>45% vs <26%). However, overweight women were more likely than overweight men to select a normal PBI (48.5% vs 36.0%). The data in African American college freshman do not suggest that greater weight gain in women than men is driven by a desire to be heavier. The high proportion of overweight women with a normal PBI may contribute to greater weight gain. Of concern, nearly half of men with normal BMI want to be heavier, while approximately 5/8 of overweight men are satisfied with being overweight or want to be heavier.

Pressure for drug development in lysosomal storage disorders - a quantitative analysis thirty years beyond the US orphan drug act.

BACKGROUND: Lysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited orphan conditions. A defect leads to the storage of complex molecules in the lysosome, and patients develop a complex multisystemic phenotype of high morbidity often associated with premature death. More than 30 years ago the Orphan Drug Act of 1983 passed the United States legislation intended to facilitate the development of drugs for rare disorders. We directed our efforts in assessing which lysosomal diseases had drug development pressure and what distinguished those with successful development and approvals from diseases not treated or without orphan drug designation. METHODS: Analysis of the FDA database for orphan drug designations through descriptive and comparative statistics. RESULTS: Between 1983 and 2013, fourteen drugs for seven conditions received FDA approval. Overall, orphan drug status was designated 70 times for 20 conditions. Approved therapies were enzyme replacement therapies (N = 10), substrate reduction therapies (N = 1), small molecules facilitating lysosomal substrate transportation (N = 3). FDA approval was significantly associated with a disease prevalence higher than 0.5/100,000 (p = 0.00742) and clinical development programs that did not require a primary neurological endpoint (p = 0.00059). Orphan drug status was designated for enzymes, modified enzymes, fusion proteins, chemical chaperones, small molecules leading to substrate reduction, or facilitating subcellular substrate transport, stem cells as well as gene therapies. CONCLUSIONS: Drug development focused on more common diseases. Primarily neurological diseases were neglected. Small clinical trials with either somatic or biomarker endpoints were successful. Enzyme replacement therapy was the most successful technology. Four factors played a key role in successful orphan drug development or orphan drug designations: 1) prevalence of disease 2) endpoints 3) regulatory precedent, and 4) technology platform. Successful development seeded further innovation.

Potential return on investment for implementation of perioperative goal-directed fluid therapy in major surgery: a nationwide database study.

BACKGROUND: Preventable postsurgical complications are increasingly recognized as a major clinical and economic burden. A recent meta-analysis showed a 17-29 % decrease in postoperative morbidity with goal-directed fluid therapy. Our objective was to estimate the potential economic impact of perioperative goal-directed fluid therapy. METHODS: We studied 204,680 adult patients from 541 US hospitals who had a major non-cardiac surgical procedure between January 2011 and June 2013. Hospital costs (including 30-day readmission costs) in patients with and without complications were extracted from the Premier Inc. research database, and potential cost-savings associated with a 17-29 % decrease in postoperative morbidity were estimated. RESULTS: A total of 76,807 patients developed one or more postsurgical complications (morbidity rate 37.5 %). In patients with and without complications, hospital costs were US$27,607 ± 32,788 and US$15,783 ± 12,282 (p < 0.0001), respectively. Morbidity rate was anticipated to decrease to 26.6-31.1 % with goal-directed fluid therapy, yielding potential gross cost-savings of US$153-263 million for the study period, US$61-105 million per year, or US$754-1286 per patient. Potential savings per patient were highly variable from one surgical procedure to the other, ranging from US$354-604 for femur and hip-fracture repair to US$3515-5996 for esophagectomies. When taking into account the volume of procedures, the total potential savings per year were the most significant (US$32-55 million) for colectomies. CONCLUSIONS: Postsurgical complications occurred in more than one third of our study population and had a dramatic impact on hospital costs. With goal-directed fluid therapy, potential cost-savings per patient were US$754-1286. The highest cost-savings per year were observed for colectomies. These projections should help hospitals estimate the return on investment when considering the implementation of goal-directed fluid therapy.

The treatment of lupus pernio: results of 116 treatment courses in 54 patients.

BACKGROUND: Lupus pernio is a disfiguring sarcoidosis skin lesion that is difficult to treat and often causes a major psychosocial impact that may adversely affect the patient's quality of life. We reviewed the treatment outcome of 54 patients with lupus pernio who received 116 individual courses of treatment in our sarcoidosis clinic. METHODS: Lupus pernio patients were identified from an institution-approved database. All patients were assessed at each clinic visit with facial photographs. By examining the photographs, the percentage of face involved (< 10%, 10 to 25%, > 25 to 50%, > 50%) was determined as was the effect of therapy (resolution, near resolution, improvement, no change, worsening). Medications included infliximab-containing regimens; systemic corticosteroids; noninfliximab, noncorticosteroid agents; and corticosteroids plus noncorticosteroid agents. RESULTS: In terms of achieving resolution or near resolution, infliximab regimens were superior to all others (infliximab, 77%; corticosteroids plus noncorticosteroids, 29%; corticosteroids, 20%; noncorticosteroids, 11%; infliximab vs other therapies: corticosteroids plus noncorticosteroids, p = 0.0015; corticosteroids, p = 0.0005; noncorticosteroids, p = 0.0002). The percentage of facial involvement also improved most with infliximab. Evaluating a secondary analysis of achieving resolution, near resolution, or improvement, infliximab (92%) was superior to noncorticosteroids (20%; p < 0.0001) and corticosteroids plus noncorticosteroids (56%; p = 0.0098), but not corticosteroids (72%; p = 0.2456); and noncorticosteroid agents were inferior to all other regimens. CONCLUSIONS: Infliximab appears superior to systemic corticosteroids with or without additional agents for the treatment of lupus pernio. Noninfliximab, noncorticosteroid-containing regimens are of limited use for this condition.

Comparison of cardiovascular risk factors for high brachial pulse pressure in blacks versus whites (Charleston Heart Study, Evans County Study, NHANES I and II Studies).

We examined whether the risk factors for increased brachial pulse pressure (PP) are similar for blacks and whites. Many studies have reported the strong association of increased brachial PP and the prevalence of cardiovascular disease. Participants were from 4 major epidemiologic studies in the United States (26,083 subjects): Charleston Heart Study, Evans County Heart Study, the National Health and Nutrition Examination Survey (NHANES) I study, and the NHANES II study. At baseline, there was no history or clinical evidence of coronary heart disease (CHD). The CHD mortality as a function of brachial PP and the association of traditional risk factors for CHD with PP were analyzed for each of the 4 studies and for the 4 studies combined. Multiple regression analysis showed that the most significant predictors of high brachial PP are body mass index > or =30 kg/m(2) (regression coefficient 3.79, p <0.0001), diabetes mellitus (5.14, p <0.0001), serum total cholesterol > or =240 mg/dl (0.51, p <0.0157), age (0.60, p <0.0001), gender (-1.77, p <0.0001), and race (3.75, p <0.0001). In conclusion, the same risk factors for CHD (namely, increase in body mass index > or =30 kg/m(2), diabetes mellitus, hypercholesterolemia, and age) are significantly associated with high brachial PP for blacks and whites. These risk factors were stronger in whites compared with blacks. However, female gender and age variables were even more associated with brachial PP in blacks. Smoking was significant but not reflected in peripheral brachial PP as it is in aortic PP.

Thirty-year Survival for Black and White Hypertensive Individuals in the Evans County Heart Study and the Hypertension Detection and Follow-up Program.

The Evans County Heart Study (ECHS), initiated in 1960, was one of the first major studies to document cardiovascular disease (CVD) risks for African Americans and Caucasians with elevated blood pressures. In the early 1970's, the Hypertension Detection and Follow-up Program (HDFP), with a site in Georgia (HDFP-GA) was one of the first major studies to demonstrate that treating hypertension with stepped care (SC), versus referred care (RC), has better short-term outcomes. With this background, study objectives were to evaluate 30-year survival and cardiovascular outcomes of the HDFP-GA and to compare outcomes of these patients with 1619 hypertensive individuals (30-69 years of age) from the ECHS. HDFP-GA patients included 688 individuals (black [n=267]; white [n=421]) randomized to RC (n=341) and SC (n=347). The ECHS was comprised of 733 black and 886 white hypertensives. All-cause mortality and CVD mortality were assessed in the HDFP-GA and compared to the ECHS hypertensives. After 30-years of follow-up, 65.7% of the HDFP-GA cohort had died compared with a similar 65.8% of the ECHS hypertensives. However, CVD mortality rates, while similar for the SC and RC arms, were lower than in the HDFP-GA total study group than the hypertensive participants of ECHS (32.6% vs. 40.3% p<.001). CVD survival rates for both SC and RC HDFP-GA arms were significantly better than population-based hypertensive individuals in the ECHS, with consistent benefits in all four race-sex groups. These results identify the importance of long-term follow-up of individuals in hypertension studies and trials that include CVD outcomes.

Diabetes-related lower extremity amputation rates fall significantly in South Carolina.

BACKGROUND: The aims of this study are to compare the diabetes-related lower extremity amputation (LEA) rate trend in South Carolina (SC) to that of the United States (US) and to determine changes in LEA rates in SC according to age, race, gender, and amputation METHODS: National Hospital Discharge Survey (NHDS) and SC hospital discharge data for 1996 to 2002 were analyzed. ICD-9-CM codes identified all diabetic patients and occurrences of LEA. Linear regression was used to compare the LEA rate trends between SC and the US. RESULTS: LEA rates are decreasing throughout the study period. The slope is greater in SC compared with US (US slope = -0.00082; SC slope = -0.0015; P = 0.002), signifying a decrease in LEA rates of 1.5/1000 per year in SC and 0.8/1000 per year in the US. Furthermore, LEA rate decreases in SC are significant throughout all ages, races, genders, and amputation levels. CONCLUSIONS: Diabetes-related LEA rates are decreasing in SC more rapidly than in the US. Ongoing community-level education may be assisting in the favorable trends.