Although numerous risk-prediction models exist in patients presenting with acute coronary syndromes (ACS), they are subject to important short-comings, including lack of contemporary information. Short-term models are frequently biased by in-hospital events. Accordingly, we sought to create contemporary risk-prediction models for clinical outcomes following ACS up to 1 year following discharge. Models were constructed for death at 30 days and 1 year, death/myocardial infarction (MI)/revascularization at 30 days and death/MI at 1 year in consecutive patients presenting with ACS at our institution between 2006 and 2008, and discharged alive. Logistic regression was used to model the 30 day outcomes and Cox proportional hazards were used to model the 1 year outcomes. No linearity assumptions were made for continuous variables. The final model coefficients were used to create a prediction nomogram, which was incorporated into an online risk calculator. A total of 2,681 patients were included, of which about 9.5% presented with ST-elevation MI. All-cause mortality was 2.6% at 30 days and 13% at 1 year. Demographic, past medical history, laboratory, pharmacological and angiographic parameters were identified as being predictive of adverse ischemic outcomes at 30 days and 1 year. The c-indices for these models ranged from 0.73 to 0.82. Our study thus identified risk factors that are predictive of short- and long-term ischemic and revascularization outcomes in contemporary patients with ACS, and incorporated them into an easy-to-use online calculator, with equal or better discriminatory power than currently available models.

Purpose: To identify and examine polymorphisms of genes associated with aggressive and clinical significant forms of prostate cancer among a screening cohort.

 

 

Experimental Design: We conducted a genome-wide association study among patients with aggressive forms of prostate cancer and biopsy-proven normal controls ascertained from a prostate cancer screening program. We then examined significant associations of specific polymorphisms among a prostate cancer screened cohort to examine their predictive ability in detecting prostate cancer.

Results: We found significant associations between aggressive prostate cancer and five single nucleotide polymorphisms (SNPs) in the 10q26 (rs10788165, rs10749408, and rs10788165, p value for association 1.3 × 10−10 to 3.2 × 10−11) and 15q21 (rs4775302 and rs1994198, p values for association 3.1 × 10−8 to 8.2 × 10−9) regions. Results of a replication study done in 3439 patients undergoing a prostate biopsy, revealed certain combinations of these SNPs to be significantly associated not only with prostate cancer but with aggressive forms of prostate cancer using an established classification criterion for prostate cancer progression (odds ratios for intermediate to high-risk disease 1.8–3.0, p value 0.003–0.001). These SNP combinations were also important clinical predictors for prostate cancer detection based on nomogram analysis that assesses prostate cancer risk.

Conclusions: Five SNPs were found to be associated with aggressive forms of prostate cancer. We demonstrated potential clinical applications of these associations.

BACKGROUND

Accurate preoperative and postoperative risk assessment has been critical for counseling patients regarding radical prostatectomy for clinically localized prostate cancer. In addition to other treatment modalities, neoadjuvant or adjuvant therapies have been considered. The growing literature suggested that the experience of the surgeon may affect the risk of prostate cancer recurrence. The purpose of this study was to develop and internally validate nomograms to predict the probability of recurrence, both preoperatively and postoperatively, with adjustment for standard parameters plus surgeon experience.

METHODS

The study cohort included 7724 eligible prostate cancer patients treated with radical prostatectomy by 1 of 72 surgeons. For each patient, surgeon experience was coded as the total number of cases conducted by the surgeon before the patient’s operation. Multivariable Cox proportional hazards regression models were developed to predict recurrence. Discrimination and calibration of the models was assessed following bootstrapping methods, and the models were presented as nomograms.

RESULTS

In this combined series, the 10-year probability of recurrence was 23.9%. The nomograms were quite discriminating (preoperative concordance index, 0.767; postoperative concordance index, 0.812). Calibration appeared to be very good for each. Surgeon experience seemed to have a quite modest effect, especially postoperatively.

CONCLUSIONS

Nomograms have been developed that consider the surgeon’s experience as a predictor. The tools appeared to predict reasonably well but were somewhat little improved with the addition of surgeon experience as a predictor variable.

Hypoxemia is the most common adverse event that happened during gastrointestinal endoscopy. To estimate risk of hypoxemia prior to endoscopy, American Society of Anesthesiology (ASA) classification scores were used as a major predictive factor. But the accuracy of ASA scores for predicting hypoxemia incidence was doubted here, considering that the classification system ignores much information about general health status and fitness of patient that may contribute to hypoxemia. In this retrospective review of clinical data collected prospectively, the data on 4904 procedures were analyzed. The Pearson’s chi-square test or the Fisher exact test was employed to analyze variance of categorical factors. Continuous variables were statistically evaluated using t-tests or Analysis of variance (ANOVA). As a result, only 245 (5.0%) of the enrolled 4904 patients were found to present hypoxemia during endoscopy. Multivariable logistic regressions revealed that independent risk factors for hypoxemia include high BMI (BMI 30 versus 20, Odd ratio: 1.52, 95% CI: 1.13–2.05; P = 0.0098), hypertension (Odd ratio: 2.28, 95% CI: 1.44–3.60; P = 0.0004), diabetes (Odd ratio: 2.37, 95% CI: 1.30–4.34; P = 0.005), gastrointestinal diseases (Odd ratio: 1.77, 95% CI: 1.21–2.60; P = 0.0033), heart diseases (Odd ratio: 1.97, 95% CI: 1.06–3.68; P = 0.0325) and the procedures that combined esophagogastroduodenoscopy (EGD) and colonoscopy (Odd ratio: 4.84, 95% CI: 1.61–15.51; P = 0.0292; EGD as reference). It is noteworthy that ASA classification scores were not included as an independent predictive factor, and susceptibility of youth to hypoxemia during endoscopy was as high as old subjects. In conclusion, some certain pre-existing diseases of patients were newly identified as independent risk factors for hypoxemia during GI endoscopy. High ASA scores are a confounding predictive factor of pre-existing diseases. We thus recommend that youth (≤18 yrs), obese patients and those patients with hypertension, diabetes, heart diseases, or GI diseases should be monitored closely during sedation endoscopy.

Background

Although the American Board of Internal Medicine (ABIM) certification is valued as a reflection of physicians’ experience, education, and expertise, limited methods exist to predict performance in the examination.

Purpose

The objective of this study was to develop and validate a predictive tool based on variables common to all residency programs, regarding the probability of an internal medicine graduate passing the ABIM certification examination.

Methods

The development cohort was obtained from the files of the Cleveland Clinic internal medicine residents who began training between 2004 and 2008. A multivariable logistic regression model was built to predict the ABIM passing rate. The model was represented as a nomogram, which was internally validated with bootstrap resamples. The external validation was done retrospectively on a cohort of residents who graduated from two other independent internal medicine residency programs between 2007 and 2011.

Results

Of the 194 Cleveland Clinic graduates used for the nomogram development, 175 (90.2%) successfully passed the ABIM certification examination. The final nomogram included four predictors: In-Training Examination (ITE) scores in postgraduate year (PGY) 1, 2, and 3, and the number of months of overnight calls in the last 6 months of residency. The nomogram achieved a concordance index (CI) of 0.98 after correcting for over-fitting bias and allowed for the determination of an estimated probability of passing the ABIM exam. Of the 126 graduates from two other residency programs used for external validation, 116 (92.1%) passed the ABIM examination. The nomogram CI in the external validation cohort was 0.94, suggesting outstanding discrimination.

Conclusions

A simple user-friendly predictive tool, based on readily available data, was developed to predict the probability of passing the ABIM exam for internal medicine residents. This may guide program directors’ decision-making related to program curriculum and advice given to individual residents regarding board preparation.

Introduction: 5-alpha reductase inhibitors can reduce the risk of prostate cancer (PCa) but can be associated with significant side effects. A library of nomograms which predict the risk of clinical endpoints relevant to dutasteride treatment may help determine if chemoprevention is suited to the individual patient. Methods: Data from the REDUCE trial was used to identify predictive factors for 9 endpoints relevant to dutasteride treatment. Using the treatment and placebo groups from the biopsy cohort, Cox proportional hazards (PH) and competing risks regression (CRR) models were used to build 18 nomograms, whose predictive ability was measured by concordance index (CI) and calibration plots. Results: A total of 18 nomograms assessing the risks of cancer, high grade cancer, high grade prostatic intraepithelial neoplasia (HGPIN), atypical small acinar proliferation (ASAP), erectile dysfunction (ED), acute urinary retention (AUR), gynecomastia, urinary tract infection (UTI) and BPH-related surgery either on or off dutasteride were created. The nomograms for cancer, high grade cancer, ED, AUR, and BPH-related surgery demonstrated good discrimination and calibration while those for gynecomastia, UTI, HGPIN, and ASAP predicted no better than random chance. Conclusions: To aid patients in determining whether the benefits of dutasteride use outweigh the risks, we have developed a comprehensive metagram that can generate individualized risks of 9 outcomes relevant to men considering chemoprevention. Better models based on more predictive markers are needed for some of the endpoints but the current metagram demonstrates potential as a tool for patient counseling and decision-making that is accessible, intuitive, and clinically relevant.

OBJECTIVE

Sulfonylureas have historically been analyzed as a medication class, which may be inappropriate given the differences in properties inherent to the individual sulfonylureas (hypoglycemic risk, sulfonylurea receptor selectivity, and effects on myocardial ischemic preconditioning). The purpose of this study was to assess the relationship of individual sulfonylureas and the risk of overall mortality in a large cohort of patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A retrospective cohort study was conducted using an academic health center enterprise-wide electronic health record (EHR) system to identify 11,141 patients with type 2 diabetes (4,279 initiators of monotherapy with glyburide, 4,325 initiators of monotherapy with glipizide, and 2,537 initiators of monotherapy with glimepiride), ≥18 years of age with and without a history of coronary artery disease (CAD) and not on insulin or a noninsulin injectable at baseline. The patients were followed for mortality by documentation in the EHR and Social Security Death Index. Multivariable Cox models were used to compare cohorts.

RESULTS

No statistically significant difference in the risk of overall mortality was observed among these agents in the entire cohort, but we did find evidence of a trend toward an increased overall mortality risk with glyburide versus glimepiride (hazard ratio 1.36 [95% CI 0.96–1.91]) and glipizide versus glimepiride (1.39 [0.99–1.96]) in those with documented CAD.

CONCLUSIONS

Our results did not identify an increased mortality risk among the individual sulfonylureas but did suggest that glimepiride may be the preferred sulfonylurea in those with underlying CAD.

Purpose

Norrie disease (ND), a rare X-linked recessive disorder, is characterized by congenital blindness and, occasionally, mental retardation and hearing loss. ND is caused by the Norrie Disease Protein gene (NDP), which codes for norrin, a cysteine-rich protein involved in ocular vascular development. Here, we report a novel mutation of NDP that was identified in a Chinese family in which three members displayed typical ND symptoms and other complex phenotypes, such as cerebellar atrophy, motor disorders, and mental disorders.

Methods

We conducted an extensive clinical examination of the proband and performed a computed tomography (CT) scan of his brain. Additionally, we performed ophthalmic examinations, haplotype analyses, and NDP DNA sequencing for 26 individuals from the proband’s extended family.

Results

The proband’s computed tomography scan, in which the fifth ventricle could be observed, indicated cerebellar atrophy. Genome scans and haplotype analyses traced the disease to chromosome Xp21.1-p11.22. Mutation screening of the NDP gene identified a novel nonsense mutation, c.343C>T, in this region.

Conclusions

Although recent research has shown that multiple different mutations can be responsible for the ND phenotype, additional research is needed to understand the mechanism responsible for the diverse phenotypes caused by mutations in the NDP gene.

OBJECTIVE—The objective of this study was to create a tool that predicts the risk of mortality in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—This study was based on a cohort of 33,067 patients with type 2 diabetes identified in the Cleveland Clinic electronic health record (EHR) who were initially prescribed a single oral hypoglycemic agent between 1998 and 2006. Mortality was determined in the EHR and the Social Security Death Index. A Cox proportional hazards regression model was created using medication class and 20 other predictor variables chosen for their association with mortality. A prediction tool was created using the Cox model coefficients. The tool was internally validated using repeated, random subsets of the cohort, which were not used to create the prediction model.

RESULTS—Follow-up in the cohort ranged from 1 day to 8.2 years (median 28.6 months), and 3,661 deaths were observed. The prediction tool had a concordance index (i.e., c statistic) of 0.752.

CONCLUSIONS—We successfully created a tool that accurately predicts mortality risk in patients with type 2 diabetes. The incorporation of medications into mortality predictions in patients with type 2 diabetes should improve treatment decisions.

Background

Older women with early-stage breast cancer experience higher rates of non—breast cancer-related death. We examined factors associated with cause-specific death in a large cohort of breast cancer patients treated with extended adjuvant endocrine therapy.

Methods

In the MA.17 trial, conducted by the National Cancer Institute of Canada Clinical Trials Group, 5170 breast cancer patients (median age = 62 years; range = 32–94 years) who were disease free after approximately 5 years of adjuvant tamoxifen treatment were randomly assigned to treatment with letrozole (2583 women) or placebo (2587 women). The median follow-up was 3.9 years (range = 0–7 years). We investigated the association of 11 baseline factors with the competing risks of death from breast cancer, other malignancies, and other causes. All statistical tests were two-sided likelihood ratio criterion tests.

Results

During follow-up, 256 deaths were reported (102 from breast cancer, 50 from other malignancies, 100 from other causes, and four from an unknown cause). Non—breast cancer deaths accounted for 60% of the 252 known deaths (72% for those ≥70 years and 48% for those <70 years). Two baseline factors were differentially associated with type of death: cardiovascular disease was associated with a statistically significant increased risk of death from other causes (P = .002), and osteoporosis was associated with a statistically significant increased risk of death from other malignancies (P = .05). An increased risk of breast cancer—specific death was associated with lymph node involvement (P < .001). Increased risk of death from all three causes was associated with older age (P < .001).

Conclusions

Non—breast cancer-related deaths were more common than breast cancer—specific deaths in this cohort of 5-year breast cancer survivors, especially among older women.

Purpose

To evaluate the clinical, histopathologic, and genetic characteristics of a microphthalmia pedigree.

Methods

A five-generation Chinese family with microphthalmia was recruited. Clinical and histological examinations were performed in the affected patients and their family members. Cyrillic software was used to map the pedigree. Genomic DNA was extracted from peripheral blood, and linkage analysis was performed using short tandem repeat polymorphism markers. Two-point LOD scores were calculated using the MLINK program.

Results

Microphthalmia was inherited in an autosomal dominant manner in this family. All nine affected members had hyperopia (mean: +8.00 diopters) and physiologically reduced axis oculi (mean: 19.29 mm) with a visual acuity of less than 0.5. Refractory angle-closure glaucoma occurred in three of them and atrophia bulbi in two. Histological examination showed diffuse degenerated collagen fibers in the scleral stroma. Two-point LOD score linkage analysis excluded all known genetic loci associated with simple microphthalmia in all patients.

Conclusions

Simple microphthalmia was dominantly inherited in this Chinese pedigree with typical phenotypes, which resulted in severe visual deterioration by middle age. A novel locus is predicted to be responsible for the microphthalmia in this family, which may prove a high genetic heterogeneity in microphthalmia.

Background

In general, prognosis and impact of prognostic/predictive factors are assessed with Kaplan-Meier plots and/or the Cox proportional hazard model. There might be substantive differences from the results using these models for the same patients, if different statistical methods were used, for example, Boag log-normal (cure-rate model), or log-normal survival analysis.

Methods

Cohort of 244 limited-stage small-cell lung cancer patients, were accrued between 1981 and 1998, and followed to the end of 2005. The endpoint was death with or from lung cancer, for disease-specific survival (DSS). DSS at 1-, 3- and 5-years, with 95% confidence limits, are reported for all patients using the Boag, Kaplan-Meier, Cox, and log-normal survival analysis methods. Factors with significant effects on DSS were identified with step-wise forward multivariate Cox and log-normal survival analyses. Then, DSS was ascertained for patients with specific characteristics defined by these factors.

Results

The median follow-up of those alive was 9.5 years. The lack of events after 1966 days precluded comparison after 5 years. DSS assessed by the four methods in the full cohort differed by 0–2% at 1 year, 0–12% at 3 years, and 0–1% at 5 years. Log-normal survival analysis indicated DSS of 38% at 3 years, 10–12% higher than with other methods; univariate 95% confidence limits were non-overlapping. Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction significantly impacted DSS. DSS assessed by the Cox and log-normal survival analysis methods for four clinical risk groups differed by 1–6% at 1 year, 15–26% at 3 years, and 0–12% at 5 years; multivariate 95% confidence limits were overlapping in all instances.

Conclusion

Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction all significantly impacted DSS. Apparent DSS for patients was influenced by the statistical methods of assessment. This would be clinically relevant in the development or improvement of clinical management strategies.

To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family, molecular genetic investigation via haplotype analysis and direct sequencing were performed Sequencing of the CRYGD gene revealed a c.127T>C transition, which resulted in a substitution of a highly conserved tryptophan with arginine at codon 43 (p.Trp43Arg). This mutation co-segregated with all affected individuals and was not observed in either unaffected family members or in 200 normal unrelated individuals. Biophysical studies indicated that the p.Trp43Arg mutation resulted in significant tertiary structural changes. The mutant protein was much less stable than the wild-type protein, and was more prone to aggregate when subjected to environmental stresses such as heat and UV irradiation. © 2010 Wiley-Liss, Inc.