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A three-metabolite microbiota-associated signature for early risk stratification of gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes and long-term metabolic and cardiovascular risk. However, oral glucose tolerance testing at 24-28 gestational weeks limits early risk stratification. Gut microbiota-associated metabolites may reflect early metabolic abnormalities, including those relevant to cardiometabolic health, but robust early-pregnancy biomarkers remain limited. METHODS: We conducted a multicenter nested case-control and prospective study involving 2,693 pregnant women. Untargeted metabolomics and metagenomics were integrated to identify GDM-associated metabolites and gut microbial alterations. Three consistently dysregulated metabolites, 3-hydroxydecanoic acid, γ-Glu-Leu, and propionic acid, were quantified by targeted LC-MS/MS. Candidate algorithms were compared using repeated 10-fold cross-validation, and a final generalized linear model was externally and prospectively validated. RESULTS: Women who later developed GDM showed an adverse early-pregnancy metabolic profile, including higher BMI, triglycerides, and platelet count. Untargeted metabolomics identified 14 persistently altered metabolites enriched in energy, oxidative stress, and amino acid metabolism pathways. Metagenomics revealed taxonomic restructuring and coordinated microbiota-metabolite associations. The three-metabolite model achieved AUCs of 0.838 (95% CI, 0.791-0.885) in training, 0.840 (95% CI, 0.769-0.911) in internal validation, 0.955 (95% CI, 0.925-0.985) and 0.917 (95% CI, 0.875-0.958) in two external cohorts, and 0.969 (95% CI, 0.937-1.000) in the prospective cohort. CONCLUSION: Early microbiota-associated metabolic dysregulation is detectable before routine GDM diagnosis. This compact three-metabolite panel may support early GDM risk stratification and provides metabolic evidence relevant to broader cardiometabolic risk assessment in pregnancy.

Humans↗

A simple stratification factor prognostic for survival in advanced cancer: the good/bad/uncertain index.

PURPOSE: This article summarizes the third step of a research program to identify variables that supplement the predictive power of the the Eastern Cooperative Oncology Group (ECOG) performance status (PS) for survival. The objective was to produce a simple, practical, stratification factor for phase III oncology clinical trials involving patients with advanced malignant disease. PATIENTS AND METHODS: A questionnaire was administered to 729 patients with metastatic colorectal or lung cancers. Patients provided a Karnofsky index and appetite rating while physicians provided a survival estimate and the ECOG-PS. Scores for each item were categorized as having a positive, neutral, or negative indication for survival. A patient was classified as having a relatively good prognosis if three or more of the four items showed a positive indication, a bad prognosis if three or more items were negative, and an uncertain prognosis otherwise (Good/Bad/Uncertain [GBU] index). RESULTS: The GBU index improved on the prognostic power of a Cox model quartile index and PS alone and increased the accuracy of survival classification estimates by 5% to 10% more than ECOG-PS alone. For patients with PS of 0 or 1, significant survival patterns exist between GBU groups (P=.002 and.0001, respectively). CONCLUSION: The GBU index may be recommended as a supplementary stratification factor for certain future phase III trials in metastatic lung or colorectal cancer where patient heterogeneity is a particular concern. The GBU represents a relatively modest increase to the cost and patient burden of a clinical trial given the additional control that is achieved over the potentially confounding concomitant to the treatment variable.

Aged↗

Quality assessment of genetic markers used for therapy stratification.

PURPOSE: Therapy stratification based on genetic markers is becoming increasingly important, which makes commitment to the highest possible reliability of the involved markers mandatory. In neuroblastic tumors, amplification of the MYCN gene is an unequivocal marker that indicates aggressive tumor behavior and is consequently used for therapy stratification. To guarantee reliable and standardized quality of genetic features, a quality-assessment study was initiated by the European Neuroblastoma Quality Assessment (ENQUA; connected to International Society of Pediatric Oncology) Group. MATERIALS AND METHODS: One hundred thirty-seven coded specimens from 17 tumors were analyzed in 11 European national/regional reference laboratories using molecular techniques, in situ hybridization, and flow and image cytometry. Tumor samples with divergent results were re-evaluated. RESULTS: Three hundred fifty-two investigations were performed, which resulted in 23 divergent findings, 17 of which were judged as errors after re-evaluation. MYCN analyses determined by Southern blot and in situ hybridization led to 3.7% and 4% of errors, respectively. Tumor cell content was not indicated in 32% of the samples, and 11% of seemingly correct MYCN results were based on the investigation of normal cells (eg, Schwann cells). Thirty-eight investigations were considered nonassessable. CONCLUSION: This study demonstrated the importance of revealing the difficulties and limitations for each technique and problems in interpreting results, which are crucial for therapeutic decisions. Moreover, it led to the formulation of guidelines that are applicable to all kinds of tumors and that contain the standardization of techniques, including the exact determination of the tumor cell content. Finally, the group has developed a common terminology for molecular-genetic results.

Biomarkers, Tumor↗

Customized oligonucleotide microarray gene expression-based classification of neuroblastoma patients outperforms current clinical risk stratification.

PURPOSE: To develop a gene expression-based classifier for neuroblastoma patients that reliably predicts courses of the disease. PATIENTS AND METHODS: Two hundred fifty-one neuroblastoma specimens were analyzed using a customized oligonucleotide microarray comprising 10,163 probes for transcripts with differential expression in clinical subgroups of the disease. Subsequently, the prediction analysis for microarrays (PAM) was applied to a first set of patients with maximally divergent clinical courses (n = 77). The classification accuracy was estimated by a complete 10-times-repeated 10-fold cross validation, and a 144-gene predictor was constructed from this set. This classifier's predictive power was evaluated in an independent second set (n = 174) by comparing results of the gene expression-based classification with those of risk stratification systems of current trials from Germany, Japan, and the United States. RESULTS: The first set of patients was accurately predicted by PAM (cross-validated accuracy, 99%). Within the second set, the PAM classifier significantly separated cohorts with distinct courses (3-year event-free survival [EFS] 0.86 +/- 0.03 [favorable; n = 115] v 0.52 +/- 0.07 [unfavorable; n = 59] and 3-year overall survival 0.99 +/- 0.01 v 0.84 +/- 0.05; both P < .0001) and separated risk groups of current neuroblastoma trials into subgroups with divergent outcome (NB2004: low-risk 3-year EFS 0.86 +/- 0.04 v 0.25 +/- 0.15, P < .0001; intermediate-risk 1.00 v 0.57 +/- 0.19, P = .018; high-risk 0.81 +/- 0.10 v 0.56 +/- 0.08, P = .06). In a multivariate Cox regression model, the PAM predictor classified patients of the second set more accurately than risk stratification of current trials from Germany, Japan, and the United States (P < .001; hazard ratio, 4.756 [95% CI, 2.544 to 8.893]). CONCLUSION: Integration of gene expression-based class prediction of neuroblastoma patients may improve risk estimation of current neuroblastoma trials.

Biomarkers, Tumor↗

Role of stromal and epithelial estrogen receptors in vaginal epithelial proliferation, stratification, and cornification.

Estradiol 17-beta (E2) induces epithelial proliferation, stratification, and cornification in vaginal epithelium. Our aim was to determine the respective roles of epithelial and stromal estrogen receptor-alpha (ER alpha) in these E2-induced events. Vaginal epithelium (E) and stroma (S) from adult ER alpha knockout (ko) and wild-type (wt) neonatal Balb/c mice were enzymatically separated and used to produce four types of tissue recombinants in which epithelium, stroma, or both lack functional ER alpha. Tissue recombinants were grafted into female nude mice, which were subsequently ovariectomized and treated with oil or E2. In response to E2 treatment, grafts prepared with wt-S (wt-S + wt-E and wt-S + ko-E) showed similar large increases in epithelial labeling index, indicating that E2 stimulated epithelial proliferation despite a lack of epithelial ER alpha in wt-S + ko-E tissue recombinants. Conversely, in tissue recombinants prepared with ko-S (ko-S + wt-E and ko-S + ko-E), epithelial labeling index remained at baseline levels after E2 or oil treatment, even though epithelial ER alpha were detected in ko-S + wt-E grafts. Epithelial cornification was present in wt-S + wt-E grafts from E2-treated hosts, whereas epithelium in all other tissue recombinants failed to cornify. Grafts composed of wt-S + wt-E from E2-treated hosts had highly stratified epithelium, whereas epithelial thickness was reduced almost 60% in wt-S + ko-E tissue recombinants grown in E2-treated hosts and was atrophic in all other tissue recombinants. In addition, cytokeratin 10, a marker of epithelial differentiation, was strongly expressed in wt-S + wt-E tissue recombinants grown in E2-treated hosts but was markedly reduced or absent in all other tissue recombinants. These results indicate that E2-induced vaginal epithelial proliferation is mediated indirectly through stromal ER alpha, consistent with our recent findings in uterus. Conversely, both epithelial and stromal ER alpha are required for E2-induced cornification and normal epithelial stratification. These are the first known functions attributed to epithelial ER alpha in vivo and the first time any epithelial response to E2 has been shown to involve both stromal and epithelial ER alpha.

Animals↗

The hSkn-1a POU transcription factor enhances epidermal stratification by promoting keratinocyte proliferation.

Skn-1a is a POU transcription factor that is primarily expressed in the epidermis and is known to modulate the expression of several genes associated with keratinocyte differentiation. However, the formation of a stratified epidermis requires a carefully controlled balance between keratinocyte proliferation and differentiation, and a role for Skn-1a in this process has not been previously demonstrated. Here, our results show, surprisingly, that human Skn-1a contributes to epidermal stratification by primarily promoting keratinocyte proliferation and secondarily by enhancing the subsequent keratinocyte differentiation. In organotypic raft cultures of both primary human keratinocytes and immortalized HaCaT keratinocytes, human Skn-1a expression is associated with increased keratinocyte proliferation and re-epithelialization of the dermal substrates, resulting in increased numbers of keratinocytes available for the differentiation process. In these same raft cultures, human Skn-1a expression enhances the phenotypic changes of keratinocyte differentiation and the upregulated expression of keratinocyte differentiation genes. Conversely, expression of a dominant negative human Skn-1a transcription factor lacking the C-terminal transactivation domain blocks keratinocytes from proliferating and stratifying. Keratinocyte stratification is dependent on a precise balance between keratinocyte proliferation and differentiation, and our results suggest that human Skn-1a has an important role in maintaining epidermal homeostasis by promoting keratinocyte proliferation.

Cell Differentiation↗

Carcinoid of the rectum risk stratification (CaRRS): a strategy for preoperative outcome assessment.

BACKGROUND: Predicting rectal carcinoid behavior exclusively on the basis of tumor size is imprecise. We sought to identify factors associated with outcome and incorporate them into a preoperative risk stratification scheme. METHODS: Seventy patients with rectal carcinoid evaluated at our institution were identified. Demographic, clinical, and histopathologic data were collected and correlated with recurrence and survival. RESULTS: The mean age of our cohort was 53.6 years. Fifty-seven percent of patients were women. The mean tumor size was 1.3 cm (range, .1-5 cm). Twenty-five percent of patients had deeply invasive tumors (into the muscularis propria or deeper); an equal percentage had tumors with lymphovascular invasion (LVI) or an increased mitotic rate (two or more mitoses per 50 high-power fields). Eleven patients (17%) had distant metastases at presentation. Sixty-one patients were followed for a median of 22 months (range, 2-308 months), during which seven patients developed recurrence and seven died of disease (including two of seven whose disease recurred). Poor outcome was associated with large tumor size, deep invasion, presence of LVI, and increased mitotic rate. These factors were incorporated into a Carcinoid of the Rectum Risk Stratification (CaRRS) score. CaRRS predicted recurrence-free and disease-specific survival better than any single factor alone. CONCLUSIONS: Poor prognostic features of rectal carcinoids include large size, deep invasion, LVI, and increased mitotic rate. The CaRRS score incorporates these features and accurately predicts outcome. Because the CaRRS score is based on values available by preoperative biopsy, it can identify patients with favorable prognosis and those with poor prognosis who may benefit from additional staging or surveillance.

Adult↗

Evaluation of the quality of cardiovascular surgery care using risk stratification analysis according to the EuroSCORE additive model.

Risk stratification according to the EuroSCORE additive model of 803 consecutive patients undergoing heart and thoracic aorta surgery using cardiopulmonary bypass from August 1994 to December 2000 was performed. The population was divided into 5 clinically relevant risk categories: 0-2% risk, 3-5% risk, 6-8% risk, 9-11% risk, and 12+% risk. Observed and predicted mortalities were compared within 3 groups of patients divided by year of operation (early: August 1994 to September 1996, n=260; middle: October 1996 to September 1998, n=259; late: October 1998 to December 2000, n=284). Overall hospital mortality was 4.5%; predicted mortality was 5.3% in the early, 5.1% in the middle, and 5.4% in the late period; observed mortality was 6.5%, 3.9%, and 3.2%, respectively (p=0.0024 in early vs late). In the early period, observed mortality was lower than predicted mortality in the 0-2% and 3-5% risk categories, but higher in the other categories. Moreover, observed mortality increased markedly with the increase in predicted mortality. In the late period, observed mortality was lower than predicted mortality in all 5 risk categories. The EuroSCORE is clinically relevant index for constructing a risk stratification scoring system for Japanese cardiovascular patients as well and shows that the quality of surgical care has improved gradually over the years.

Adolescent↗

Value of pharmacologic stress myocardial perfusion imaging for preoperative risk stratification for aortic surgery.

BACKGROUND: Aortic surgery is an invasive, high-risk noncardiac procedure and the patients who require it have a high prevalence of coronary artery disease. Therefore, preoperative risk stratification for this subset is essential. METHODS AND RESULTS: To assess the perioperative risk for aortic surgery, pharmacologic stress single-photon emission computed tomography (SPECT) was performed in 302 patients: aortic dissection in 56, thoracic aortic aneurysm in 124, and abdominal aortic aneurysm in 122. Not only was the presence or absence of perfusion defects analyzed, but also the 20-segment model. Pharmacologic thallium SPECT revealed negative findings in 210 patients and positives in 92. Perioperative cardiac events occurred in 9 patients: 7 occurred in patients with positive SPECT, and in only 2 of those with negative SPECT (2/210 vs 7/92; p<0.05). Multivariate analysis using logistic regression model revealed that a summed stress score>or=14 was the most important factor to identify patients who subsequently had perioperative cardiac events. CONCLUSIONS: Pharmacologic stress SPECT has significant value in the risk stratification of patients before aortic surgery. In patients with positive SPECT, an aggressive approach to reduce the preoperative risk is necessary, whereas aortic surgery can be performed safely in patients with negative SPECT.

Aged↗

The histopathologic spectrum of cryofibrinogenemia in four anatomic sites. Skin, lung, muscle, and kidney.

Although the histologic characteristics of cryofibrinogenemia have been described in skin lesions, the literature is largely devoid of descriptions of this disorder in other organs. This series is the first to document the histopathologic manifestations of intrapulmonary, intramuscular, and renal cryofibrinogenemia. We describe the histopathologic manifestations of cryofibrinogenemia in 10 cases with manifestations in 4 organ systems: skin in 7 cases, skeletal muscle in 2, lung in 2, and kidney in 1. Irrespective of anatomic site, all lesions showed an occlusive thrombotic diathesis comprising eosinophilic refractile deposits within vessel lumina with extension into the intima, with or without an accompanying characteristic granulomatous vasculitic component. Ultrastructural examination of the renal deposits showed fibrillary material within glomerular capillary lumina with unique morphologic features not previously described. Analysis of plasma from several cases revealed a cold-precipitable protein, which in most cases included a monoclonal paraprotein. The laboratory and histologic distinctions between cryofibrinogenemia and cryoglobulinemia are addressed. We provide guidelines for the proper handling of patient specimens in the workup of cryofibrinogenemia.

Adult↗

Role of N-terminal pro-B-type natriuretic peptide in risk stratification in patients presenting in the emergency room.

BACKGROUND: Natriuretic peptides are promising markers in diagnosing acute and chronic heart failure and assessing prognosis in these patients. Increasing routine use to unselected patients is challenged by false-positive results. The aims of this study were to assess (a) the distributions of N-terminal B-type natriuretic peptide (NT-proBNP) values in various diagnostic groups, (b) factors that influence NT-proBNP, and (c) the value of NT-proBNP in risk stratification in unselected emergency room (ER) patients. METHODS: NT-proBNP was measured in 876 unselected consecutive patients [mean (SD) age, 58 (18) years; 53% male] attending the ERs of 2 university hospitals and 1 community hospital. Diagnoses, age, sex, hemoglobin, creatinine (CREA), C-reactive protein (CRP), troponin T, and intensity of care were documented. In a subset consisting of all 417 patients at 1 center, in-hospital follow-up was completed with respect to a complicated clinical course, including intensive care treatment and death. RESULTS: NT-proBNP was significantly increased in patients with cardiac diagnoses or histories compared with patients with only pulmonary or other diagnoses. In patients with other diagnoses, NT-proBNP values increased significantly with the number of atherosclerotic risk factors (P=0.044). Age, renal function, CRP, and to a much lesser extent, hemoglobin significantly influenced NT-proBNP values. The amount of care was positively correlated with NT-proBNP (P<0.001). Classification and regression tree analysis showed a superior impact of NT-proBNP for identification of high-risk patients. CONCLUSIONS: NT-proBNP is a promising marker for identification of patients with structural heart disease in the ER and a suitable tool for risk stratification. Its use in the ER should be limited to clearly clinically defined patient groups at present to avoid a potential excess of additional diagnostic procedures in positive but asymptomatic patients.

Acute Disease↗

Stratification of patients according to prior cardiopulmonary disease and probability assessment based on the number of mismatched segmental equivalent perfusion defects. Approaches to strengthen the diagnostic value of ventilation/perfusion lung scans in acute pulmonary embolism.

A categorical diagnosis of "high probability" or "intermediate probability" encompasses a spectrum of diagnostic probabilities of pulmonary embolism (PE) that is not communicated to the referring physician. The diagnostic value of ventilation/perfusion lung scans, in the present investigation, was strengthened by use of a table to determine the likelihood of PE in individual patients on the basis of the observed number of mismatched segmental equivalent perfusion defects. In addition, we tested the hypothesis that stratification of patients according to the presence or absence of prior cardiopulmonary disease may enhance the ventilation/perfusion scan assessment of the probability of PE among both of these clinical categories of patients. Data were derived from the collaborative study of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). Ventilation/perfusion lung scans were evaluated in 378 patients with acute PE and 672 patients in whom suspected PE was excluded. Among patients with no prior cardiopulmonary disease, > or = 1.0 mismatched segmental equivalents was indicative of PE in 102 of 118 (86 percent) vs 113 of 155 (73 percent) among patients with prior cardiopulmonary disease (p < 0.02). Among patients with prior cardiopulmonary disease, > or = 2 mismatched segmental equivalents were required to indicate > or = 80 percent probability of PE. Stratification on the basis of the presence or absence of prior cardiopulmonary disease, therefore, enhanced the ability of ventilation/perfusion scan readers to assign an accurate positive predictive value and specificity to individual patients based on the observed number of mismatched segmental equivalent defects. Among patients with no prior cardiopulmonary disease, fewer mismatched segmental equivalent defects were required to indicate a high probability of PE than were required by PIOPED criteria. The findings from some of these patients, by PIOPED criteria, would have indicated intermediate probability. Some indeterminate probability readings, therefore, will be eliminated among patients stratified with no prior cardiopulmonary disease.

Acute Disease↗

Risk stratification for lung cancer surgery: impact of induction therapy and extended resection.

STUDY OBJECTIVES: Current surgical strategies for lung cancer are directed toward the following two distinct targets: the increased prevalence of early-stage lung cancer; and locally advanced lung cancer treated with induction therapy (IT). To establish the risk stratification for operative morbidity from this viewpoint, we evaluated the impact of IT and/or an extended surgical procedure on operative results. DESIGN: Retrospective study. SETTING: A 674-bed teaching hospital. PATIENTS AND METHODS: The morbidity and mortality of 758 consecutive patients who underwent surgery for the treatment of non-small cell lung cancer were analyzed. There were 666 patients who underwent surgery alone (S group; 560 standard lobectomies and 106 extended resections) and 92 patients who received IT (IT group; 35 standard lobectomies and 57 extended resections). Comparisons between the groups were performed using unpaired t tests or chi(2) tests. Univariate and multivariate logistic regression analyses were used to determine the risk factors for operative morbidity and mortality. RESULTS: IT and extended surgery were strong independent factors for predicting postoperative morbidity (p < 0.0001). Significant differences were observed for pathologic stage (p < 0.0001), preoperative hemoglobin and Dlco levels (p < 0.001), the ratio of extended resection (p < 0.0001), and operation time and intraoperative bleeding (p < 0.001) between the S and IT groups. The overall morbidity and mortality rates were 16.8% and 0.9%, respectively, in the S group, and 55.4% and 5.4%, respectively, in the IT group (p < 0.01). The overall morbidity and mortality rates were 63.2% and 7.0%, respectively, for extended resection after IT, and 12.8% and 0.3%, respectively, for those who underwent a standard resection without IT. CONCLUSIONS: The morbidity and mortality of lung resection are both significantly increased after IT, and the patients with the greatest risk are those who have undergone IT and extended resection. The impact of IT on risk stratification should be emphasized in perioperative care.

Adenocarcinoma↗

Compression entropy contributes to risk stratification in patients with cardiomyopathy.

Sudden cardiac death (SCD) is a leading cause of mortality with an incidence of 3 million cases per year worldwide. Therapies for patients who have survived an SCD episode or have a high risk of developing lethal ventricular arrhythmia are well established and depend mainly on risk stratification. In this study we investigated the suitability of the non-linear measure compression entropy (Hc) for improved risk prediction in cardiac patients. We recorded 24-h Holter ECG for 300 patients with congestive heart failure (CHF). During a mean follow-up period of 12 months, 32 patients died due to a cardiac event. Hc depends on the compression parameters window length w and buffer length b, which were optimised by analysing a subgroup of patients. Compression entropies based on the beat-to-beat interval (BBI) were subsequently calculated and compared with standard heartrate variability parameters. Statistical analysis revealed significant differences between high- and low-risk CHF patients in standard HRV measures, as well as compression entropy based on the BBI (cardiac death, p = 0.005; SCD, p = 0.02). In conclusion, the implementation of non-linear compression entropy analysis in multivariate analysis seems to be useful for enhanced risk stratification of cardiac death, especially SCD, in ischaemic cardiomyopathy patients.

Aged↗

[Vertical stratification of phlebotomine sandfly fauna (Diptera, Psychodidae) in a primary non-flooded forest of the Central Amazon, Amazonas State, Brazil].

Studies on the vertical stratification of phlebotomine sandfly fauna were conducted in a non-flooded primary forest at a Tropical Forest Experimental Station of the National Institute of Amazonian Research from October 1998 to March 1999. CDC light traps were placed at one, 10, and 20 meters above ground. A total of 2,859 sandflies were captured, belonging to the Lutzomyia (99.93%) and Brumtomyia (0.07%) genera, represented by 38 species. In the Lutzomyia gender, the most frequent sub-gender was Nyssomyia (43.4%), followed by Psychodopygus (22.8%). Lutzomyia umbratilis, L. anduzei, L. rorotaensis, L. trichopyga, and L. olmeca nociva predominated at one meter above ground, while L. davisi, L. infraspinosa, L. umbratilis, L. trichopyga, and L. anduzei predominated at 10 meters. L. anduzei, L. tuberculata, L. dendrophyla, and L. dreisbachi were the most abundant species at 20 meters. L. umbratilis, which appeared at all three levels of vertical stratification, has great epidemic significance as a vector of Leishmania (Viannia) guyanensis.

Animals↗

[Social stratification in epidemiological studies of dental caries and periodontal diseases: a profile of the scientific literature in the 1990s].

Several epidemiological studies have analyzed the association between oral health and social development. However, the use of different variables assessing socioeconomic status impairs the comparative analysis of their findings. The present study describes how recent dental studies have classified population segments according to categories of social stratification. We selected 86 papers on social determinants of dental caries or periodontal conditions, and published in MEDLINE-indexed journals from 1990 to 2001. The studies used different strategies to stratify populations, but occupation, schooling, and income were the most frequently assessed variables. Ethnic differentials, characteristics of households and schools, and access to material resources were also frequently appraised. We also observed a large portion of Brazilian studies focusing on socioeconomic differentials in the distribution of caries and periodontal disease. Knowledge of strategies for social stratification can improve the understanding of factors associated with dental diseases, fostering further studies and allowing the comparison of their results.

Adolescent↗

Risk stratification in non-ST segment elevation acute coronary syndromes with special focus on recent guidelines.

Patients with unstable angina or non-ST segment elevation (non-Q-wave) myocardial infarction are a heterogeneous group with respect to their risk of developing clinically significant adverse events such as subsequent myocardial infarction and death. Recent guidelines promote risk stratification of these patients, targeting high-risk patients for maximal antithrombotic and antiischemic therapy and low-risk patients for early discharge. We reviewed current and future modalities for risk stratification of patients and the predictive value of these methods in context with available pharmacologic agents. Unfortunately, most of the data identifying a particular pharmacologic regimen as beneficial in high-risk patients are retrospectively derived from large trials. Until prospective studies that use markers to guide therapy are available, clinicians should be familiar with the use of these risk markers and their application to the role of a given management strategy, including pharmacologic therapy.

Acute Disease↗

Microarray genotyping resource to determine population stratification in genetic association studies of complex disease.

We have developed a robust microarray genotyping chip that will help advance studies in genetic epidemiology. In population-based genetic association studies of complex disease, there could be hidden genetic substructure in the study populations, resulting in false-positive associations. Such population stratification may confound efforts to identify true associations between genotype/haplotype and phenotype. Methods relying on genotyping additional null single nucleotide polymorphism (SNP) markers have been proposed, such as genomic control (GC) and structured association (SA), to correct association tests for population stratification. If there is an association of a disease with null SNPs, this suggests that there is a population subset with different genetic background plus different disease susceptibility. Genotyping over 100 null SNPs in the large numbers of patient and control DNA samples that are required in genetic association studies can be prohibitively expensive. We have therefore developed and tested a resequencing chip based on arrayed primer extension (APEX) from over 2000 DNA probe features that facilitate multiple interrogations of each SNP, providing a powerful, accurate, and economical means to simultaneously determine the genotypes at 110 null SNP loci in any individual. Based on 1141 known genotypes from other research groups, our GC SNP chip has an accuracy of 98.5%, including non-calls.

Animals↗