Some Issues of Sample Size Calculation for Time-to-Event Endpoints Using the Freedman and Schoenfeld Formulas

This article deals with seven special issues related to the assumptions, applicability, and practical use of formulas for calculating power or sample size, respectively, for comparative clinical trials with time-to-event endpoints, with particular focus on the well-known Freedman and Schoenfeld methods. All problems addressed are illustrated by numerical examples, and recommendations are given on how to deal with them in the planning of clinical trials.     

Capability of B-type natriuretic peptide (BNP) and amino-terminal proBNP as indicators of cardiac structural disease in asymptomatic patients with systemic arterial hypertension

BACKGROUND: The aim of the present study was to prospectively evaluate the diagnostic utility of B-type natriuretic peptide (BNP) and amino-terminal proBNP (NT-proBNP) measurements for the detection of cardiac structural disease in asymptomatic patients with systemic arterial hypertension and to test the hypothesis that the 2 analytes are equally useful in this clinical setting. METHODS: We studied a consecutive series of 149 asymptomatic patients referred for echocardiographic evaluation of the cardiac effects of systemic arterial hypertension. Diagnosis of cardiac structural disease was based on the presence of systolic or diastolic dysfunction, left atrial dilatation, left ventricular dilatation or hypertrophy, pulmonary hypertension, and wall motion or valvular abnormalities. Blood concentrations of BNP and NT-proBNP were measured by 2 commercially available assays (Abbott AxSYM and Roche Elecsys, respectively). Diagnostic accuracies of BNP and NT-proBNP were assessed by ROC curve analysis. Areas under the curves were compared by analysis of equivalency. RESULTS: In distinguishing between hypertensive patients with cardiac structural disease (n = 118) and hypertensive patients without (n = 31), areas under the curves were 0.740 (95% confidence interval, 0.662-0.808) for BNP and 0.762 (0.685-0.828) for NT-proBNP and were significantly equivalent (P = 0.015). Cutoff values with a 90% sensitivity for cardiac structural disease were 17 ng/L for BNP and 39 ng/L for NT-proBNP, with 29% and 32% specificity, respectively. CONCLUSIONS: BNP and NT-proBNP have similar capabilities for detecting cardiac structural disease in asymptomatic patients with systemic arterial hypertension. However, in the setting evaluated, a screening strategy relying on measurement of BNP or NT-proBNP may be of limited value because of the low specificity at the selected cutoff values.     

Plasma B-type natriuretic peptide in patients with pleural effusions: preliminary observations

STUDY OBJECTIVES: To address the value of plasma B-type natriuretic peptide (BNP) concentrations as a diagnostic tool for determining the cardiac etiology of pleural effusions, and to determine possible differences of plasma BNP concentrations before and after pleurocentesis in patients with congestive heart failure (CHF). DESIGN: Observational study. SETTING: Tertiary care hospital. PATIENTS: Consecutive series of 64 patients with indications for diagnostic pleurocentesis. The final diagnosis of the underlying disease was assessed by clinical criteria. Seven patients were excluded due to pleural effusions of equivocal origin or due to obvious hemothorax secondary to trauma. INTERVENTION: Pleurocentesis attempting to drain effusions dry. Plasma BNP concentrations were measured directly before pleurocentesis and 24 h after the intervention. During these 24 h, the dosages of patients' medications were held constant. MEASUREMENTS AND RESULTS: In distinguishing between patients with pleural effusions caused by CHF (n = 31) and patients with pleural effusions attributable to other causes (n = 26), the area under the curve was 0.974 (SE, 0.021; 95% confidence interval, 0.892 to 0.997) for plasma BNP. A BNP cutoff concentration of 2,201 ng/L had a sensitivity of 77% and a specificity of 100% in the diagnosis of CHF. The median plasma BNP concentrations in patients with pleural effusions caused by CHF (n = 31) did not change within 24 h after pleurocentesis compared with the concentrations obtained before the procedure (before pleurocentesis, 3,227 ng/L; 24 h after pleurocentesis, 2,759 ng/L; p = 0.189), despite a median removal of 1,100 mL pleural fluid. CONCLUSIONS: Plasma BNP concentrations of patients with pleural effusions of unknown origin may be an aid in the diagnosis of CHF as the underlying cause. If plasma BNP is used as a surrogate marker of global cardiac function, there is no indication of hemodynamic improvement caused by pleurocentesis alone in patients with CHF and pleural effusions.     

ERCP or EUS for tissue diagnosis of biliary strictures? A prospective comparative study

BACKGROUND: The accuracy of ERCP-based brush cytology or forceps biopsy for tissue diagnosis is relatively low (usually not exceeding 70%). By contrast, reported accuracy rates for EUS-guided FNA of pancreatobiliary masses are over 80%. This prospective study compared these two modalities for the first time in the diagnosis of indeterminate biliary strictures and pancreatic tumors. METHODS: Fifty consecutive patients (29 men, 21 women; mean age 62.1 years) with obstructive jaundice in whom a tissue diagnosis was required were included. During ERCP, intraductal specimens were obtained with a forceps and with two different types of brush (conventional and spiral suction) in random order. During EUS, only visible mass lesions or localized bile duct wall thickening were aspirated (22-gauge needle), with at least two passes yielding material sufficient for assessment. A cytopathologist was not present in the procedure room to evaluate specimen adequacy. The reference methods were surgery, other biopsy results, follow-up until death, or the conclusion of the study (mean follow-up 20 months). RESULTS: The final diagnoses were malignancy, 28 (16 pancreatic, 12 biliary), and benign biliary stricture, 22. Sensitivity and specificity for ERCP-guided biopsy were 36% and 100%, respectively; for ERCP-guided cytology (when using conventional and spiral suction brushes), 46% and 100%, respectively; and for EUS-guided FNA, 43% and 100%, respectively. If the punctured lesions are considered (n=28) alone, the sensitivity of EUS-guided FNA was 75%. In general, sensitivity was better for ERCP-based techniques in the subgroup biliary tumor (ERCP 75% vs. EUS 25%), whereas EUS-guided biopsy was superior for pancreatic mass (EUS 60% vs. ERCP 38%). CONCLUSIONS: For biliary strictures, combined ERCP- and EUS-guided tissue acquisition seems to be the best approach to tissue diagnosis. From a clinical standpoint, it appears reasonable, when a tissue diagnosis is required, to start with ERCP if biliary malignancy is suspected and with EUS when a pancreatic tumor is thought to be the cause of a biliary stricture.     

Urinary excretion of high molecular weight adiponectin is an independent predictor of decline of renal function in type 2 diabetes

Adiponectin and urinary adiponectin excretions have been ascribed a function in glomerular physiology and seem to indicate vascular disease in diabetes. The aim of this study was to compare the urinary excretion of albumin and adiponectin as predictors for decline of renal function in patients with type 2 diabetes and early kidney disease. Over 141 patients were screened for renal function (estimated GFR, ml/min*1.73 m²), albumin excretion rate (AER, mg/24 h), total as well as high molecular weight (HMW) urinary adiponectin excretion (ng/mol u-creatinine). AER and adiponectin excretion were studied as predictors of renal function after 1 year. After 1 year, 36 patients were in the upper quartile of eGFR decline and defined as progressors (delta eGFR = ? 12.3 ± 6.3) while the remaining 105 patients were defined as non-progressors (delta eGFR = 1.4 ± 6.0). At baseline, HMW-adiponectin excretion was positively correlated with HbA_1c (p < 0.001) and negatively with eGFR (p < 0.001), but not with AER (p = 0.14). Progressors showed increased urinary HMW-adiponectin at baseline (158[IQR41/479] vs. 65[24/168] ng/mol; p < 0.01), while total adiponectin (182[101/1534] vs. 345[118/1361] ng/mol) and AER (48[23/109] vs. 46[25/108] mg/24 h) excretion showed no differences between the groups. Multivariate logistic regression showed that HMW-adiponectin excretion was an independent predictor of renal progression in all patients (OR 1.86 [95 % CI 1.34–2.59]; p < 0.01), especially in those (n = 45) with normal AER at baseline (OR 2.16 [95 % CI 1.1–4.56]; p < 0.05). Urinary HMW-adiponectin but not AER improved the prediction of progressors in ROC analysis (AUC 0.72 [95 % CI 0.63–0.81] vs. 0.80 [95 % CI 0.71–0.90], p < 0.05). In conclusion, urinary HMW-adiponectin excretion may identify diabetes patients at increased risk for progression of kidney disease.     

Human fetal bone marrow early progenitors for T, B, and myeloid cells are found exclusively in the population expressing high levels of CD34

Experimentation on human stem cells is hampered by the relative paucity of this population and by the lack of assays identifying multilineage differentiation, particularly along the lymphoid lineages. In our current study, phenotypic analysis of low-density fetal bone marrow cells showed two distinct populations of CD34+ cells: those expressing a high density of CD34 antigen on their surface (CD34hi) and those expressing an intermediate level of CD34 antigen (CD34lo). Multiple tissues were used to characterize the in vitro and in vivo potential of these subsets and showed that only CD34hi cells support long-term B lymphopoiesis and myelopoiesis in vitro and mediate T, B, and myeloid repopulation of human tissues implanted into SCID mice. CD34lo cells repeatedly failed to provide long-term hematopoietic activity in vivo or in vitro. These results indicate that a simple fractionation based on well-defined CD34 antigen levels can be used to reproducibly isolate cells highly enriched for in vivo long-term repopulating activity and for multipotent progenitors, including T- and B-cell precursors. Additionally, given the limited variability in the results and the high correlation between in vitro and in vivo hematopoietic potential, we propose that the CD34hi population contains virtually all of the stem cell activity in fetal bone marrow and therefore is the population of choice for future studies in hematopoietic stem cell development and gene therapy.     

采用蛋白指纹图谱技术筛选大肠癌肝转移特异性相关蛋白

目的:应用表面增强激光解析电离飞行时间质谱技术从大肠癌及大肠癌肝转移患者中筛选出大肠癌肝转移患者血清特异性相关蛋白。方法:实验于2005-07/2006-09分别在南方医院消化中心实验室与解放军第一五○医院实验室完成。应用美国CipherGen公司IMAC3(ImmobilizedMetalAffinityCapture,金属亲和表面)芯片和蛋白芯片仪检测44例大肠癌患者及36例大肠癌肝转移患者血清中的蛋白质相对含量。设定所有血清样本检测的蛋白质相对分子质量区间在1500～20000。利用PBSⅡ型蛋白质芯片阅读仪对IMAC3芯片进行检测,所得到的蛋白质以波谱的形式表示。采用BiomarkerWizard软件对2组血清在相同质荷比的蛋白质含量数据进行方差分析,将分析所得到的含量有显著性差异(P<0.05)的蛋白质建立数据库,导入BiomarkerPattern智能统计分析软件,选择相应条件,对其进行分组统计,从而得到能够正确分组的特异性蛋白标志物并构建大肠癌肝转移的诊断模型。采用酶联免疫法检测相同血清标本中的CEA水平,与构建的诊断模型在大肠癌肝转移诊断中作比较。结果:①44例大肠癌患者与36例大肠癌肝转移患者的血清蛋白质在质荷比为2685.64～11813间有16个蛋白质含量有显著差异。②大肠癌组在质荷比为5909处的蛋白质的相对含量高于大肠癌肝转移组[(30.1±9.6)%,(14.5±10.4)%,P≤0.01]。③其中44例大肠癌患者中有38例患者被正确分组,36例大肠癌肝转移患者被正确识别,准确率为92.5%(74/80),灵敏度和特异性分别为100%(36/36),86.4%(38/44)。结论:表面增强激光解析电离飞行时间质谱技术快速、准确、灵敏度、特异性高,通过蛋白芯片仪发现的特异性相关蛋白,有望成为大肠癌肝转移诊断中有应用价值的临床检测指标。