近年随着精准医疗的发展,越来越多的药物针对疾病的分子作用机制和特定靶点进行开发. 在创新药物研发上,以生物标志物为导向的临床试验研究,即探索与药物疗效或安全性相关的生物标志物,根据其识别亚组并制定个体化治疗的临床试验方案,从而使患者接受更有益的治疗、加速药物研发进程、最大限度地规避新药研发的风险,已引起人们的极大关注[1-3] .本文将对以生物标志物为导向的临床试验设计方法和特点进行简要综述,以期对创新药物研究起到一定的助力作用.

目的 本文介绍一种新的处理临床试验转组数据的统计学方法——校正迭代参数法(MIPE),并通过模拟试验在不同情形下比较MIPE、IPE、意向性分析(ITT)三种方法对治疗效果估计的准确性.方法 通过模拟数据探讨不同的治疗效应真值、潜在预后、转组率等24个假设场景中试验药疗效估计值的差异,并将MIPE、IPE、ITT方法应用于每个场景下进行效果比较.结果 当试验药与安慰剂组疗效存在差异时,ITT和IPE方法得出的治疗效应估计均有偏,这种有偏估计与不同的治疗效应真值、潜在预后和转组率等因素相关,而MIPE方法不受上述因素影响,估计结果较为准确且稳定.结论 MIPE方法不受实际治疗效应、潜在预后、转组率等因素的影响,在各场景中治疗效应估计值的均值较为稳定,与其他方法相比,更接近真实值,在临床试验评价中使用更为可靠.

The purpose of this study was to assess the association of blood pressure (BP) measurements with the risk of cardiovascular disease (CVD) and examine whether central systolic BP (CSBP) predicts CVD better than brachial BP measurements (SBP and pulse pressure [PP]). Based on a cross‐sectional study conducted in 2009‐2010 with follow‐up in 2016‐2017 among 35‐ to 64‐year‐old subjects in China, we evaluated the performance of non‐invasively predicted CSBP over brachial BP measurements on the first CVD events. Each BP measurement, individually and jointly with another BP measurement, was entered into the multivariate Cox proportional‐hazards models, to examine the predictability of central and brachial BP measurements. Mean age of participants (n = 8710) was 50.1 years at baseline. After a median follow‐up of 6.36 years, 187 CVD events occurred. CSBP was a stronger predictor for CVD than brachial BP measurements (CSBP, 1‐standard deviation increment HR = 1.49, 95%CI: 1.31‐1.70). With CSBP and SBP entering into models jointly, the HR for CSBP and SBP was 1.28 (1.04‐1.58) and 1.22 (0.98‐1.50), respectively. With CSBP and PP entering into models jointly, the HR for CSBP and PP was 1.51 (1.28‐1.78) and 0.98 (0.83‐1.15), respectively. For subgroup analysis, the association of CSBP with CVD was stronger than brachial BP measurements in women, those with hypertension and obesity. In the middle‐aged Chinese population, noninvasively estimated CSBP may offer advantages over brachial BP measurements to predict CVD events, especially for participants with higher risk. These findings suggest prospective assessment of CSBP as a prevention and treatment target in further trials.

Background: Inflammation is actively involved in the clinical manifestation of peripheral artery disease (PAD). Sonodynamic therapy (SDT), a novel non-invasive, plaque-based, macrophage-targeted anti-inflammatory regimen for atherosclerosis has the potential to improve walking performance by reducing plaque inflammation. Methods: This phase-2, randomized, sham-controlled, double-blind clinical trial enrolled 32 participants with symptomatic femoropopliteal PAD. The primary outcome was the 30-day change in the target-to-background ratio (TBR) within the most diseased segment (MDS) of the femoropopliteal artery assessed through positron emission tomography/computed tomography (PET/CT). The secondary outcomes were changes in walking performance, limb perfusion, lesional morphology and quality of life measurements. Results: The mean age was 64.7 years and 63% were male. Thirty-one completed follow-up. SDT significantly decreased the MDS TBR by 0.53 ( 95% CI, -0.70 to -0.36, P < 0.001) compared with control. Furthermore, SDT increased peak walking time by 118.6 s (95% CI, 74.3 to 163.0, P < 0.001), increased ankle-brachial index by 0.11 (95% CI, 0.07 to 0.14, P < 0.001), decreased lesional diameter and area stenosis by 72% (95% CI, -8.6 to -4.5, P < 0.001) and 9.6% (95% CL -24.5 to -5.3, P = 0.005), respectively, and increased the walking speed score of the Walking Impairment Questionnaire by 16.1 (95% CI, 2.6 to 29.5, P 0.021) and the physical functioning score of the 36-item Short-Form Health Survey by 10.0 (95% CI, 5.0 to 20.0, P = 0.003) compared with control. These improvements were maintained in the SDT group up to 6-month. Conclusions: SDT rapidly reduced plaque inflammation and improved walking performance among patients with symptomatic PAD. (C) 2020 Elsevier B.V. All rights reserved.

BackgroundThis study aimed to assess the association of high sensitivity C-reactive protein (hs-CRP) with cardiovascular disease (CVD) in middle-aged Chinese population.MethodsThe baseline was collected 2009–2010, and follow-up was conducted in 2016–2017. Data of hs-CRP were from baseline examination and re-examination in 2016–2017 using transmission turbidimetry with a measurement range of 0–42 000. The primary outcome was CVD including coronary heart disease events and stroke events.ResultsAmong 8688 participants free from CVD (at baseline, mean age, 50.1 years, 3897 were males), there were 189 CVD events, occurred during a median follow-up of 6.34 years (54 685 person-years at risk). From the Kaplan-Meier curve, we found that there was a progressive increase in CVD event rates by hs-CRP tertiles (log-rank test, p<0.001). Baseline hs-CRP was linearly associated with CVD (p for trend=0.015) even after adjusting for known CVD risk factors. Furthermore, the net reclassification improvement when hs-CRP was added to a model based on traditional factors was 7.85% for CVD (p=0.003). In addition, the correlation between change of hs-CRP and CVD was conducted in a subgroup (n=4778). However, we did not find the correlation between hs-CRP change and CVD (correlation coefficient: −0.003, p=0.846).ConclusionsIn the middle-aged Chinese population, hs-CRP was associated with increased risk of developing CVD. Although there was no correlation between hs-CRP change and CVD, the level of hs-CRP was higher at follow-up than baseline even among those with CVD. More attention should be given to those with higher level of hs-CRP for CVD prevention.

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer-related death due to its nonspecific characteristics compared to benign cases and poor prognosis after conventional therapies. Small peptides (SPs) demonstrated to have potential for diagnosis and prognosis were focused on in our study for the discovery of biomarkers that address these issues. Metabolic profiles of 15 SPs, including nine dipeptides and six tripeptides were acquired from plasma samples of 140 EOC and 158 benign ovarian tumor (BOT) patients. Partial least square discriminant analysis showed separations between EOC and BOT subjects of different age brackets. Hyp-Leu, Glu-Trp and Phe-Phe were selected as promising predictive SP-biomarkers for better EOC diagnosis compared to conventional biomarkers. Combined Hyp-Leu, Glu-Trp and CA125 presented an area under the curve (AUC) of 0.904, with a sensitivity and specificity of 0.804 and 0.944, respectively. This finding suggested that the combination of these biomarkers performed much better than CA125 alone. Hyp-Leu and Gly-Phe-Trp showed significantly improved performances in the log-rank tests and Kaplan-Meier curves demonstrating their prognostic potential. All SP-biomarkers proved to have excellent stabilities at room temperature. Correlation network analysis implied latent conversions among amino acids, dipeptides and tripeptides during EOC. In conclusion, the selected SPs in combination with CA125 show profound promise for discriminating EOCs from BOTs and for predicting the progression after surgery, which provides invaluable information for clinicians in the precision diagnosis and treatment of EOC.

Background: To develop and validate a nomogram based on the conventional measurements and log of odds between the number of positive lymph node and the number of negative lymph node (LODDS) in predicting prognosis for cervical cancer patients after surgery.Methods: A total of 8202 cervical cancer patients with pathologically confirmed between 2004 and 2014 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database.All the patients were divided into training (n=3603) and validation (n=4599) cohorts based on consecutive age of diagnosis.Demographic and clinical pathological factors were evaluated the association with overall survival (OS).Parameters significantly correlating with OS were used to create a nomogram.An independent external validation cohort was subsequently used to assess the predictive performance of the model.Results: In the training set, age at diagnosis, race, marital status, tumor grade, FIGO stage, histology, size and LODDS were correlated significantly with outcome and used to develop a nomogram.The calibration curve for probability of survival showed excellent agreement between prediction by nomogram and actual observation in the training cohort, with a bootstrap-corrected concordance index of 0.749(95% CI, 0.731-0.767).Importantly, our nomogram performed favorably compared to the currently utilized FIGO model, with concordance indices of 0.786 (95% CI, 0.764 to 0.808) vs 0.685 (95%CI, 0.660 to 0.710) for OS in the validation cohort, respectively.Conclusions: By incorporating LODDS, our nomogram may be superior to the currently utilized FIGO staging system in predicting OS in cervical cancer patients after surgery.

Biological requirements for tumor cell proliferation include the sustained increase of structural, energetic, signal transduction and biosynthetic precursors. Because lipids participate in membrane construction, energy storage, and cell signaling. We hypothesized that the differences in lipids between malignant carcinoma and normal controls could be reflected in the bio-fluids. A total of 100 pre-operative plasma samples were collected from 50 oral squamous cell carcinoma (OSCC), 50 normal patients and characterize by lipid profiling using ultra performance liquid chromatography/electro spray ionization mass spectrometry (UPLC-MS). The lipid profiles of the OSCC and control samples as well as the different stages were compared. Differentially expressed lipids were categorized as glycerophospholipids and sphingolipids. All glycerophospholipids were decreased, especially phosphatidylcholine and phosphoethanolamine plasmalogens, whereas sphingolipids were increased in the OSCC patients compared to the controls. We further identified 12 staging related lipids, which could be utilized to discriminate early stage patients from advanced stage patients. In the future, the differential lipids may provide biologists with additional information regarding lipid metabolism and guide clinicians in making individualized therapeutic decisions if these results are confirmed in a larger study.

High-grade serous ovarian cancer (HGSC) is an aggressive cancer with a worse clinical outcome. Therefore, studies about the prognosis of HGSC may provide therapeutic avenues to improve patient outcomes. Since genome alteration are manifested at the protein level, we integrated protein and mRNA data of ovarian cancer from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) and utilized the sparse overlapping group lasso (SOGL) method, a new mechanism-driven variable selection method, to select dysregulated pathways and crucial proteins related to the survival of HGSC. We found that biosynthesis of amino acids was the main biological pathway with the best predictive performance (AUC = 0.900). A panel of three proteins, namely EIF2B1, PRPS1L1 and MAPK13 were selected as potential predictive proteins and the risk score consisting of these three proteins has predictive performance for overall survival (OS) and progression free survival (PFS), with AUC of 0.976 and 0.932, respectively. Our study provides additional information for further mechanism and therapeutic avenues to improve patient outcomes in clinical practice.

This cross‐sectional study carried out from November 2014 to December 2014 aimed to determine whether the interankle systolic blood pressure ( SBP ) difference is an independent marker of prevalent stroke. Simultaneous four‐limb blood pressure measurements (oscillometric devices) and calculated SBP difference between the lower limbs were collected from 1485 participants aged 35 years and older. Questionnaires about traditional stroke risk factors were completed. Interankle SBP difference ≥7 mm Hg was independently associated with a history of stroke after adjusting for traditional stroke risk factors (odds ratio, 1.64; 95% confidence interval, 1.53–3.59; P =.0123). Net reclassification improvement analysis showed that adding the interankle SBP difference to traditional risk factors improved the predictive ability for stroke risk by 18.5% ( P <.001). In conclusion, an interankle SBP difference ≥7 mm Hg could be an independent marker of stroke history in Chinese adults. It could offer an extra benefit in identifying individuals with risk of stroke beyond conventional clinical features.

Biological requirements for tumor cell proliferation include the sustained increase of structural, energetic, signal transduction and biosynthetic precursors. Because lipids participate in the self-assembly of phospholipids to form biological membranes, they play important roles in membrane construction, energy storage, and cell signaling. We hypothesized that the differences in lipids between malignant ovarian carcinomas, benign ovarian tumors and normal controls could be reflected in the bio-fluids. A total of 215 pre-operative plasma samples were collected from 139 epithelial ovarian cancer (EOC), 38 benign ovarian tumor (BOT) and 38 uterine fibroid (UF) patients; these samples were then characterized by lipid profiling using ultra performance liquid chromatography/electrospray ionization mass spectrometry (UPLC–MS). The lipid profiles of the EOC and control samples (BOT/UF) as well as the different stages and histological subtypes of EOC were compared. Differentially expressed lipids were categorized as glycerophospholipids, sphingolipids and glyceroglycolipids and were found to be linked with three pathways. Almost all glycerophospholipids were down-regulated, especially phosphatidylcholine and phosphoethanolamine plasmalogens, whereas sphingolipids were up-regulated in the EOC patients compared to the controls. Lipids associated with pathological stage and histological subtype were also identified. We further identified five diagnostic lipids that were complementary to CA125. The predictive accuracy of five diagnostic lipids together with CA125 was higher than that of CA125 alone when distinguishing EOC and BOT/UF. In the future, the differential lipids identified may provide biologists with additional information regarding lipid metabolism and guide clinicians in making individualized therapeutic decisions if these results are confirmed in a larger study.

Objective: The interankle systolic blood pressure (SBP) difference has been found to predict the risk for overall and cardiocerebrovascular events; however, few studies have evaluated the association between the interankle SBP difference and stroke. Our study aimed to determine whether the interankle SBP difference is associated with prevalent stroke in a Chinese adult population. Design and Method: This cross-sectional study included 1485 participants aged ≥35 years in the framework of the China Hypertension Survey. We performed simultaneous 4-limb BP measurements using oscillometric devices and calculated the SBP difference between the 2 lower limbs. Logistic regression analysis was used to estimate the association between the interankle SBP difference and history of stroke. The contribution of the interankle SBP difference for predicting stroke risk was evaluated by receiver operating characteristic analysis and net reclassification improvement (NRI). Results: In univariate analyses, participants with an interankle SBP difference ≥ 7 mmHg had a higher prevalence of stroke than those without (p < 0.0001). In multiple logistic regression analysis, the interankle SBP difference was independently associated with prior stroke after adjusting for conventional risk factors of stroke (p = 0.0123). The addition of the interankle SBP difference marginally increased 1.4% (p = 0.0073), but significantly improved the predictive ability for stroke risk by 18.45% by using the NRI approach (p = 0.00001). Conclusions: An interankle SBP difference ≥ 7 mmHg is an independent risk indicator for prevalent stroke in Chinese adults; it could offer an extra benefit in identifying individuals with risk of prevelant stroke beyond conventional clinical features (age, family history of stroke, and SBP).

OBJECTIVE:We investigated the association of ankle-brachial blood pressure index (ABI), interarm blood pressure (BP) difference and interankle BP difference, obtained by simultaneous four-limb BP measurement, with history of stroke in a Chinese adult population.METHODS:This cross-sectional study included 1485 participants aged ≥35 years in the framework of the China Hypertension Survey. We performed simultaneous four-limb BP measurement using oscillometric devices with the participants in the supine position and calculated ABI and interarm/interankle BP differences between the 4 limbs. Logistic regression analysis was used to estimate the association of these BP parameters and other factors with a history of stroke.RESULTS:In univariate analyses, participants with ABI <0.9, interarm BP difference ≥15 mmHg, and interankle BP difference ≥10 mmHg had a higher prevalence of stroke than those without (p < 0.0001, p = 0.0152, p = 0.002, respectively). Multiple logistic regression analyses suggested, ABI <0.9 was independently associated with a history of stroke after adjustment for interarm BP difference ≥15 mmHg, interankle BP difference ≥10 mmHg, and traditional risk factors for stroke (p = 0.001). An interankle BP difference ≥10 mmHg was associated with prior stroke after the two variables of hypertension and ABI were removed from the logistic regression model (p = 0.0142). Net reclassification improvement analysis showed that inclusion of interankle BP difference ≥10 mmHg to the independent risk factors (age, family history of stroke, hypertension, and ABI) improved net reclassification by 11.92%.CONCLUSION:ABI <0.9 is an independent risk factor for stroke prevalence in Chinese adults and it just detected a small propotion of paticipants. The addition of interankle BP difference ≥10 mmHg to the independent risk factors for stroke may improve the prediction of stroke.

Cervical cancer is a clinical and pathological heterogeneity disease, which requires different types of treatments and leads to a variety of outcomes. In clinical practice, only some patients benefit from chemotherapy treatment. Identifying patients who will be responsive to chemotherapy could increase their survival time, which has important implications in personalized treatment and outcomes, while identifying non-responders may reduce the likelihood for these patients to receive ineffective treatment and thereby enable them to receive other potentially effective treatments. Plasma metabolite profiling was performed in this study to identify the potential biomarkers that could predict the response to neoadjuvant chemotherapy (NACT) for cervical cancer patients. The metabolic profiles of plasma from 38 cervical cancer patients with a complete, partial and non-response to NACT were studied using a combination of liquid chromatography coupled with mass spectrometry (LC/MS) and multivariate analysis methods. L-Valine and L-tryptophan were finally identified and verified as the potential biomarkers. A prediction model constructed with L-valine and L-tryptophan correctly identified approximately 80% of patients who were non-response to chemotherapy and 87% of patients who were had a pathologically complete response to chemotherapy. The model has an excellent discriminant performance with an AUC of 0.9407. These results show promise for larger studies that could produce more personalized treatment protocols for cervical cancer patients.

目的 探讨orthogonal projection to latent structures(OPLS)方法的原理、特点及其在代谢组学高维数据分析中的应用.方法 通过R语言编程实现OPLS方法,利用模拟试验探索OPLS的特性及适用条件,并通过实际数据进行验证.结果 利用一个OPLS预测主成分的模型拟合效果与利用偏最小二乘(PLS)多个主成分的模型拟合效果相同,同时具有较好的判别能力,其得分图的可视化效果优于PLS.结论 OPLS能够有效去除自变量矩阵X中与因变量y无关的信息,使模型变得简单、易于解释,同时具有较好的可视化效果,可有效地用于代谢组学数据分析中.

Objective To explore the influence of the wavelet transformation on the signal decomposition of ultra performance liquid chromatography. Methods We use different continuous wavelet base functions with scales changing for the chromatographic data from ovarian cancer and benign tumors,and random forest model is used to conduct feature selection for training samples and discriminate analysis for test samples,then the area under the ROC curve is calculated. Results The classification performance with the wavelet transformation data is better than with the original data,where the performance with the Mexican hat wavelet is better than other wavelet base functions. Conclusion The feature selection method based on the continuous wavelet transformation and the discrimination model can significantly improve the classification ability and is worthy of further study.

MRI does not always reflect tumor response after chemotherapy. Therefore, it is necessary to explore additional parameters to more accurately evaluate tumor response for the subsequent clinical determination about radiotherapy or radical surgery. A training cohort and an external validation cohort were used to examine the predictive performance of SCC-ag to evaluate tumor response from teaching hospital of Harbin Medical University. The study included 397 women with SCC (age: 28-73 years). Patients consecutively enrolled between August 2008 and January 2010 (n = 205) were used as training cohort. Patients consecutively enrolled between February 2010 and May 2011 (n = 192) were used as validation cohort. A multivariate regression analysis of the data from the training cohort indicated that serum SCC-ag level is an independent factor for neo-adjuvant chemotherapy (NACT) response. Analysis of the data from the validation cohort suggested that chemotherapy response could be more accurately predicted by SCC-ag than by magnetic resonance imaging (MRI) (sensitivity (Se): 0.944 vs. 0.794; specificity (Sp): 0.727 vs. 0.636; positive predictive value (PPV): 0.869 vs. 0.806; negative predictive value (NPV): 0.873 vs. 0.618; the area under ROC curve (AUC): 0.898 vs. 0.734). Combining SCC-ag with MRI was more powerful than MRI alone (Se: 0.952 vs. 0.794; Sp: 0.833 vs. 0.636; PPV: 0.916 vs. 0.806; NPV: 0.902 vs. 0.618; AUC: 0.950 vs. 0.734). Our study indicates that serum SCC-ag level is a sensitive and reliable measure to evaluate cervical cancer response to chemotherapy. Using SCC-ag in combination with MRI findings further improves the predictive power.