Maximizing the Value of Real-World Data and Real-World Evidence to Accelerate Healthcare Transformation in China: Summary of External Advisory Committee Meetings.

Use of real-world data (RWD) is gaining wide attention. To bridge the gap between diverse healthcare stakeholders and to leverage the impact of Chinese real-world evidence (RWE) globally, a multi-stakeholder External Advisory Committee (EAC) and EAC meetings were initiated, aiming to elucidate the current and evolving RWD landscape in China, articulate the values of RWE in ensuring Chinese patients' equitable access to affordable medicines and solutions, and identify strategic opportunities and partnerships for expansion of RWE generation in China. Chinese and international experts who are clinicians and academic researchers were selected as EAC members based on their professional background and familiarity with RWD/RWE. Three EAC meetings were held quarterly in 2023. Various topics were presented and discussed for insights and suggestions. Nine experts from China, one from South Korea, and two from Europe were selected as EAC members and attended these meetings. Experts' presentations were summarized by theme, including the RWD landscape and RWE enablement in China, as well as global development of a patient-centric ecosystem. Experts' insights and suggestions on maximizing the RWD/RWE value to accelerate healthcare transformation in China were collected. We concluded that though data access, sharing, and quality are still challenging, RWD is developing to support evidence generation in the medicinal product lifecycle, inform clinical practice, and empower patient management in China. RWD/RWE creates value, accelerates healthcare transformation, and improves patient outcomes. Fostering a patient-centric ecosystem across healthcare stakeholders and maintaining global partnerships and collaboration are essential for unlocking the power of RWD/RWE.

Effectiveness of Levoamlodipine Maleate for Hypertension Compared with Amlodipine Besylate: a Pragmatic Comparative Effectiveness Study.

PURPOSE: Antihypertensive treatment is the most important method to reduce the risk of cardiovascular events in hypertensive patients. However, there is scant evidence of the benefits of levoamlodipine maleate for antihypertensive treatment using a head-to-head comparison in the real-world. This study aims to examine the effectiveness of levoamlodipine maleate used to treat outpatients with primary hypertension compared with amlodipine besylate in a real-world setting. METHODS: This was a pragmatic comparative effectiveness study carried out at 110 centers across China in outpatients with primary hypertension treated with levoamlodipine maleate or amlodipine besylate, with 24 months of follow-up. The primary outcomes used for evaluating the effectiveness were composite major cardiovascular and cerebrovascular events (MACCE), adverse reactions, and cost-effectiveness. RESULTS: Among the included 10,031 patients, there were 482 MACCE, 223 (4.4%) in the levoamlodipine maleate group (n = 5018) and 259 (5.2%) in the amlodipine besylate group (n = 5013) (adjusted hazard ratio = 0.90, 95%CI: 0.75-1.08, P = 0.252). The levoamlodipine maleate group had lower overall incidences of any adverse reactions (6.0% vs. 8.4%, P < 0.001), lower extremity edema (1.1% vs. 3.0%, P < 0.001) and headache (0.7% vs. 1.1%, P = 0.045). There was a nearly 100% chance of the levoamlodipine maleate being cost-effective at a willingness to pay threshold of 150,000 Yuan per quality-adjusted life years (QALYs) gained, resulting in more QALYs (incremental QALYs: 0.00392) and cost savings (saving 2725 Yuan or 28.8% reduction in overall costs) per patient. CONCLUSION: In conclusion, levoamlodipine maleate could reduce cost by 29% with a similar MACCE incidence rate and lower occurrence of adverse reactions (especially edema and headache) compared with amlodipine besylate. TRIAL REGISTRATION: Clinicaltrials.gov NCT01844570 registered at May 1, 2013.

Efficient statistical tests to compare Youden index: accounting for contingency correlation.

Youden index is widely utilized in studies evaluating accuracy of diagnostic tests and performance of predictive, prognostic, or risk models. However, both one and two independent sample tests on Youden index have been derived ignoring the dependence (association) between sensitivity and specificity, resulting in potentially misleading findings. Besides, paired sample test on Youden index is currently unavailable. This article develops efficient statistical inference procedures for one sample, independent, and paired sample tests on Youden index by accounting for contingency correlation, namely associations between sensitivity and specificity and paired samples typically represented in contingency tables. For one and two independent sample tests, the variances are estimated by Delta method, and the statistical inference is based on the central limit theory, which are then verified by bootstrap estimates. For paired samples test, we show that the estimated covariance of the two sensitivities and specificities can be represented as a function of kappa statistic so the test can be readily carried out. We then show the remarkable accuracy of the estimated variance using a constrained optimization approach. Simulation is performed to evaluate the statistical properties of the derived tests. The proposed approaches yield more stable type I errors at the nominal level and substantially higher power (efficiency) than does the original Youden's approach. Therefore, the simple explicit large sample solution performs very well. Because we can readily implement the asymptotic and exact bootstrap computation with common software like R, the method is broadly applicable to the evaluation of diagnostic tests and model performance.

A powerful association test for qualitative traits incorporating imprinting effects using general pedigree data.

For qualitative traits and diallelic marker loci, the pedigree disequilibrium test (PDT) based on general pedigrees and its extension (Monte Carlo PDT (MCPDT)) for dealing with missing genotypes are simple and powerful tests for association. There is an increasing interest of incorporating imprinting into association analysis. However, PDT and MCPDT do not take account of the information on imprinting effects in the analysis, which may reduce their test powers when the effects are present. On the other hand, the transmission disequilibrium test with imprinting (TDTI*) combines imprinting into the mapping of association variants. However, TDTI* only accommodates two-generation nuclear families and thus is not suitable for extended pedigrees. In this article, we first extend PDT to incorporate imprinting and propose PDTI for complete pedigrees (no missing genotypes). To fully utilize pedigrees with missing genotypes, we further develop the Monte Carlo PDTI (MCPDTI) statistic based on Monte Carlo sampling and estimation. Both PDTI and MCPDTI are derived in a two-stage framework. Simulation study shows that PDTI and MCPDTI control the size well under the null hypothesis of no association and are more powerful than PDT and TDTI* (based on a sample of nuclear families randomly selecting from pedigrees) when imprinting effects exist.

Detection of parent-of-origin effects for quantitative traits using general pedigree data.

Genomic imprinting is a genetic phenomenon in which certain alleles are differentially expressed in a parent-of-origin-specific manner, and plays an important role in the study of complex traits. For a diallelic marker locus in human, the parentalasymmetry tests Q-PAT(c) with any constant c were developed to detect parent-of-origin effects for quantitative traits. However, these methods can only be applied to deal with nuclear families and thus are not suitable for extended pedigrees. In this study, by making no assumption about the distribution of the quantitative trait, we first propose the pedigree parentalasymmetry tests Q-PPAT(c) with any constant c for quantitative traits to test for parent-of-origin effects based on nuclear families with complete information from general pedigree data, in the presence of association between marker alleles under study and quantitative traits. When there are any genotypes missing in pedigrees, we utilize Monte Carlo (MC) sampling and estimation and develop the Q-MCPPAT(c) statistics to test for parent-of-origin effects. Various simulation studies are conducted to assess the performance of the proposed methods, for different sample sizes, genotype missing rates, degrees of imprinting effects and population models. Simulation results show that the proposed methods control the size well under the null hypothesis of no parent-of-origin effects and Q-PPAT(c) are robust to population stratification. In addition, the power comparison demonstrates that Q-PPAT(c) and Q-MCPPAT(c) for pedigree data are much more powerful than Q-PAT(c) only using two-generation nuclear families selected from extended pedigrees.

[Multiple comparisons in categorical data analysis].

OBJECTIVE: To discuss the method for multiple comparisons of categorical data and propose an approach to deal with the percentage data. METHODS: The method of multiple comparisons for percentages was verified based on Bonferroni methodology and Monte Carlo method using SAS 9.13 software. RESULTS: The type I error could be enlarged if the statistical tests were conducted without adjustment of the significant level after dividing the data of several categories or percentages into several four-fold tables. For the percentage data, the correction of adjustment of the significant level was the number of pairwise comparison minus one, as supported by the results of Monte Carlo simulation. CONCLUSION: Multiple comparisons of categorical data should be applied appropriately. Multiple comparisons of percentages data need to be conducted with the number of pairwise comparison minus one.

Postoperative pain assessment with three intensity scales in Chinese elders.

PURPOSE: To evaluate the reliability and validity of the Faces Pain Scale Revised (FPS-R), the Numeric Rating Scale (NRS), and the Iowa Pain Thermometer (IPT) for pain assessment in Chinese elders who have had surgery. DESIGN: A descriptive correlational design with repeated measures was used. A convenience sample of 180 Chinese elders (age range 65 to 95 years) undergoing scheduled surgery at a university-affiliated hospital was recruited. METHODS: On the day before surgery, recalled pain and anticipated postoperative pain intensity were rated by patients with three scales presented in randomized order, and then cognitive function was measured. On the first 3 postoperative days, participants completed the three scales in random order to assess current, worst, and least pain on each day. On the 3rd postoperative day, single retrospective ratings on worst, least, and average pain over the 3 days for each scale were also obtained and scale preferences were investigated. FINDINGS: The failure rates for all three scales were extremely low. The intraclass correlation coefficients across current, worst, and least pain on each postoperative day were consistently high (0.949 to 0.965), and all scales at each rating were strongly correlated (r=.833 to .962). Pain scores significantly decreased during the 3 postoperative days and all three scales were found to be sensitive in evaluating patient-controlled analgesia (PCA) efficacy. The scale mostly preferred was the IPT (54.7%), followed by the FPS-R (28.5%) and the NRS (15.6%). No significant differences were noted in participant preference by age and cognitive status, but preference for the IPT and the FPS-R were significantly related to gender and education level. CONCLUSIONS: Although all three scales show good reliability, validity, and sensitivity for assessing postoperative pain intensity in Chinese elders, the IPT appears to be a better choice based on patient preference. CLINICAL RELEVANCE: The FPS-R, the NRS, and the IPT can be used confidently to assess postoperative pain in Chinese surgical elders.

[Comparative assessment of clinical efficacy of percutaneous transhepatic metal versus plastic biliary stent implantation for malignant biliary obstruction: a multi-centered investigation].

OBJECTIVE: To compare the clinical efficacy of metal versus plastic biliary stent implantation for treatment of malignant biliary obstruction. METHODS: Percutaneous transhepatic implantations of self-expandable metal stent (MS, n=61) or 10F plastic stent (PS, n=34) were performed in 95 patients with malignant biliary obstruction selected from 3 hospitals of Guangdong Province. All patients were followed up until death or at least one year after the procedure. Kaplan-Meier analysis was used to compare the patients' survival and stent patency rates. RESULTS: The 30-day mortality rate was lower in MS group (6/61, 9.8%) than in PS group (9/34, 26.5%, P<0.05). The 30-day reobstruction rate and incidence of complications were 15.0%, 16.4% in MS group and 32.4%, 29.4% in PS group, respectively (P<0.01). The median patency period of the stents and median survival period of the patients were 230 d, 224 d in MS group and 90 d, 94 d in PS group, respectively (P<0.01). CONCLUSION: Metal stent implantation is superior to plastic stent for treatment of malignant biliary obstruction.