Blinding assessment in clinical trials of traditional Chinese medicine: Exploratory principles and protocol.

As one of the key components of clinical trials, blinding, if successfully implemented, can help to mitigate the risks of implementation bias and measurement bias, consequently improving the validity and reliability of the trial results. However, successful blinding in clinical trials of traditional Chinese medicine (TCM) is hard to achieve, and the evaluation of blinding success through blinding assessment lacks established guidelines. Taking into account the challenges associated with blinding in the TCM field, here we present a framework for assessing blinding. Further, this study proposes a blinding assessment protocol for TCM clinical trials, building upon the framework and the existing methods. An assessment report checklist and an approach for evaluating the assessment results are presented based on the proposed protocol. It is anticipated that these improvements to blinding assessment will generate greater awareness among researchers, facilitate the standardization of blinding, and augment the blinding effectiveness. The use of this blinding assessment may further advance the quality and precision of TCM clinical trials and improve the accuracy of the trial results. The blinding assessment protocol will undergo continued optimization and refinement, drawing upon expert consensus and experience derived from clinical trials. Please cite this article as: Wang XC, Liu XY, Shi KL, Meng QG, Yu YF, Wang SY, Wang J, Qu C, Lei C, Yu XP. Blinding assessment in clinical trials of traditional Chinese medicine: Exploratory principles and protocol. J Integr Med. 2023; 21(6): 528-536.

Assessing household financial burdens for preprimary education and associated socioeconomic inequalities: a case study in China.

BACKGROUND: Providing young children with universal access to preprimary education (PPE) is considered a powerful tool for human capital development and eliminating the intergenerational transmission of poverty. To remove household financial barrier for achieving universal PPE, this study proposed a measure to identify households incurring 'heavy financial burdens from paying for PPE' (HBPPE) and conducted a case study in China. METHODS: Using nationally representative data in 2019, we estimated the percentage of households with HBPPE (spent 7% or more of their total annual expenditure) and associated socioeconomic inequalities. We also applied a three-level logit regression model to investigate the factors associated with the probabilities of households incurring HBPPE. RESULTS: Half of the sampled households spent 7% or more of their expenditures on PPE. Households in the lowest wealth quintile (54%) or households with children attending private PPE (55%) had higher percentages of HBPPE than households in other wealth quintiles (eg, 51% in the highest wealth quintile) or households with children attending public kindergartens (41%). Logit regression analysis shows that the poorest households and households with children attending private kindergarten were more likely to incur HBPPE than their counterparts. CONCLUSION: To ensuring universal access to PPE in China, future policy should consider increasing the enrolment of children from low-income families in public kindergartens and increasing governmental investments in low-income households by subsidising children attending PPE.

Cost-Optimization-Based Quantum Key Distribution over Quantum Key Pool Optical Networks.

The Measurement-Device-Independent-Quantum Key Distribution (MDI-QKD) has the advantage of extending the secure transmission distances. The MDI-QKD combined with the Hybrid-Trusted and Untrusted Relay (HTUR) is used to deploy large-scale QKD networks, which effectively saves deployment cost. We propose an improved scheme for the QKD network architecture and cost analysis, which simplifies the number of QKD transmitters and incorporates the quantum key pool (QKP) in the QKD network. We developed a novel Hybrid-QKD-Network-Cost (HQNC) heuristic algorithm to solve the cost optimization problem. Simulations verified that the scheme in this paper could save the cost by over 50 percent and 90 percent, respectively.

[Distribution Characteristics and Ecological Risk Assessment of Soil Heavy Metals in Baiyangdian Lake].

To understand the spatial distribution characteristics and potential ecological risk of heavy metals in soil of Baiyangdian Lake, 55 soil samples were collected and the contents of eight heavy metals (Mn, Cr, Cu, Zn, As, Cd, Pb, and Ni) were detected. The spatial variation structure and distribution pattern were analyzed using geostatistical methods (Moran index and semi-variance model). The degree of heavy metal pollution and its risk were assessed using the geoaccumulation index (Igeo) and potential ecological risk index (Eri and RI). The results showed that the average of ω(Mn), ω(Cr), ω(Cu), ω(Zn), ω(As), ω(Cd), ω(Pb), and ω(Ni) were 467.75, 43.59, 28.57, 89.04, 12.32, 0.18, 19.26, and 30.56 mg·kg-1, respectively, all of which were lower than the screening values of soil pollution risk in agricultural land. However, the contents of Cu, Zn, and Cd were significantly higher than their background values, with two highly variable elements of Cu (48.65%) and Cd (37.52%). The Moran index indicated that Mn, Cu, Cd, and Pb showed weak spatial autocorrelation. Nugget coefficients of both of Cd and Pb shown by the semi-variance model were 100%, suggesting random variation as a main spatial variation driven by anthropogenic factors. High values of soil heavy metals were mainly distributed in the southwest of Baiyangdian Lake with a significant correlation between the heavy metals. The Igeo of soil heavy metals from high to low was Cd>Cu>Zn>Ni>As>Pb>Mn>Cr. Cd pollution was the most common, in which 67.27% of the samples were lightly polluted. Ecological risk assessment revealed that the average Eri of Cd was 58.81, belonging to the middle ecological risk level, and the rest were at light ecological risk. As a whole, the RI of soil heavy metal pollution in Baiyangdian Lake was at a light ecological risk level (87.81), with the highest contribution rate of Cd to RI (66.39%). Thus, it is necessary to strengthen the control of soil heavy metal Cd pollution in Baiyangdian Lake in the future.

[Risk Assessment and Attribution Analysis of "Five Toxic" Heavy Metals in Cultivated Land in Lanzhou].

Heavy metals in cultivated soil may migrate and transform through the food chain to harm the ecological environment and human health. At present, the ecological environment and human health risks of heavy metals in cultivated soil in Lanzhou city remain unclear, which impacts the effective management and control of heavy metals. The potential ecological risk hazard index was used to evaluate the ecological environmental risks of As, Cd, Cr, Hg, and Pb in the surface soil of cultivated land in Lanzhou, and the health risk model proposed by USEPA and the recommended standard were used to evaluate their human health risk. The main factors influencing the spatial differentiation of human health risk were explored by using geographic detectors. The risk of heavy metals to the ecological environment of the cultivated land surface soil in the study area was mainly medium (65.25%), and small portions were low (13.80%) and high (20.95%). The low-risk areas were mainly located in the southeast of Yongdeng County, the middle and north of Yuzhong County, and the southwest of Gaolan County. Moderate risk areas were distributed in three counties and five districts. The high-risk areas were located in the north and southeast of Yongdeng County, the south of Chengguan District, the northeast of Qilihe, the east of Xigu District, and the middle of Yuzhong County. The non-carcinogenic and carcinogenic risks of five types of heavy metal exposure pathways were as follows:oral ingestion>skin contact>respiratory ingestion; generally speaking, children were at higher risk than adults. The non-carcinogenic risk in children was higher than that in adults; however, there was no such risk for local residents, as they were all less than 1. At the same time, the carcinogenic risk of As was greater than 1×10-5 (children 2.04×10-5) and less than 1×10-4 (adults 1.91×10-5), respectively. This indicated an acceptable medium risk to the local residents, and the risk to children was again greater than that to adults. Geographical detector analysis showed that average precipitation during the sampling season had the greatest impact on the spatial differentiation of human health risks of As and Cd, GDP had the greatest impact on the spatial differentiation of human health risks of Cr, and distance from the railway had the greatest impact on the spatial differentiation of human health risks of Hg and Pb. Interaction detection showed that all factors were enhanced by double factors. In addition to leading factors, other factors such as pH, slope, and altitude also enhanced the influence of leading factors on the spatial differentiation of heavy metal risk in cultivated soil.

Prediction of patient outcomes through social determinants of health: The Pulmonary Hypertension Association Registry (PHAR) evaluation.

Outcomes of patients with pulmonary arterial hypertension (PAH) may be associated with social determinants of health (SDOH) and other baseline patient characteristics. At present, there is no prognostic model to predict important patient outcomes in PAH based on SDOH. Utilizing information from the Pulmonary Hypertension Association Registry (PHAR), we derive a model (PHAR Evaluation or PHARE) to predict an important composite patient outcomes based on SDOH and other patient characteristics. Baseline data regarding SDOH from adult patients with PAH enrolled in the PHAR between 2015 and March 23, 2020, were included for analysis. We performed repeated measures logistic regression modeling with dichotomous outcome data (0 for no events, 1 for one or more events) to derive the PHARE. Here, 1275 consecutive adult patients enrolled in the PHAR from 47 participating centers were included. Variables included in our model are race, gender, ethnicity, household income, level of education, age, body mass index, drug use, alcohol use, marital status, and type of health insurance. Interaction effect between variables was analyzed and several interactions were also included in the PHARE. The PHARE shows a c-statistic of 0.608 (p < 0.0001) with 95% confidence intervals (0.583, 0.632). Using SDOH and baseline characteristics from the PHAR, the PHARE correlates with our composite patient outcome. Further work evaluating the role of SDOH in prognostic modeling of PAH is indicated.

Interleukin-1 blockade in cardiac sarcoidosis: study design of the multimodality assessment of granulomas in cardiac sarcoidosis: Anakinra Randomized Trial (MAGiC-ART).

BACKGROUND: Sarcoidosis is an inflammatory disease characterized by the formation of granulomas, which involve the heart in up to 25% of patients. Cardiac sarcoidosis can lead to life threatening arrhythmias and heart failure. While corticosteroids have been used as a treatment for over 50 years, they are associated with hypertension, diabetes, and weight gain, further increasing cardiovascular risk. Interleukin-1 (IL-1) is the prototypical proinflammatory cytokine that works to activate the nuclear transcription factor NF-kB, one of the targets of glucocorticoids. IL-1 also plays an important role also in the pathophysiology of heart disease including atherosclerosis, myocardial infarction, and myocarditis. METHODS: Building on a network of research collaborators developed in the Cardiac Sarcoidosis Consortium, we will investigate the feasibility and tolerability of treatment of CS with anakinra at two National Institute of Health Clinical and Translational Science Award (CTSA) hubs with expertise in cardiac sarcoidosis. In this pilot study, up to 28 patients with cardiac sarcoidosis will be recruited to compare the administration of an IL-1 blocker, anakinra, 100 mg daily on top of standard of care versus standard of care only for 28 days and followed for 180 days. Utilizing surrogate endpoints of changes in systemic inflammatory biomarkers and cardiac imaging, we aim to determine whether IL-1 blockade with anakinra can combat systemic and cardiac inflammation in patients with cardiac sarcoidosis. DISCUSSION: The current trial demonstrates an innovative collaborative approach to clinical trial development in a rare, understudied disease that disproportionately affects females and minorities. Trial Registration The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936.

Assessing the Inequality of Early Child Development in China - A Population-Based Study.

BACKGROUND: As a country with the second largest child population in the world, China has little population-level evidence on who has been left behind in early childhood development (ECD). Knowledge of inequalities in ECD will inform the Chinese government in policies on promoting ECD and guide global-level monitoring on ECD progress. METHODS: Using data from the first wave of ECD surveys conducted in China at the least-developed region, most-developed region, and a megacity (Shanghai) in 2017 and 2018, we measured population-level ECD with early Human Capability Index for a total of 63,559 children aged 36-59 months old. A child was classified as developmentally on track if his/her overall development score was above the 20th percentile of the pooled populations. We measured inequalities in ECD with the absolute inequality in five domains: gender/sex, family income, maternal schooling, residential Hukou, and migrant- or left-behind status. Besides observed inequalities, we used a multilevel logistic regression model to generate adjusted inequalities. FINDINGS: Children developmentally on track ranges from 71% (95% CI 70 to 72%) in the least-developed region, 82% (95% CI 81 to 83%) in the most-developed region, and 86% (95% CI 85 to 87%) in Shanghai. Significant unadjusted inequalities in ECD were observed in all five dimensions. After controlling for other socioeconomic factors, significant differences remained in three dimensions: those living in the poorest families, or with lower maternal schooling, or boys were less likely to be developmentally on track than their counterparts (lower by 10[95% CI 8 to 11]-15[95% CI 13 to 17], 7[95% CI 5 to 10]-10[95% CI 7 to 12], and 5[95% CI 4 to 6]-6[95% CI 5 to 8] percentage points respectively). INTERPRETATION: Efforts of reducing ECD inequalities in China shall focus primarily on reducing poverty and improving maternal education. FUNDING: National Natural Science Foundation of China (81773443), Shanghai Committee of Science and Technology (2018SHZDZX05), Shanghai Municipal Health Commission (GWV-10.1-XK07; GDEK201708), Shanghai Education Committee, Chinese Social Science Foundation (BFA140046), Macao Tong Chai Charity Association, Beijing Sany Charitable Foundation, China Medical Board (#20-388), UNICEF, Faculty Grant of Brigham & Women's Hospital, Economic and Social Research Council [grant reference number ES/T003936/1'] as a UKRI Collective Fund Award "UKRI GCRF Harnessing the Power of Global Data to Support Young Children's Learning and Development Collaborative."

Special Significance of Non-Drosophila Insects in Aging.

Aging is the leading risk factor of human chronic diseases. Understanding of aging process and mechanisms facilitates drug development and the prevention of aging-related diseases. Although many aging studies focus on fruit fly as a canonical insect system, minimal attention is paid to the potentially significant roles of other insects in aging research. As the most diverse group of animals, insects provide many aging types and important complementary systems for aging studies. Insect polyphenism represents a striking example of the natural variation in longevity and aging rate. The extreme intraspecific variations in the lifespan of social insects offer an opportunity to study how aging is differentially regulated by social factors. Insect flight, as an extremely high-intensity physical activity, is suitable for the investigation of the complex relationship between metabolic rate, oxidative stress, and aging. Moreover, as a "non-aging" state, insect diapause not only slows aging process during diapause phase but also affects adult longevity during/after diapause. In the past two decades, considerable progress has been made in understanding the molecular basis of aging regulation in insects. Herein, the recent research progress in non-Drosophila insect aging was reviewed, and its potential utilization in aging in the future was discussed.

Endoscopic Cyanoacrylate Injection with Post-injection Audible Doppler Assessment of Gastric Varices: A Single-Institution Experience.

BACKGROUND AND AIMS: Gastric varices (GV) have higher rates of morbidity and mortality from hemorrhage than esophageal varices. Several studies have shown the safety and efficacy of cyanoacrylate (CA) injection for acute gastric variceal hemorrhage. We report data from our experience with CA injection for GV before and after routine use of post-injection audible Doppler assessment (ADA) for GV obturation and describe long-term outcomes after this therapy. METHODS: We retrospectively identified patients who had documented GV, underwent CA injection, and had at least 2 weeks of follow-up. We recorded and analyzed the survival and rebleeding rates with patient demographics, clinical data, and endoscopy findings between two groups of patients who were categorized by CA injection prior to and after inception of the ADA technique. RESULTS: Seventy-one patients were identified with 16 patients analyzed in a group where ADA was not used (Pre-ADA) and 55 analyzed where ADA was used (Post-ADA). No rebleeding events were observed within 1 week of initial CA injection. No embolic events were reported after any initial CA injection within 4 weeks. The rate of bleed-free survival at 1 year was 69.6% in the Pre-ADA group and 85.8% in the Post-ADA without statistical significance. The all-cause 1-year mortality was 13.8% in the Pre-ADA group and 10.7% in the Post-ADA group without statistical significance. CONCLUSIONS: ADA of CA-injected GV does not appear to significantly affect adverse events or clinical outcomes; however, our findings are limited by small sample size and cohort proportions allowing for significant type II statistical error. Further prospective investigation is required to determine the impact of ADA on clinical outcomes after GV obturation.

Effectiveness of novel, lower cost molecular human papillomavirus-based tests for cervical cancer screening in rural china.

This study examined the efficacy of the OncoE6™ Cervical Test, careHPV™ and visual inspection with acetic acid (VIA) in identifying women at risk for cervical cancer and their capability to detect incident cervical precancer and cancer at 1-year follow-up. In a population of 7,543 women living in rural China, women provided a self-collected and two clinician-collected specimens and underwent VIA. All screen positive women for any of the tests, a ∼ 10% random sample of test-negative women that underwent colposcopy at baseline, and an additional ∼ 10% random sample of test-negative women who did not undergo colposcopy at baseline (n = 3,290) were recruited. 2,904 women were rescreened 1 year later using the same tests, colposcopic referral criteria, and procedures. Sensitivities of baseline tests to detect 1-year cumulative cervical intraepithelial neoplasia Grade 3 or cancer (CIN3+) were 96.5% and 81.6% for careHPV™ on clinician-collected and self-collected specimens, respectively, and 54.4% for OncoE6™ test. The OncoE6™ test was very specific (99.1%) and had the greatest positive predictive value (PPV; 47.7%) for CIN3+. Baseline and 1-year follow-up cervical specimens testing HPV DNA positive was sensitive (88.0%) but poorly predictive (5.5-6.0%) of incident CIN2+, whereas testing repeat HPV16, 18 and 45 E6 positive identified only 24.0% of incident CIN2+ but had a predictive value of 33.3%. This study highlights the different utility of HPV DNA and E6 tests, the former as a screening and the latter as a diagnostic test, for detection of cervical precancer and cancer.

Retroactive application of the new kidney allocation system to renal transplants performed in the ECD/SCD era.

The kidney allocation system (KAS) aims to improve deceased donor kidney transplant outcomes by matching of donor allografts and kidney recipients using the kidney donor risk index (KDRI) and recipient estimated post-transplant survival (EPTS) indices. In this single-center study, KAS was retroactively applied to 573 adult deceased donor kidney transplants (2004-2012) performed in the extended criteria/standard criteria donor (ECD/SCD) era. Donor KDRI and recipient EPTS were calculated, and transplants were analyzed to identify KAS fits. These were defined as allocation of top 20% allografts to top 20% recipients and bottom 80% allografts to bottom 80% recipients. On retroactive calculation, 70.2% of all transplants fit the KAS. Transplants that fit the KAS had inferior 1- and 5-yr patient survival (95.5% vs. 98.8%, p = 0.048, and 83.4% vs. 91.7%, p = 0.018) and similar 1- and 5-yr graft survival compared to transplants that did not fit the KAS (91.3% vs. 94.1%, p = 0.276, and 72.7% vs. 73.9%, p = 0.561). While EPTS correlated with recipient survival (HR = 2.96, p < 0.001), KDRI correlated with both recipient (HR = 3.56, p < 0.001) and graft survival (HR = 3.23, p < 0.001). Overall, retroactive application of the KAS to transplants performed in the ECD/SCD era did not identify superior patient survival for kidneys allocated in accordance with the KAS.

Strategies to alleviate poverty and grassland degradation in Inner Mongolia: intensification vs production efficiency of livestock systems.

Semi-nomadic pastoralism was replaced by sedentary pastoralism in Inner Mongolia during the 1960's in response to changes in land use policy and increasing human population. Large increases in numbers of livestock and pastoralist households (11- and 9-fold, respectively) during the past 60 yrs have variously degraded the majority of grasslands in Inner Mongolia (78 M ha) and jeopardize the livelihoods of 24 M human inhabitants. A prevailing strategy for alleviating poverty and grassland degradation emphasizes intensification of livestock production systems to maintain both pastoral livelihoods and large livestock numbers. We consider this strategy unsustainable because maximization of livestock revenue incurs high supplemental feed costs, marginalizes net household income, and promotes larger flock sizes to create a positive feedback loop driving grassland degradation. We offer an alternative strategy that increases both livestock production efficiency and net pastoral income by marketing high quality animal products to an increasing affluent Chinese economy while simultaneously reducing livestock impacts on grasslands. We further caution that this strategy be designed and assessed within a social-ecological framework capable of coordinating market expansion for livestock products, sustainable livestock carrying capacities, modified pastoral perceptions of success, and incentives for ecosystem services to interrupt the positive feedback loop that exists between subsistence pastoralism and grassland degradation in Inner Mongolia.

Lower cost strategies for triage of human papillomavirus DNA-positive women.

Using human papillomavirus (HPV) testing for cervical cancer screening in lower-resource settings (LRS) will result in a significant number of screen-positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV-positive women in LRS. This was a population-based study of women aged 25-65 years living in China (n = 7,541). Each woman provided a self-collected and two clinician-collected specimens. The self-collected and one clinician-collected specimen were tested by two HPV DNA tests-careHPV™ and Hybrid Capture 2; the other clinician-collected specimen was tested for HPV16/18/45 E6 protein. CareHPV™-positive specimens were tested for HPV16/18/45 DNA. HPV DNA-positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA-positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8-17.4% for VIA, 17.8-20.9% for an abnormal colposcopic impression; 7.9-10.5% for HPV16/18/45 E6; 23.4-28.4% for HPV16/18/45 DNA; and 48.0-62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA-positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.

A fast Monte Carlo EM algorithm for estimation in latent class model analysis with an application to assess diagnostic accuracy for cervical neoplasia in women with AGC.

In this article we use a latent class model (LCM) with prevalence modeled as a function of covariates to assess diagnostic test accuracy in situations where the true disease status is not observed, but observations on three or more conditionally independent diagnostic tests are available. A fast Monte Carlo EM (MCEM) algorithm with binary (disease) diagnostic data is implemented to estimate parameters of interest; namely, sensitivity, specificity, and prevalence of the disease as a function of covariates. To obtain standard errors for confidence interval construction of estimated parameters, the missing information principle is applied to adjust information matrix estimates. We compare the adjusted information matrix based standard error estimates with the bootstrap standard error estimates both obtained using the fast MCEM algorithm through an extensive Monte Carlo study. Simulation demonstrates that the adjusted information matrix approach estimates the standard error similarly with the bootstrap methods under certain scenarios. The bootstrap percentile intervals have satisfactory coverage probabilities. We then apply the LCM analysis to a real data set of 122 subjects from a Gynecologic Oncology Group (GOG) study of significant cervical lesion (S-CL) diagnosis in women with atypical glandular cells of undetermined significance (AGC) to compare the diagnostic accuracy of a histology-based evaluation, a CA-IX biomarker-based test and a human papillomavirus (HPV) DNA test.

On the assessment of the added value of new predictive biomarkers.

BACKGROUND: The surge in biomarker development calls for research on statistical evaluation methodology to rigorously assess emerging biomarkers and classification models. Recently, several authors reported the puzzling observation that, in assessing the added value of new biomarkers to existing ones in a logistic regression model, statistical significance of new predictor variables does not necessarily translate into a statistically significant increase in the area under the ROC curve (AUC). Vickers et al. concluded that this inconsistency is because AUC "has vastly inferior statistical properties," i.e., it is extremely conservative. This statement is based on simulations that misuse the DeLong et al. method. Our purpose is to provide a fair comparison of the likelihood ratio (LR) test and the Wald test versus diagnostic accuracy (AUC) tests. DISCUSSION: We present a test to compare ideal AUCs of nested linear discriminant functions via an F test. We compare it with the LR test and the Wald test for the logistic regression model. The null hypotheses of these three tests are equivalent; however, the F test is an exact test whereas the LR test and the Wald test are asymptotic tests. Our simulation shows that the F test has the nominal type I error even with a small sample size. Our results also indicate that the LR test and the Wald test have inflated type I errors when the sample size is small, while the type I error converges to the nominal value asymptotically with increasing sample size as expected. We further show that the DeLong et al. method tests a different hypothesis and has the nominal type I error when it is used within its designed scope. Finally, we summarize the pros and cons of all four methods we consider in this paper. SUMMARY: We show that there is nothing inherently less powerful or disagreeable about ROC analysis for showing the usefulness of new biomarkers or characterizing the performance of classification models. Each statistical method for assessing biomarkers and classification models has its own strengths and weaknesses. Investigators need to choose methods based on the assessment purpose, the biomarker development phase at which the assessment is being performed, the available patient data, and the validity of assumptions behind the methodologies.

An evaluation of novel, lower-cost molecular screening tests for human papillomavirus in rural China.

New, lower-cost tests that target high-risk human papillomavirus (HR-HPV) have been developed for cervical cancer screening in lower-resource settings but large, population-based screening studies are lacking. Women ages 25 to 65 years and living in rural China (n = 7,543) self-collected a cervicovaginal specimen, had 2 cervical specimens collected by a clinician, and underwent visual inspection after acetic acid (VIA). The self- and one clinician-collected specimens underwent HR-HPV DNA testing by careHPV (QIAGEN) and Hybrid Capture 2 (HC2; QIAGEN) and the other clinician-collected specimen was tested for HPV16, 18, and 45 E6 using OncoE6 (Arbor Vita Corporation). Women who screened positive for any test and a random sample of those negative on all tests underwent colposcopic evaluation. The percent test positive was 1.8% for HPV E6 oncoprotein, between 14% and 18% for HR-HPV DNA testing, and 7.3% for VIA. The sensitivity for cervical intraepithelial neoplasia grade 3 or more severe (CIN3(+); n = 99) was 53.5% for OncoE6, 97.0% for both careHPV and HC2 testing of the clinician-collected specimen, 83.8% for careHPV testing and 90.9% for HC2 testing of the self-collected specimen, and 50.5% for VIA. OncoE6 had the greatest positive predictive value (PPV), at 40.8% for CIN3(+), compared with the other tests, which had a PPV of less than 10%. OncoE6 tested 70.3% positive for HPV16, 18, or 45-positive CIN3(+) and tested negative for all HPV16-, 18-, or 45-negative CIN3(+) (P < 0.0001). HPV E6 oncoprotein detection is useful for identifying women who have cervical precancer and cancer.

A modified Latent Class Model assessment of human papillomavirus-based screening tests for cervical lesions in women with atypical glandular cells: a Gynecologic Oncology Group study.

PURPOSE: In the absence of gold standard diagnoses, we estimate age-specific false-positive and false-negative prediction rates of HPV-, cytology-, and histology-based tests for significant cervical lesions (SCL) in US women with AGC-NOS Pap smear diagnoses. METHODS: Modified Latent Class Model (LCM) analyses, with prevalence of SCL modeled as a function of age, were applied to GOG-0171 study data (n = 122). The accuracies of several HPV-based tests, including Hybrid Capture II high-risk HPV (HC2 H-HPV); carbonic anhydrase IX (CA-IX); and invasive histological diagnosis, were compared. 1-PPV and 1-NPV were written as functions of sensitivity, specificity, and prevalence to obtain age-specific false-positive and false-negative rates. RESULTS: The histology-based test was nearly perfect (sensitivity = 1.00, CI = 0.98-1.00; specificity = 0.99, CI = 0.96-1.00). Otherwise, HC2 H-HPV performed best (sensitivity = 1.00, CI = 1.00-1.00; specificity = 0.87, CI = 0.79-0.94). The false-positive detection rates (1-PPV) for HC2 H-HPV were high (>17 %) at each age, while those of the histological diagnoses were low (<5 % at ages ≤60 and <17 % overall ages). False-negative prediction rates (1-NPV) for HC2 H-HPV were <0.11 % at each age and were uniformly lower than those of other tests, including the histology-based test (<0.25 %). CA-IX together with HC2 H-HPV did not improve performance. CONCLUSIONS: Women with negative HC2 H-HPV can safely forego invasive treatment (i.e., cone or LEEP biopsy, hysterectomy) in favor of observational follow-up. Additional biomarkers must be found for use in combination with HC2 H-HPV to reduce false-positive rates. This novel application of a modified LCM exemplifies methods for potential use in future cancer screening studies when gold standard diagnoses are not available.

Empirical and parametric likelihood interval estimation for populations with many zero values: application for assessing environmental chemical concentrations and reproductive health.

BACKGROUND: Understanding the health effects associated with environmental chemicals is challenging when individuals have concentrations at or below the laboratory limits of detection as well as when the values may round to zero or are presented in the form of 0 to substitute for missing values, which may result in many zeros in the database. Comparison of mean concentrations between individuals with and without disease necessitates estimation procedures that allow for data with many zero values. The main aim of this article is to propose and examine parametric and distribution-free methods for comparing data sets containing many zero observations. An important application of this approach is related to assessing environmental chemical concentrations and reproductive health. METHODS: We extended the empirical likelihood technique for estimating confidence intervals (CIs) in data sets with many zeros. We examined the proposed empirical likelihood interval estimations via a broad Monte Carlo study that compares the proposed method with parametric techniques. Certain characteristics of Monte Carlo simulations were chosen to be close to parameters of the real data set. We applied the method to a cohort study comprising 84 women aged 18-40 years who had undergone laparoscopy between 1999 and 2000 in whom serum concentrations of 2 organochlorine pesticides--Aldrin and beta-Benzene hexachloride (ß-BHC) were measured using gas chromatography with electron capture. RESULTS: When applied to the cohort study, the method produced efficient 95% CIs, allowing for the comparison of mean serum Aldrin concentrations for women with and without endometriosis (0.000338, 0.003561) and (0.000803, 0.004211), respectively. Mean ß-BHC concentrations also could be compared (0.000493, 0.005869) and (0.000680, 0.003807) based on individuals with and without the disease, respectively. Differences in mean concentrations for Aldrin and ß-BHC could be estimated (-0.001563, 0.003025) and (-0.003522, 0.002890), respectively. CONCLUSIONS: We found the empirical likelihood method for estimating CIs robust when data sets contain many zeros. In so doing, mean concentrations of Aldrin or ß-BHC did not differ by endometriosis diagnosis.