Evaluating joint confidence region of hypervolume under ROC manifold and generalized Youden index.

In biomarker evaluation/diagnostic studies, the hypervolume under the receiver operating characteristic manifold ( HUM K $$ {\mathrm{HUM}}_K $$ ) and the generalized Youden index ( J K $$ {J}_K $$ ) are the most popular measures for assessing classification accuracy under multiple classes. While HUM K $$ {\mathrm{HUM}}_K $$ is frequently used to evaluate the overall accuracy, J K $$ {J}_K $$ provides direct measure of accuracy at the optimal cut-points. Simultaneous evaluation of HUM K $$ {\mathrm{HUM}}_K $$ and J K $$ {J}_K $$ provides a comprehensive picture about the classification accuracy of the biomarker/diagnostic test under consideration. This article studies both parametric and non-parametric approaches for estimating the confidence region of HUM K $$ {\mathrm{HUM}}_K $$ and J K $$ {J}_K $$ for a single biomarker. The performances of the proposed methods are investigated by an extensive simulation study and are applied to a real data set from the Alzheimer's Disease Neuroimaging Initiative.

Medical diagnostic accuracy measures: an innovative approach based on the area under predictive values curves.

Positive and negative estimates are commonly used by clinicians to evaluate the likelihood of a disease stage being present based on test results. The predicted values are dependent on the prevalence of the underlying illness. However, for certain diseases or clinical conditions, the prevalence is unknown or different from one region to another or from one population to another, leading to an erroneous diagnosis. This article introduces innovative post-test diagnostic precision measures for continuous tests or biomarkers based on the combined areas under the predictive value curves for all possible prevalence values. The proposed measures do not vary as a function of the prevalence of the disease. They can be used to compare different diagnostic tests and/or biomarkers' abilities for rule-in, rule-out, and overall accuracy based on the combined areas under the predictive value curves. The relationship of the proposed measures to other diagnostic accuracy measures is discussed. We illustrate the proposed measures numerically and use a real data example on breast cancer.

Dose-Response Relationship between Red Blood Cell Distribution Width and In-Hospital Mortality in Oldest Old Patients with Acute Ischemic Stroke.

INTRODUCTION: It is crucial to identify predictors of mortality in the early stage of acute ischemic stroke for the oldest old (aged ≥80 years) because of their poor overall survival outcomes. However, limited data are available as the oldest old have often been excluded from previous clinical studies. Hence, we aimed to assess the predictive effect of red blood cell distribution width on in-hospital mortality and the dose-response relationship between the red blood cell distribution width and in-hospital mortality in oldest old with acute ischemic stroke. METHODS: A retrospective cohort study was performed in two tertiary hospitals. Patients aged ≥80 years admitted due to acute ischemic stroke from January 1, 2014, to January 31, 2020, were included in the study. We divided the eligible patients into 3 groups with tertiles of red blood cell distribution width. Restrictive cubic spline and robust locally weighted regression analysis were performed to test the dose-response relationship between red blood cell distribution width and the in-hospital mortality risk. All-cause in-hospital mortality was the main study outcome. RESULTS: Overall, 606 patients were included in the final analysis. Red blood cell distribution width was categorized into 3 groups (T1: <13.7%, T2: 13.8-15.7%, and T3: >15.7%). The rationality of this categorization was then validated with restricted cubic spline and robust locally regression smoothing scatterplot, respectively. After adjusting for demographic and clinical features, a higher red blood cell distribution width was independently associated with in-hospital mortality and the hazard ratio (HR) was 3.31 (95% CI 2.47-4.45, p < 0.001). There was a positive dose-response relationship between red blood cell distribution width and mortality risk. Sensitivity analysis identified no conspicuous change in the HR. CONCLUSIONS: Red blood cell distribution width may be a valuable and simple measure for predicting in-hospital mortality in oldest old patients with acute ischemic stroke.

Net benefit of diagnostic tests for multistate diseases: an indicator variables approach.

A limitation of the common measures of diagnostic test performance, such as sensitivity and specificity, is that they do not consider the relative importance of false negative and false positive test results, which are likely to have different clinical consequences. Therefore, the use of classification or prediction measures alone to compare diagnostic tests or biomarkers can be inconclusive for clinicians. Comparing tests on net benefit can be more conclusive because clinical consequences of misdiagnoses are considered. The literature suggested evaluating the binary diagnostic tests based on net benefit, but did not consider diagnostic tests that classify more than two disease states, e.g., stroke subtype (large-artery atherosclerosis, cardioembolism, small-vessel occlusion, stroke of other determined etiology, stroke of undetermined etiology), skin lesion subtype, breast cancer subtypes (benign, mass, calcification, architectural distortion, etc.), METAVIR liver fibrosis state (F0- F4), histopathological classification of cervical intraepithelial neoplasia (CIN), prostate Gleason grade, brain injury (intracranial hemorrhage, mass effect, midline shift, cranial fracture) . Other diseases have more than two stages, such as Alzheimer's disease (dementia due to Alzheimer's disease, mild cognitive disability (MCI) due to Alzheimer's disease, and preclinical presymptomatics due to Alzheimer's disease). In diseases with more than two states, the benefits and risks may vary between states. This paper extends the net-benefit approach of evaluating binary diagnostic tests to multi-state clinical conditions to rule-in or rule-out a clinical condition based on adverse consequences of work-up delay (due to false negative test result) and unnecessary workup (due to false positive test result). We demonstrate our approach with numerical examples and real data.

Estimation of gastric cancer burden attributable to Helicobacter pylori infection in Asia.

BACKGROUND: Helicobacter pylori causes large burden of gastric cancer (GC) in Asia. We aimed to comprehensively quantify the burden of GC attributable to H. pylori infection in Asia. METHODS: We searched related articles from January 1998 to December 2020 to obtain the prevalence and relative risks (or odds ratio) of GC associated with H. pylori in Asia. The burden of GC attributable to H. pylori infection was quantified by Population Attributable Fraction (PAF) and Disability-adjusted life-years (DALYs). RESULTS: We quantified the burden of GC attributable to H. pylori infection with 415.6 thousand DALYs and 38.03% PAF through the five included Asian countries in 2019. The study found that the burden had obvious regional differences. The DALYs ranged from 298.9 thousand in China to 1.9 thousand in Malaysia, and the PAFs were between 58.00% in Japan and 30.89% in China. The average prevalence of H. pylori in the included general population was estimated to be 56.29%. CONCLUSIONS: Helicobacter pylori poses a huge disease burden of GC to the population, and its eradication should receive attention, especially in the countries with high incidence of and mortality due to GC.

Immunomodulatory effect of IL-2 induced bone marrow mononuclear cell therapy on control of allergic asthma.

Asthma is a chronic airway disease. Allergic reactions and T helper (h)2 immune response play a key role in asthma occurrence. Cell therapy can control inflammation and remodeling responses in allergic asthma, and cytokines can change this effect. Therefore, in this study, the effect of treated cell therapy with IL-2 to control allergic asthma was studied. Bone marrow cells were extracted and co-cultured with IL-2 and the cells were used via intra-tracheal administration in allergic asthma mice. Levels of IL-4, IL-5, IL-13, Leukotriene B4 and C4, and remodeling factors were measured. At least, a histopathology test of lung tissue was done. Type2 cytokines, leukotrienes, remodeling factors, mucus secretion, goblet cell hyperplasia, peri-bronchial and peri-vascular inflammation were significantly (p˂0.05) decreased by treating with bone marrow-derived mononuclear cells (BMDMCs) and IL-2-BMDMCs. Treatment with IL-2-BMDMCs could significantly decrease IL-13, transforming growth factor (TGF)-ß, HP levels, and mucus secretion (p˂0.05) compared to BMDMCs treatment. In this study, BMDMCs and IL-2-BMDMCs therapy could decrease inflammation, allergic, and remodeling factors in allergic asthma. Cell therapy with BMDMCs had a strong and notable effect on the control of allergic asthma pathophysiology when co-cultured and used with IL-2.

Turnover, COVID-19, and Reasons for Leaving and Staying Within Governmental Public Health.

BACKGROUND AND OBJECTIVES: Public health workforce recruitment and retention continue to challenge public health agencies. This study aims to describe the trends in intention to leave and retire and analyze factors associated with intentions to leave and intentions to stay. DESIGN: Using national-level data from the 2017 and 2021 Public Health Workforce Interests and Needs Surveys, bivariate analyses of intent to leave were conducted using a Rao-Scott adjusted chi-square and multivariate analysis using logistic regression models. RESULTS: In 2021, 20% of employees planned to retire and 30% were considering leaving. In contrast, 23% of employees planned to retire and 28% considered leaving in 2017. The factors associated with intentions to leave included job dissatisfaction, with adjusted odds ratio (AOR) of 3.8 (95% CI, 3.52-4.22) for individuals who were very dissatisfied or dissatisfied. Odds of intending to leave were significantly high for employees with pay dissatisfaction (AOR = 1.83; 95% CI, 1.59-2.11), those younger than 36 years (AOR = 1.58; 95% CI, 1.44-1.73) or 65+ years of age (AOR = 2.80; 95% CI, 2.36-3.33), those with a graduate degree (AOR = 1.14; 95% CI, 1.03-1.26), those hired for COVID-19 response (AOR = 1.74; 95% CI, 1.49-2.03), and for the BIPOC (Black, Indigenous, and people of color) (vs White) staff (AOR = 1.07; 95% CI, 1.01-1.15). The leading reasons for employees' intention to stay included benefits such as retirement, job stability, flexibility (eg, flex hours/telework), and satisfaction with one's supervisor. CONCLUSIONS: Given the cost of employee recruitment, training, and retention of competent employees, government public health agencies need to address factors such as job satisfaction, job skill development, and other predictors of employee retention and turnover. IMPLICATIONS: Public health agencies may consider activities for improving retention by prioritizing improvements in the work environment, job and pay satisfaction, and understanding the needs of subgroups of employees such as those in younger and older age groups, those with cultural differences, and those with skills that are highly sought-after by other industries.

Fast but steady: An integrated leaf-stem-root trait syndrome for woody forest invaders.

Successful control and prevention of biological invasions depend on identifying traits of non-native species that promote fitness advantages in competition with native species. Here, we show that, among 76 native and non-native woody plants of deciduous forests of North America, invaders express a unique functional syndrome that combines high metabolic rate with robust leaves of longer lifespan and a greater duration of annual carbon gain, behaviours enabled by seasonally plastic xylem structure and rapid production of thin roots. This trait combination was absent in all native species examined and suggests the success of forest invaders is driven by a novel resource-use strategy. Furthermore, two traits alone-annual leaf duration and nuclear DNA content-separated native and invasive species with 93% accuracy, supporting the use of functional traits in invader risk assessments. A trait syndrome reflecting both fast growth capacity and understorey persistence may be a key driver of forest invasions.

RMRP inhibition prevents NAFLD progression in rats via regulating miR-206/PTPN1 axis.

This study aimed to investigate the regulatory function of lncRNA RMRP in non-alcoholic fatty liver disease (NAFLD). In vitro and in vivo NAFLD models were constructed. Hematoxylin & Eosin (H&E) and Oil-Red O staining assays were conducted to observe the morphology and lipid accumulation in liver tissues. Triglycine (TG) secretion was detected by ELISA assay. The expression levels of RMRP, microRNA-206, PTPN1 (protein tyrosine phosphatase, non-receptor type 1), and their downstream genes were assessed by qRT-PCR and Western blot. The regulatory relationship among these molecules was determined by luciferase reporter and RNA pull-down assays. RMRP and PTPN1 were up-regulated, while miR-206 was down-regulated in the liver tissues of NAFLD patients and rat model. RMRP inhibition improved the pathological state and liver function-related indexes of liver lipid deposition in the liver tissues of NAFLD rats. RMRP inhibition alleviated steatosis and TG secretion in free fatty acids (FFA)-treated AML-12 cells. RMRP could bind to miR-206 and downregulate its expression. Meanwhile, RMRP inhibition attenuated lipid accumulation by downregulating the PTPN1-PP2ASP1-SREBP1C pathway. Furthermore, RMRP inhibited the miR-206/PTPN1-SREBP1C signaling pathway in NAFLD rats and FFA-treated AML-12 cells. RMRP inhibition prevented NAFLD progression in rats via targeting the miR-206/PTPN1 axis.

Joint inference about the AUC and Youden index for paired biomarkers.

It is common to compare biomarkers' diagnostic or prognostic performance using some summary ROC measures such as the area under the ROC curve (AUC) or the Youden index. We propose to compare two paired biomarkers using both the AUC and the Youden index since the two indices describe different aspects of the ROC curve. This comparison can be made by estimating the joint confidence region (an elliptical area) of the differences of the paired AUCs and the Youden indices. Furthermore, for deciding if one marker is better than the other in terms of both the AUC and the Youden index (J), we can test H0:AUCa≤AUCb or Ja≤Jb against Ha:AUCa>AUCb and Ja>Jb using the paired differences. The construction of such a joint hypothesis is an example of the multivariate order-restricted hypotheses. For such a hypothesis, we propose and compare three testing procedures: (1) the intersection-union test ( IUT ); (2) the conditional test; and (3) the joint test. The performance of the proposed inference methods was evaluated and compared through simulations. The simulation results demonstrate that the proposed joint confidence region maintains the desired confidence level, and all three tests maintain the type I error under the null. Furthermore, among the three proposed testing methods, the conditional test is the preferred approach with markedly larger power consistently than the other two competing methods.

Aberrant mitochondrial DNA methylation and declined pulmonary function in a population with polycyclic aromatic hydrocarbon composition in particulate matter.

Air pollution exposure has been found to be associated with epigenetic modification of the mitochondrial genome, which could subsequently induce adverse health outcomes. However, very limited studies exist regarding the association between fine particulate matter (PM2.5) exposure and pulmonary function at the molecular level of mitochondrial epigenetic changes. This study aimed to investigate the association of platelet mitochondrial DNA (mtDNA) methylation with occupational PM2.5 exposure and pulmonary function. First, 768 participants were occupationally exposed to polycyclic aromatic hydrocarbon (PAH)-enriched PM2.5 in a coke-oven plant in East China. The levels of PM2.5, PAH components bound to PM2.5, and urinary PAH metabolites in the workplace environment were measured as an internal dose, respectively. mtDNA methylation was measured by bisulfite pyrosequencing of two genes of ATP synthase (MT-ATP6 and MT-ATP8). Mediation analysis was conducted to evaluate the role of mtDNA methylation in pulmonary alteration induced by PAH. A decreasing trend of platelet mtDNA methylation was observed with increase in PM2.5 exposure across all participants. As an important PAH metabolite in urine, 1-hydroxypyrene (1-OHP) was significantly negatively associated with FEV1/FVC (Forced Expiratory Volume in 1s/Forced Vital Capacity) ratio. The participants with high serum folate levels (≥10 nmol/L) showed positive association between MT-ATP6 methylation and FEV1/FVC ratio. Mediation analysis suggested that MT-ATP6 methylation mediated the significant association of urinary 1-OHP with FEV1/FVC. Our findings suggested the methylation of platelet mitochondrial gene MT-ATP6 and FEV1/FVC to be negatively associated with PM exposure. Platelet mtDNA methylation acted as an intermediary between PAH exposure and lung function decline. The mitochondrial epigenetic regulation in platelets, in response to PM exposure, might be involved in subsequent progress of abnormal pulmonary function.

Effects of the presence of phosphate buffer solution on removal efficiency of Pb and Zn in soil by solid phase microbial fuel cells.

Simple, effective and environment-friendly ways for remediating toxic metal pollution are necessary. In this study, the effect of different concentrations phosphate buffer solution (PBS) on removal efficiency of Pb and Zn in soil by solid phase microbial fuel cell (SMFC) was investigated. During 100 days of operation, the SMFC with 150 mM PBS generated the highest power density of 21.7 mW m-2 and the lowest internal resistance of 161 Ω. The addition of PBS can also increase soil conductivity and maintain a suitable pH for microbial activity. Furthermore, the removal rate of Pb and Zn in the SMFC with 150 mM PBS can reach 14.7% and 22.3%, respectively. The microbial community analyses demonstrated that Anditalea as an exoelectrogen in alkaline-saline conditions was significantly enriched in the SMFC with 150 mM PBS. This study provides an effective strategy for strengthening SMFC to remove toxic metals in soil.

Cellular transport of uranium and its cytotoxicity effects on CHO-k1 cells.

Uranium is a radioactive heavy metal and a significant public health concern; however, its associated underlying toxicological mechanisms remain largely unknown. In this work, the uptake and efflux processes of uranium in CHO-k1 cells were studied and the cytotoxicity effects were explored. It was found that both the uptake and efflux processes took place rapidly and half of the internalized uranium was expelled within 8 h. The uranium exposure caused a decrease of cell viability and adhesion ability in a dose-dependent manner and blocked the cell cycle at the G1 stage. In addition, gene expression analysis revealed relative changes in the transcription of metabolism related genes. Further studies revealed that the cytotoxicity of uranium could be alleviated by exposing cells to a lower temperature or by the addition of amantadine-HCl, an endocytosis inhibitor. Interestingly, after uranium exposure, needle-like precipitates were observed in both intracellular and extracellular regions. These findings collectively suggest that the cellular transport of uranium is a rapid process that disturbs cell metabolism and induces cytotoxicity, and this impact could be reduced by slowing down endocytic processes.

Changes in cerebrospinal fluid interleukin-10 levels display better performance in predicting disease relapse than conventional magnetic resonance imaging in primary central nervous system lymphoma.

BACKGROUD: Establishing diagnostic and prognostic biomarkers of primary central nervous system lymphoma (PCNSL) is a challenge. This study evaluated the value of dynamic interleukin (IL)-10 cerebrospinal fluid (CSF) concentrations for prognosis and relapse prediction in PCNSL. METHODS: Consecutive 40 patients newly diagnosed with PCNSL between April 2015 and April 2019 were recruited, and serial CSF specimens were collected by lumbar punctures (LP) or by Ommaya reservoir at diagnosis, treatment, and follow-up phase. RESULTS: We confirmed that an elevated IL-10 cutoff value of 8.2 pg/mL for the diagnosis value of PCNSL showed a sensitivity of 85%. A persistent detectable CSF IL-10 level at the end of treatment was associated with poor progression-free survival (PFS) (836 vs. 481 days, p = 0.049). Within a median follow-up of 13.6 (2-55) months, 24 patients relapsed. IL-10 relapse was defined as a positive conversion in patients with undetectable IL-10 or an increased concentration compared to the last test in patients with sustained IL-10. IL-10 relapse was detected a median of 67 days (28-402 days) earlier than disease relapse in 10/16 patients. CONCLUSION: This study highlights a new perspective that CSF IL-10 relapse could be a surrogate marker for disease relapse and detected earlier than conventional magnetic resonance imaging (MRI) scan. Further evaluation of IL-10 monitoring in PCNSL follow-up is warranted.

A small molecule compound IX inhibits telomere and attenuates oncogenesis of drug-resistant leukemia cells.

Drug resistance is a common obstacle in leukemia treatment and failing to eradicate leukemia stem cells is the main cause of leukemia relapse. Previous studies have demonstrated that telomerase activity is associated with deregulated self-renewal of leukemia stem cells (LSCs). Here, we identified a novel compound IX, an imatinib derivative with a replacement fragment of a telomerase inhibitor, which can effectively eradicate LSCs but had no influence on normal hematopoietic stem cells (HSCs) survival. We showed that compound IX can decrease the viability of drug-resistant K562/G cells and blast crisis CML primary patient cells. Besides, IX can affect LSC survival, inhibit the colony-forming ability, and reduce LSC frequency. In vivo results showed that IX can relieve the tumor burden in patient-derived xenograft (PDX) model and prolong the lifespan. We observed that compound IX can not only decrease telomerase activity, but also affect the alternative lengthening of telomeres. In addition, IX can inhibit both the canonical and non-canonical Wnt pathways. Our data suggested this novel compound IX as a promising candidate for drug-resistant leukemia therapy.

Admission Hemoglobin Is Prognostic for In-Hospital Mortality in Oldest-Old Patients with Acute Ischemic Stroke.

INTRODUCTION: Anemia is a common condition encountered in acute ischemic stroke, and only a few pieces of evidence has been produced suggesting its possible association with short-term mortality have been produced. The study sought to assess whether admission anemia status had any impact on short-term clinical outcome among oldest-old patients with acute ischemic stroke. MATERIALS AND METHODS: A retrospective review of Electronic Medical Recording System was performed in 2 tertiary hospitals. Data, from the oldest-old patients aged > = 80 years consecutively admitted with a diagnosis of acute ischemic stroke between January 1, 2015, and December 31, 2019, were analyzed. Admission hemoglobin was used as indicator for anemia and severity. Univariate and multivariate regression analyses were used to compare in-hospital mortality and length of in-hospital stay in different anemia statuses and normal hemoglobin patients. RESULTS: A total of 705 acute ischemic stroke patients were admitted, and 572 were included in the final analysis. Of included patients, 240 of them were anemic and 332 nonanemic patients. A statistical difference between the 2 groups was found in in-hospital mortality (p < 0.001). After adjustment for baseline characteristics, the odds ratio value of anemia for mortality were 3.91 (95% confidence intervals (CI) 1.60-9.61, p = 0.003) and 7.15 (95% CI: 1.46-34.90, p = 0.015) in moderate and severely anemic patients, respectively. Similarly, length of in-hospital stay was longer in anemic patients (21.64 ± 6.17 days) than in nonanemic patients (19.08 ± 5.48 days, p < 0.001). CONCLUSIONS: Increased severity of anemia may be an independent risk factor for increased in-hospital mortality and longer length of stay in oldest-old patients with acute ischemic stroke.

Variant of SNPs at lncRNA NEAT1 contributes to gastric cancer susceptibility in Chinese Han population.

BACKGROUND: The long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) has been implicated in many tumors risk including gastric cancer. However, the association of single nucleotide polymorphisms (SNPs) at NEAT1 with gastric cancer risk has not been studied. The aim of this study was to investigate the association between SNPs in NEAT1 and gastric cancer susceptibility. METHODS: In this study, four SNPs in lncRNA NEAT1 were selected for genotyping in 484 gastric cancer patients and 484 controls in Chinese Han population. Quantitative real-time PCR (qRT-PCR) was conducted to evaluate the potential function of rs3825071. Attributable risk percentage (ARP) and population attributable risk percentage (PARP) were used to assess the epidemiological effect. RESULTS: In the dominant model (GG), the genotypes AG + AA of rs3825071 and rs7943779 were associated with an increased risk of gastric cancer (OR = 1.72, 95%CI = 1.27-2.32 and OR = 1.63, 95%CI = 1.19-2.22). Individuals harboring ≥ 3 risk alleles have higher risk of gastric cancer (OR = 1.88, 95% CI = 1.26-2.80, P = 0.002). ARP and PARP associated with gastric cancer were 42.53% and 10.88% for rs3825071, and were 33.78% and 6.26% for rs7943779, respectively. Furthermore, compared with the genotype GG of rs3825071, the genotypes AG and AA had higher expression of NEAT1. CONCLUSIONS: We found that the genetic variations in NEAT1 were significantly associated with risk of gastric cancer. The G > A variant of rs3825071 may confer gastric cancer susceptibility by changed biological effects to increase the expression of NEAT1.

Joint confidence region estimation on predictive values.

For evaluating diagnostic accuracy of inherently continuous diagnostic tests/biomarkers, sensitivity and specificity are well-known measures both of which depend on a diagnostic cut-off, which is usually estimated. Sensitivity (specificity) is the conditional probability of testing positive (negative) given the true disease status. However, a more relevant question is "what is the probability of having (not having) a disease if a test is positive (negative)?". Such post-test probabilities are denoted as positive predictive value (PPV) and negative predictive value (NPV). The PPV and NPV at the same estimated cut-off are correlated, hence it is desirable to make the joint inference on PPV and NPV to account for such correlation. Existing inference methods for PPV and NPV focus on the individual confidence intervals and they were developed under binomial distribution assuming binary instead of continuous test results. Several approaches are proposed to estimate the joint confidence region as well as the individual confidence intervals of PPV and NPV. Simulation results indicate the proposed approaches perform well with satisfactory coverage probabilities for normal and non-normal data and, additionally, outperform existing methods with improved coverage as well as narrower confidence intervals for PPV and NPV. The Alzheimer's Disease Neuroimaging Initiative (ADNI) data set is used to illustrate the proposed approaches and compare them with the existing methods.

Joint hypothesis testing of the area under the receiver operating characteristic curve and the Youden index.

In the receiver operating characteristic (ROC) analysis, the area under the ROC curve (AUC) serves as an overall measure of diagnostic accuracy. Another popular ROC index is the Youden index (J), which corresponds to the maximum sum of sensitivity and specificity minus one. Since the AUC and J describe different aspects of diagnostic performance, we propose to test if a biomarker beats the pre-specified targeting values of AUC0 and J0 simultaneously with H0 : AUC ≤ AUC0 or J ≤ J0 against Ha : AUC > AUC0 and J > J0 . This is a multivariate order restrictive hypothesis with a non-convex space in Ha , and traditional likelihood ratio-based tests cannot apply. The intersection-union test (IUT) and the joint test are proposed for such test. While the IUT test independently tests for the AUC and the Youden index, the joint test is constructed based on the joint confidence region. Findings from the simulation suggest both tests yield similar power estimates. We also illustrated the tests using a real data example and the results of both tests are consistent. In conclusion, testing jointly on AUC and J gives more reliable results than using a single index, and the IUT is easy to apply and have similar power as the joint test.

has_circ_CCNB1 and has_circ_0009024 function as potential biomarkers for the diagnosis of type 2 diabetes mellitus.

Circular RNAs (circRNAs) have been reported to be associated with various diseases, including type 2 diabetes mellitus (T2DM). The aim of present study was to investigate the clinical value of has_circ_CCNB1 and has_circ_0009024 in T2DM. Serum samples from patients with T2DM (n = 166) and healthy volunteers (n = 166) were recruited. Then, real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) analysis and enzyme-linked immunosorbent (ELISA) assays were conducted to detect the expression levels of circRNAs and inflammatory factors. Furthermore, the correlation analysis and receiver operating characteristic (ROC) curve were used to evaluate diagnostic accuracy. From the results, circ_CCNB1 was significantly increased while circ_0009024 was decreased in serum samples from T2DM patients. Moreover, has_circ_CCNB1 was positively correlated with glucose (GLU), glycosylated hemoglobin (GHb), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) while has_circ_0009024 was negatively correlated with them. Importantly, the AUC of has_circ_CCNB1 and has_and circ_0009024 was 0.9255 (95% CI = 0.8909-0.9601) and 0.9592 (95% CI = 0.9381-0.9803), while the AUC of combinative curve is 0.8875 (95% CI = 0.8204-0.8547). In a word, has_circ_CCNB1 and has_circ_0009024 may exhibit as potential biomarkers for the diagnosis of T2DM.