Aiyi Liu

Optimal Cut-point and Its Corresponding Youden Index to Discriminate Individuals Using Pooled Blood Samples

Costs can hamper the evaluation of the effectiveness of new biomarkers. Analysis of smaller numbers of pooled specimens has been shown to be a useful cost-cutting technique. The Youden index (J), a function of sensitivity (q) and specificity (p), is a commonly used measure of overall diagnostic effectiveness. More importantly, J is the maximum vertical distance or difference between the ROC curve and the diagonal or chance line; it occurs at the cut-point that optimizes the biomarkers differentiating ability when equal weight is given to sensitivity and specificity. Using the additive property of the gamma and normal distributions, we present a method to estimate the Youden index and the optimal cut-point, and extend its applications to pooled samples. We study the effect of pooling when only a fixed number of individuals are available for testing, and pooling is carried out to save on the number of assays. We measure loss of information by the change in root mean squared error of the estimates of the optimal cut-point and the Youden index, and we study the extent of this loss via a simulation study. In conclusion, pooling can result in a substantial cost reduction while preserving the effectiveness of estimators, especially when the pool size is not very large.

BioCycle study: design of the longitudinal study of the oxidative stress and hormone variation during the menstrual cycle.

Studies in both human and animal species have suggested that oxidative stress may be associated with health outcomes, including the risk of infertility in both males and females. Sex hormones have been shown to have antioxidant properties. The difficulty in studying the role of oxidative stress in females is partly due to fluctuation in these endogenous sex hormones across the menstrual cycle. The aim of this study was to determine the association of oxidative stress levels with endogenous reproductive hormone levels and antioxidants, including vitamin levels, across the menstrual cycle in a prospective cohort of premenopausal women. The goal was to enroll 250 healthy, regularly menstruating premenopausal women for two menstrual cycles. Participants visited the clinic up to 8 times per cycle, at which time blood and urine were collected. The visits occurred at key hormonally defined phases of the menstrual cycle, with the help of an algorithm based on cycle length and data from a fertility monitor. In addition, participants were administered standardised questionnaires, had various physical measures taken, and had other pertinent data collected. A total of 259 women were enrolled in this study, with 250 completing two cycles, despite a demanding study protocol which participants were required to follow. This report describes the study design, baseline characteristics and visit completion rate for the BioCycle study.

Comparison of CSF Cytology and Spinal Magnetic Resonance Imaging in the Detection of Leptomeningeal Disease in Pediatric Medulloblastoma or Primitive Neuroectodermal Tumor

PURPOSE Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Examination of CSF for malignant cells, detection of LMD on spinal magnetic resonance imaging (MRI), or both are the methods routinely used to diagnose LMD. A recent study suggested 100% correlation between CSF and MRI findings in children with medulloblastoma. To determine the validity of this hypothesis, we compared the rate of detection of LMD between concurrent lumbar CSF cytology and spinal MRI performed at diagnosis in patients with medulloblastoma or PNET. PATIENTS AND METHODS As a part of diagnostic staging, 106 consecutive patients newly diagnosed with medulloblastoma or PNET were evaluated with concurrent lumbar CSF cytology and spinal MRI. CSF cytology was examined for the presence of malignant cells and spinal MRI was reviewed independently for the presence of LMD. RESULTS Thirty-four patients (32%) were diagnosed with LMD based on CSF cytology, spinal MRI, or both. There were 21 discordant results. Nine patients (8.5%) with positive MRI had negative CSF cytology. Twelve patients (11.3%) with positive CSF cytology had negative MRIs. The exact 95% upper bounds on the proportion of patients with LMD whose disease would have gone undetected using either CSF cytology or MRI as the only diagnostic modality were calculated at 14.4% and 17.7%, respectively. CONCLUSION With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET. Thus, both CSF cytology and spinal MRI should routinely be used to diagnose LMD in patients with medulloblastoma or PNET.

Comparison of Lumbar and Shunt Cerebrospinal Fluid Specimens for Cytologic Detection of Leptomeningeal Disease in Pediatric Patients With Brain Tumors

PURPOSE Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with primary CNS tumors. Cytologic examination of lumbar CSF is routinely used to detect LMD. To determine whether examination of CSF obtained from ventricular shunt taps is a more sensitive method of detecting LMD in these patients, we designed a prospective study to compare the findings of cytologic examinations of CSF obtained from concurrent lumbar and ventriculoperitoneal (VP) shunt taps. PATIENTS AND METHODS As a part of diagnostic staging, follow-up testing, or both, 52 consecutive patients underwent concurrent lumbar and shunt taps on 90 separate occasions, ranging from the time of diagnosis to treatment follow-up. CSF from both sites was examined cytologically for malignant cells. RESULTS The median age of the 28 males and 24 females was 7.5 years (range, 0.6 to 21.4 years). The primary CNS tumors included medulloblastoma (n = 29), astrocytoma (n = 10), ependymoma (n = 5), germinoma (n = 3), atypical teratoid rhabdoid tumor (n = 2), choroid plexus carcinoma (n = 2), and pineoblastoma (n = 1). Each site yielded a median CSF volume of 1.0 mL. Fourteen of 90 paired CSF test results were discordant: in 12, the cytologic findings from shunt CSF were negative for malignant cells, but those from lumbar CSF were positive; in two, the reverse was true. Malignant cells were detected at a higher rate in lumbar CSF than in shunt CSF (P =.0018). When repeat analyses were excluded, examination of lumbar CSF remained significantly more sensitive in detecting malignant cells (P =.011). Analysis of the subset of patients with embryonal tumors showed similar results (P =.0008). CONCLUSION Cytologic examination of lumbar CSF is clearly superior to cytologic examination of VP shunt CSF for detecting leptomeningeal metastases in pediatric patients with primary CNS tumors.

Clinic-Integrated Behavioral Intervention for Families of Youth With Type 1 Diabetes: Randomized Clinical Trial

OBJECTIVE: To test the effect on diabetes management outcomes of a low-intensity, clinic-integrated behavioral intervention for families of youth with type 1 diabetes. METHODS: Families (n = 390) obtaining care for type 1 diabetes participated in a 2-year randomized clinical trial of a clinic-integrated behavioral intervention designed to improve family diabetes management practices. Measurement of hemoglobin A1c, the primary outcome, was obtained at each clinic visit and analyzed centrally. Blood glucose meter data were downloaded at each visit. Adherence was assessed by using a semistructured interview at baseline, mid-study, and follow-up. Analyses included 2-sample t tests at predefined time intervals and mixed-effect linear-quadratic models to assess for difference in change in outcomes across the study duration. RESULTS: A significant overall intervention effect on change in glycemic control from baseline was observed at the 24-month interval (P = .03). The mixed-effect model showed a significant intervention by age interaction (P < .001). Among participants aged 12 to 14, a significant effect on glycemic control was observed (P = .009 for change from baseline to 24-month interval; P = .035 for mixed-effect model across study duration), but there was no effect among those aged 9 to 11. There was no intervention effect on child or parent report of adherence; however, associations of change in adherence with change in glycemic control were weak. CONCLUSIONS: This clinic-integrated behavioral intervention was effective in preventing the deterioration in glycemic control evident during adolescence, offering a potential model for integrating medical and behavioral sciences in clinical care.

Maternal Serum Polychlorinated Biphenyl Concentrations across Critical Windows of Human Development

Background Few data are available on polychlorinated biphenyl (PCB) concentrations over critical windows of human reproduction and development inclusive of the periconception window. Objectives Our goal was to measure changes in PCB concentrations from preconception to pregnancy, through pregnancy, or after a year without becoming pregnant. Methods Seventy-nine women planning pregnancies were prospectively enrolled and followed for up to 12 menstrual cycles of attempting pregnancy. Blood specimens were obtained from participating women preconceptionally (n = 79), after a positive pregnancy test leading to a live birth (n = 54) or pregnancy loss (n = 10), at approximately 6 weeks postpartum (n = 53), and after 12 unsuccessful cycles (n = 9) for toxicologic analysis of 76 PCB congeners. We estimated overall and daily rate of change in PCB concentration (nanograms per gram serum) adjusting for relevant covariates, serum lipids, and baseline PCB concentration. Results Significant (p < 0.0001) decreases in the mean overall and daily rate of change in PCB concentrations were observed between the preconception and first pregnancy samples for total (–1.012 and –0.034, respectively), estrogenic (–0.444 and –0.016, respectively), and antiestrogenic (–0.106 and –0.004, respectively) PCBs among women with live births. Similar significant decreases in total (–1.452 and –0.085), estrogenic (–0.647 and –0.040), and antiestrogenic (–0.093 and –0.004) PCB concentrations were seen for women with pregnancy losses. No significant changes were observed for PCB congener 153. Conclusions These data suggest that PCB concentrations may change during the periconception interval, questioning the stability of persistent compounds during this critical window.

Pleiotropy Analysis of Quantitative Traits at Gene Level by Multivariate Functional Linear Models

In genetics, pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. A common approach is to analyze the phenotypic traits separately using univariate analyses and combine the test results through multiple comparisons. This approach may lead to low power. Multivariate functional linear models are developed to connect genetic variant data to multiple quantitative traits adjusting for covariates for a unified analysis. Three types of approximate F‐distribution tests based on Pillai–Bartlett trace, Hotelling–Lawley trace, and Wilkss Lambda are introduced to test for association between multiple quantitative traits and multiple genetic variants in one genetic region. The approximate F‐distribution tests provide much more significant results than those of F‐tests of univariate analysis and optimal sequence kernel association test (SKAT‐O). Extensive simulations were performed to evaluate the false positive rates and power performance of the proposed models and tests. We show that the approximate F‐distribution tests control the type I error rates very well. Overall, simultaneous analysis of multiple traits can increase power performance compared to an individual test of each trait. The proposed methods were applied to analyze (1) four lipid traits in eight European cohorts, and (2) three biochemical traits in the Trinity Students Study. The approximate F‐distribution tests provide much more significant results than those of F‐tests of univariate analysis and SKAT‐O for the three biochemical traits. The approximate F‐distribution tests of the proposed functional linear models are more sensitive than those of the traditional multivariate linear models that in turn are more sensitive than SKAT‐O in the univariate case. The analysis of the four lipid traits and the three biochemical traits detects more association than SKAT‐O in the univariate case.

Analytical and biological variation of biomarkers of oxidative stress during the menstrual cycle

Abstract Little information is available on the intra-individual variability of oxidative stress biomarkers in healthy individuals and even less in the context of the menstrual cycle. The objective of this study was to characterize the analytical and biological variability of a panel of 21 markers of oxidative damage, antioxidant defence and micronutrients in nine healthy, regularly menstruating women aged 18–44 years. Analyses included measurement of lipid peroxidation, antioxidant enzymes and antioxidant vitamins. Blood specimens were collected, processed and stored using standardized procedures on days 2, 7, 12, 13, 14, 18, 22 and 28 in one cycle for each subject. Replicate analyses of markers were performed and two-way nested random effects ANOVA was used to describe analytical, intra-individual and inter-individual variability. No statistically significant differences at α=0.05, or temporal effects across the menstrual cycle were observed. Analytical variability was the smallest component of variance for all variables. The ICC among replicates ranged from 0.80 to 0.98. Imprecision based on quality control materials ranged from 1 to 11%. The critical differences between serial results varied greatly between assays ranging from 6 to 216% of the mean level. These results provide important initial information on the variability of biomarkers of oxidative stress, antioxidant defence and micronutrients across the menstrual cycle.

Increased levels of copeptin before clinical diagnosis of preelcampsia.

Copeptin, a surrogate biomarker of vasopressin, has been associated with renal function decline and may serve as a useful early biomarker for preeclampsia. We measured serum copeptin using samples collected longitudinally during pregnancy among unaffected controls (n=136) and cases of preeclampsia (n=169), gestational diabetes mellitus (n=92), gestational hypertension (n=101), and preterm birth (n=86) in the Calcium for Preeclampsia Prevention trial (1992–1995). Preeclampsia and gestational hypertension were defined as having a diastolic blood pressure ≥90 mm Hg on 2 occasions with and without proteinuria, respectively. The risk of pregnancy complications associated with copeptin was estimated by logistic regression adjusting for maternal age, race, body mass index, insurance status, marital status, current smoking, and clinical site. Baseline copeptin levels, at mean 16 weeks of gestation, were associated with increased preeclampsia risk (adjusted odds ratios and 95% confidence interval being 1.55 per log unit; 1.03–2.31) when compared with controls (P=0.03). The association was stronger among cases diagnosed before 37 weeks (1.86; 1.08–3.20) than those diagnosed later (1.45; 0.91–2.32). Copeptin levels rose with increasing gestational age in both cases and controls but remained significantly higher among those who were diagnosed with preeclampsia. Differences in levels of copeptin between cases and controls became more apparent closer to time of diagnosis. No significant associations were found for gestational hypertension without proteinuria, gestational diabetes mellitus, or preterm birth without preeclampsia. Copeptin levels are elevated in pregnant women before diagnosis of preeclampsia with elevation specific to this pregnancy complication rather than hypertension alone.

A threshold sample-enrichment approach in a clinical trial with heterogeneous subpopulations.

Background Large comparative clinical trials usually target a wide-range of patients population in which subgroups exist according to certain patients’ characteristics. Often, scientific knowledge or existing empirical data support the assumption that patients’ improvement is larger among certain subgroups than others. Such information can be used to design a more cost-effective clinical trial. Purpose The goal of the article is to use such information to design a more cost-effective clinical trial. Methods A two-stage sample-enrichment design strategy is proposed that begins with enrollment from certain subgroup of patients and allows the trial to be terminated for futility in that subgroup. Results Simulation studies show that the two-stage sample-enrichment strategy is cost-effective if indeed the null hypothesis of no treatment improvement is true, as also so illustrated with data from a completed trial of calcium to prevent preeclampsia. Limitations Feasibility of the proposed enrichment design relies on the knowledge prior to the start of the trial that certain patients can benefit more than others from the treatment. Prolonged accrual and longer-waited outcomes may hinder utilization of the proposed design. Conclusions The two-stage sample-enrichment approach borrows strength from treatment heterogeneity among target patients in a large-scale comparative clinical trial, and is more cost-effective if the treatment arms are indeed of no difference. Clinical Trials 2010; 7: 537—545. http://ctj.sagepub.com