Unweighted Regression Research Articles

WinMLR, a software program for the simultaneous determination of several components in mixtures using multilinear regression analysis

The program WinMLR has been developed for the quantification of mixtures of several components by making a multilinear regression treatment of experimental data to a linear combination of standard signals. Data may be obtained with any multichannel detector having more measuring channels than components to be resolved. For a correct resolution, a linear relationship between the signal of every channel and the component concentration is required. The data must be located into ASCII files, one file for each standard or sample measurement, which contain the X and Y values in separated columns.The program allows three types of calibration methods: single standard, multiple standards and multiple standards addition. In the first case, the program requires to measure one standard per component. In the second case, the user can employ standards of both pure compounds and known mixtures under the sole constraint that the set of standards must include all components in different proportions. Similarly, the multiple standard addition method (more known as general standard addition method) requires the data obtained by adding known amounts of one or several mixture components to the sample so that all of them are included in the assays. In the multiple standards and multiple standards addition procedures, once the calibration has been done, the program allows the mixture to be resolved by weighted or unweighted regression.

Unweighted regression models perform better than weighted regression techniques for respondent-driven sampling data: results from a simulation study

BackgroundIt is unclear whether weighted or unweighted regression is preferred in the analysis of data derived from respondent driven sampling. Our objective was to evaluate the validity of various regression models, with and without weights and with various controls for clustering in the estimation of the risk of group membership from data collected using respondent-driven sampling (RDS).MethodsTwelve networked populations, with varying levels of homophily and prevalence, based on a known distribution of a continuous predictor were simulated using 1000 RDS samples from each population. Weighted and unweighted binomial and Poisson general linear models, with and without various clustering controls and standard error adjustments were modelled for each sample and evaluated with respect to validity, bias and coverage rate. Population prevalence was also estimated.ResultsIn the regression analysis, the unweighted log-link (Poisson) models maintained the nominal type-I error rate across all populations. Bias was substantial and type-I error rates unacceptably high for weighted binomial regression. Coverage rates for the estimation of prevalence were highest using RDS-weighted logistic regression, except at low prevalence (10%) where unweighted models are recommended.ConclusionsCaution is warranted when undertaking regression analysis of RDS data. Even when reported degree is accurate, low reported degree can unduly influence regression estimates. Unweighted Poisson regression is therefore recommended.

Normative comparison standards for measures of cognition in the Canadian Longitudinal Study on Aging (CLSA): Does applying sample weights make a difference?

Large-scale studies present the opportunity to create normative comparison standards relevant to populations. Sampling weights applied to the sample data facilitate extrapolation to the population of origin, but normative scores are often developed without the use of these sampling weights because the values derived from large samples are presumed to be precise estimates of the population parameter. The present article examines whether applying sample weights in the context of deriving normative comparison standards for measures of cognition would affect the distributions of regression-based normative data when using data from a large population-based study. To address these questions, we examined 3 cognitive measures from the Canadian Longitudinal Study on Aging tracking cohort (N = 14,110, Age 45-84 years at recruitment): Rey Auditory Verbal Learning Test - Immediate Recall, Animal Fluency, and the Mental Alternation Test. The use of sampling weights resulted in similar model parameter estimates to unweighted regression analyses and similar cumulative frequency distributions to the unweighted analyses. We randomly sampled progressively smaller subsets from the full database to test the hypothesis that sampling weights would help maintain the estimates from the full sample, but discovered that the weighted and unweighted estimates were similar and were less precise with smaller samples. These findings suggest that although use of sampling weights can help mitigate biases in data from sampling procedures, the application of weights to adjust for sampling biases do not appreciably impact the normative data, which lends support to the current practice in creation of normative data. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Association between Inpatient Delirium and Hospital Readmission in Patients ≥ 65 Years of Age: A Retrospective Cohort Study.

Delirium affects more than seven million hospitalized adults in the United States annually. However, its impact on postdischarge healthcare utilization remains unclear. To determine the association between delirium and 30-day hospital readmission. A retrospective cohort study. A general community medical and surgical hospital. All adults who were at least 65 years old, without a history of delirium or alcohol-related delirium, and were hospitalized from September 2010 to March 2015. The patients deemed at risk for or displaying symptoms of delirium were screened by nurses using the Confusion Assessment Method with a followup by a staff psychiatrist for a subset of screen-positive patients. Patients with delirium confirmed by a staff psychiatrist were compared with those without delirium. The primary outcome was the 30-day readmission rate. The secondary outcomes included emergency department (ED) visits 30 days postdischarge, mortality during hospitalization and 30 days postdischarge, and discharge location. The cohort included 718 delirious patients and 7,927 nondelirious patients. Using an unweighted multivariable logistic regression, delirium was determined to be significantly associated with the increased odds of readmission within 30 days of discharge (odds ratio (OR): 2.60; 95% CI, 1.96-3.44; P < .0001). Delirium was also significantly (P < .0001) associated with ED visits within 30 days postdischarge (OR: 2.18; 95% CI: 1.77-2.69) and discharge to a facility (OR: 2.52; 95% CI: 2.09-3.01). Delirium is a significant predictor of hospital readmission, ED visits, and discharge to a location other than home. Delirious patients should be targeted to reduce postdischarge healthcare utilization.

An approach to select linear regression model in bioanalytical method validation

BackgroundThe accuracy of any bioanalytical method depends on the selection of an appropriate calibration model. The most commonly used calibration model is the unweighted linear regression, where the response (y-axis) is plotted against the corresponding concentration (x-axis). The degree of association between these two variables is expressed in terms of correlation coefficient (r2). However, the satisfactory r2 alone is not adequate to accept the calibration model. The wide calibration curve range used in the bioanalytical methods is susceptible to the heteroscedasticity of the calibration curve data. The use of weighted linear regression with an appropriate weighting factor reduces the heteroscedasticity and improves the accuracy over the selected concentration range.MethodsThe present work describes a rapid and simple RP-HPLC method for the estimation of chlorthalidone in spiked human plasma. The calibration curve standards were studied in the concentration range of 100–3200 ng/mL. The chromatography was performed on a C18 column (250 × 4.6 mm, 5 μm) in an isocratic mode at a flow rate of 1 mL/min using methanol:water (60:40%, v/v) as a mobile phase. The detection was carried out at 276 nm. Both the unweighted regression model and weighted regression models with different weighting factors (1/x, 1/√x, and 1/x2) were evaluated for heteroscedasticity. The statistical approach for the selection of a suitable regression model with appropriate weighting factors was discussed and the developed bioanalytical method was further validated, as per US-FDA guidelines.ResultsIn calibration curve experiments, although the acceptable r2 of 0.998 was obtained, the % residual plot showed that the data were susceptible to heteroscedasticity. When the weighted linear regression was applied to the same calibration curve data set, no significant difference between % relative residual (% RR) was observed. Furthermore, when % relative error (% RE) was calculated for different weighting factors, it was observed that the regression model with 1/x weighting factor gave a minimum % RE. The calibration curve was found to be linear in the range of 100 to 3200 ng/mL. The validation experiments proved good accuracy, and intra- and inter-day variability and acceptable recovery. Stability studies proved that the drug was stable under tested stability cycles.ConclusionsFrom the statistical reports obtained from the present work, it was observed that the calibration curve in bioanalytical experiments was susceptible to heteroscedasticity using the unweighted linear regression model. Hence, to obtain homoscedasticity in the calibration curve experiments, there is a need for a weighted linear regression model. The appropriate regression model was further selected by evaluating the % RE for different weighting factors.

Is it possible to identify the inguinal nerves during hernioplasty? A systematic review of the literature and meta-analysis of cadaveric and surgical studies

PurposePatients who undergo inguinal hernioplasty may suffer from persistent postoperative pain due to inguinal nerve injuries. The aim of this systematic review and meta-analysis was to provide comprehensive data on the prevalence (identification rates), anatomical characteristics, and ethnic variations of the ilioinguinal (IIN), the iliohypogastric (IHN) and the genital branch of the genitofemoral (GNF) nerves.MethodsThe systematic literature search was conducted using the PubMed, Scopus and Web of Science databases.ResultsA total of 26 articles (5265 half-body examinations) were included in this study. The identification rate of the IIN was 94.4% (95% CI 89.5–97.9) using a random-effects model. Unweighted multiple regression analysis showed that study sample size (β = − 0.74, p = .036) was the only statistically significant predictor of lower prevalence. The identification rates of the IHN and GNF was 86.7% (95% CI 78.3%–93.3%) and 69.1% (95% CI 53.1%–83.0%) using a random-effects model, respectively. For those outcomes, a visual analysis of funnel and Doi plots indicated irregularity and provided evidence that larger studies tended to have lower identification rates. In terms of the synthesis of anatomical reference points, there was a large and statistically significant amount of heterogeneity for most outcomes.ConclusionsThe identification rates of the inguinal nerves in our study were lower than reported in literature. The lowest was found for GNF, suggesting that this nerve was the most difficult to identify. Knowledge regarding the anatomy of the inguinal nerves can facilitate their proper identification and reduce the risk of iatrogenic injury and postoperative pain.

Healthcare service utilization and work-related productivity in reflexology intervention for advanced breast cancer women.

This project's purpose was to determine the effects of a home-based reflexology intervention on symptom-related use of health services and work-related productivity during the 11-week study. A total of 256 patients were randomized to four weekly reflexology sessions (each lasting 30min, delivered by lay caregivers who received two training sessions by a professional reflexologist) or attention control. The Conventional Health Service and Productivity Costs Form was used to collect information on health service utilization and out-of-pocket expenditure of symptom management. The Health and Work Performance Questionnaire was used to measure workplace performance for patients during the study period. We used weighted and unweighted logistic and linear regression analyses. Patients in the reflexology group were less likely to have hospital visits compared to the control group in the weighted unadjusted (odds ratio [OR] = 0.49; 95% confidence interval [CI] = [0.25, 0.97]), unweighted adjusted (OR = 0.35; 95% CI = [0.16, 0.75]), and weighted adjusted (OR = 0.30, 95% CI = [0.13, 0.66]) logistic regressions. Compared to attention control, patients in the reflexology group had lower relative absenteeism in the unweighted adjusted (- 0.32; 95% CI = [- 0.60, - 0.03]) linear regressions and less absolute presenteeism (15.42, 95% CI = [0.87, 29.98]) in the weighted unadjusted analysis. The reflexology intervention delivered by lay caregivers reduced hospital visits and increased workplace productivity in a short-term period, which has potential for cost saving for health care systems and employers. NCT01582971.

Error Propagation in the Derivation of Noble Gas Diffusion Parameters for Minerals From Step Heating Experiments

AbstractStep heating is an important tool in the derivation of thermochronologic models based on diffusive noble‐gas loss from minerals. This technique investigates noble‐gas diffusion in minerals at length scales of natural crystals. Like any scientific measurement, step heating requires realistic assessment of assumptions and uncertainties; however, uncertainties are often not presented or roughly approximated. Here we propagate errors associated with temperature, step duration, evolved gas quantity, and diffusion domain size. Other potential error sources (e.g., nonideal shapes, fractures, and zonation of aliquots) are not discussed. We provide error propagation formulas for the derivation of diffusivities and diffusion parameters for infinite plane sheet, spherical, and infinite cylinder geometry. We show that a variance in uncertainty (heteroscedasticity) in diffusivity and temperature may lead to erroneous estimates of activation energy (Ea) and frequency factor (D0) and an underestimation of their uncertainties during unweighted regression. The effect becomes significant if the variance in uncertainty exceeds a factor of two to five. The effect of the difference in D0 values is demagnified in the calculation of closure temperature (which calls on lnD0 rather than D0) and its uncertainty. To make this a practical resource, we provide spreadsheets with a step heating data set, diffusivity calculations with associated analytical error propagation formulas, and unweighted and weighted regression models to derive Ea and D0 for all three geometries. We also provide spreadsheets with Monte Carlo and numerical error propagation for plane sheet geometry.

Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: a proof of concept

There is a relative lack of evidence about systemic treatments in patients with hepatocellular carcinoma (HCC) and moderate liver dysfunction (Child-Pugh B). In this multicenter study we retrospectively analyzed data from Child-Pugh B-HCC patients naïve to systemic therapies, treated with MC or best supportive care (BSC). To reduce the risk of selection bias, an inverse probability of treatment weighting approach was adopted. Propensity score was generated including: extrahepatic spread; macrovascular invasion; performance status, alphafetoprotein > 400 ng/ml, Child- Pugh score [B7 vs. B8–9]. We identified 35 MC-treated patients and 70 controls. Median overall survival was 7.5 [95% CI: 3.733–11.267]in MC-patients and 5.1 months [95% CI: 4.098–6.102] in the BSC group (p = 0.013). In patients treated with MC, median progression-free survival was 4.5 months (95% CI: 2.5–6.5). The univariate unweighted Cox regression showed a 42% reduction in death risk for patients on MC (95%CI: 0.370–0.906; p = 0.017). After weighting for potential confounders, death risk remained essentially unaltered. In the MC group, 12 patients (34.3%) experienced at least one adverse event, the most common of which were: fatigue (17.1%), hand-foot syndrome (8.5%), thrombocytopenia (8.5%), and neutropenia (5.7%). MC seems a safe option for Child-Pugh B-HCC patients. Its potential antitumour activity warrants prospective evaluations.

Response surface and group additivity methodology for estimation of thermodynamic properties of organosilanes

AbstractGroup additivity methods simplify the determination of thermodynamic properties of a wide range of chemically related species involved in detailed reaction schemes. In this paper, we expand Benson's group additivity method to organosilanes. Based on quantum‐chemical calculations, the thermodynamic data of 22 stable silicon‐organic species are calculated, presented in the form of NASA polynomials, and compared to the available experimental data. Based on this theoretical database, a complete set of 24 Si‐ and C‐atom‐centered, single‐bonded and nonradical group additivity values for enthalpy of formation, standard entropy, and heat capacity at temperatures from 200 to 4000 K is derived through unweighted multivariate linear regression.

Serum Calcitriol Concentrations and Kidney Function Decline, Heart Failure, and Mortality in Elderly Community-Living Adults: The Health, Aging, and Body Composition Study

Lower 25-hydroxyvitamin D concentrations have been associated with risk for kidney function decline, heart failure, and mortality. However, 25-hydroxyvitamin D requires conversion to its active metabolite, calcitriol, for most biological effects. The associations of calcitriol concentrations with clinical events have not been well explored. Case-cohort study. Well-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study. Serum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry. Major kidney function decline (≥30% decline in estimated glomerular filtration rate from baseline), incident heart failure (HF), and all-cause mortality during 10 years of follow-up. Baseline calcitriol concentrations were measured in a random subcohort of 479 participants and also in cases with major kidney function decline [n=397]) and incident HF (n=207) during 10 years of follow-up. Associations of serum calcitriol concentrations with these end points were evaluated using weighted Cox regression to account for the case-cohort design, while associations with mortality were assessed in the subcohort alone using unweighted Cox regression. During 8.6 years of mean follow-up, 212 (44%) subcohort participants died. In fully adjusted models, each 1-standard deviation lower calcitriol concentration was associated with 30% higher risk for major kidney function decline (95% CI, 1.03-1.65; P=0.03). Calcitriol was not significantly associated with incident HF (HR, 1.16; 95% CI, 0.94-1.47) or mortality (HR, 1.01; 95% CI, 0.81-1.26). We observed no significant interactions between calcitriol concentrations and chronic kidney disease status, baseline intact parathyroid or fibroblast factor 23 concentrations. Observational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race. Lower calcitriol concentrations are independently associated with kidney function decline in community-living older adults. Future studies will be needed to clarify whether theseassociations reflect lower calcitriol concentrations resulting from abnormal kidney tubule dysfunction or direct mechanisms relating lower calcitriol concentrations to more rapid loss of kidney function.

Uncertainty analysis for the experimental estimation of heat transfer correlations combining the Wilson plot method and the Monte Carlo technique

The present paper addresses several procedures for determining convective heat transfer coefficients based on the original Wilson plot method and its modified variants. Different thermal relationships based on thermal resistance and temperature differences are obtained from slight different applications of the Wilson plot method. Results from simple linear regression models extensively used in the archival literature are analyzed and compared with those obtained from weighted and unweighted nonlinear regression models, as well as with the results provided by Monte Carlo simulations.The analysis is focused on a specific problem where the heat transfer correlation to be obtained has three unknowns; however, the analysis is quite general and could be extended to more complex problems. Results show that weighted nonlinear regression models give more consistent results that unweighted methods; whereas unweighted simple linear regression analyses are not recommended. Finally, the suitability of implementing a Monte Carlo simulation is shown in terms of properly propagating the measured data uncertainty distribution through the heat transfer model.

Reductions in Average Lengths of Stays for Surgical Procedures Between the 2008 and 2014 United States National Inpatient Samples Were Not Associated With Greater Incidences of Use of Postacute Care Facilities

Diagnosis-related group (DRG) based reimbursement creates incentives for reduction in hospital length of stay (LOS). Such reductions might be accomplished by lesser incidences of discharges to home. However, we previously reported that, while controlling for DRG, each 1-day decrease in hospital median LOS was associated with lesser odds of transfer to a postacute care facility (P = .0008). The result, though, was limited to elective admissions, 15 common surgical DRGs, and the 2013 US National Readmission Database. We studied the same potential relationship between decreased LOS and postacute care using different methodology and over 2 different years. The observational study was performed using summary measures from the 2008 and 2014 US National Inpatient Sample, with 3 types of categories (strata): (1) Clinical Classifications Software's classes of procedures (CCS), (2) DRGs including a major operating room procedure during hospitalization, or (3) CCS limiting patients to those with US Medicare as the primary payer. Greater reductions in the mean LOS were associated with smaller percentages of patients with disposition to postacute care. Analyzed using 72 different CCSs, 174 DRGs, or 70 CCSs limited to Medicare patients, each pairwise reduction in the mean LOS by 1 day was associated with an estimated 2.6% ± 0.4%, 2.3% ± 0.3%, or 2.4% ± 0.3% (absolute) pairwise reduction in the mean incidence of use of postacute care, respectively. These 3 results obtained using bivariate weighted least squares linear regression were all P < .0001, as were the corresponding results obtained using unweighted linear regression or the Spearman rank correlation. In the United States, reductions in hospital LOS, averaged over many surgical procedures, are not accomplished through a greater incidence of use of postacute care.

Task-shifting of CD4 T cell count monitoring by the touchscreen-based Muse™ Auto CD4/CD4% single-platform system for CD4 T cell numeration: Implication for decentralization in resource-constrained settings

BackgroundThe accuracy of CD4 T cell monitoring by the recently developed flow cytometry-based CD4 T cell counting Muse™ Auto CD4/CD4% Assay analyzer (EMD Millipore Corporation, Merck Life Sciences, KGaA, Darmstadt, Germany) was evaluated in trained lay providers against laboratory technicians. MethodsAfter 2 days of training on the Muse™ Auto CD4/CD4% analyzer, EDTA-blood samples from 6 HIV-positive and 4 HIV-negative individuals were used for CD4 T cell counting in triplicate in parallel by 12 trained lay providers as compared to 10 lab technicians. ResultsMean number of CD4 T cells in absolute number was 829 ± 380 cells/μl by lay providers and 794 ± 409 cells/μl by technicians (P > 0.05); and in percentage 36.2 ± 14.8%CD4 by lay providers and 36.1 ± 15.0%CD4 by laboratory technician (P > 0.05). The unweighted linear regression and Passing-Bablok regression analyses on CD4 T cell results expressed in absolute count revealed moderate correlation between CD4 T cell counts obtained by lay providers and lab technicians. The mean absolute bias measured by Bland–Altman analysis between CD4 T cell/μl obtained by lay providers and lab technicians was −3.41 cells/μl. Intra-assay coefficient of variance (CV) of Muse™ Auto CD4/CD4% in absolute number was 10.1% by lay providers and 8.5% by lab technicians (P > 0.05), and in percentage 5.5% by lay providers and 4.4% by lab technicians (P > 0.05). The inter-assay CV of Muse™ Auto CD4/CD4% in absolute number was 13.4% by lay providers and 10.3% by lab technicians (P > 0.05), and in percentage 7.8% by lay providers and 6.9% by lab technicians (P > 0.05). ConclusionsThe study demonstrates the feasibility of CD4 T cell counting using the alternative flow cytometer Muse™ Auto CD4/CD4% analyzer by trained lay providers and therefore the practical possibility of decentralization CD4 T cell counting to health community centers.

Bridge of Promise: Comparing the Academic Outcomes of Kalamazoo Promise to Public School Students in a 4-Year Institution

This quantitative study compares Kalamazoo Promise (KPromise) students to non-Promise, public high school graduating students at the 4-year institution at which the largest number of KPromise students have enrolled and graduated. The sample was generated from 2009-12 Fall cohorts. To add depth and proxies for financial and academic advantages, we joined institutional longitudinal administrative data with high school and permanent residency characteristics. The final sample for this study was N=9,969; n=310 (3%) were KPromise students. Descriptive analysis suggests that KPromise students are racially more diverse and less affluent than non-Promise students. Unweighted regressions in which the differences between KPromise and other students are insufficiently account for show that being a KPromise student was correlated with lower College GPA (β=-0.10), increased chance of Academic Dismissal (OR=1.43), and lowered likelihood of Degree Attainment (OR=0.68). Correlations were not found with Academic Warning or Probation. Weighting the sample using Inverse Probability Weighing with Regression Adjustment (IPWRA), being KPromise was not significantly correlated to any of the outcomes examined. Indicating that KPromise students accessing the site institution are unique; after arrival, they perform similarly in some respects to reasonably-comparable students from other public schools. Discussion centers on how findings expand current knowledge regarding KPromise and counters recent narratives regarding tuition-free programs.

A Group of 500 Women Whose Health May Depart Notably From the Norm: Protocol for a Cross-Sectional Survey.

BackgroundLongitudinal studies of women’s health often seek to identify predictors of good health. Research has shown that following simple guidelines can halve women’s mortality. The ongoing Australian Longitudinal Study of Women’s Health (ALSWH) shows that Australian women are getting better at reducing their smoking and alcohol use, and are generally diligent about attending recommended health screenings, but are becoming less successful at dealing with obesity. There are communities of women who live unusually healthy lives (Rosetans, Seventh-Day Adventists, traditional Japanese women), but their lifestyles are unlikely to be adopted widely. Universal Medicine (UM) is a complementary-to-medicine approach that emphasizes personal empowerment and the importance of menstrual health symptoms.ObjectiveThis survey investigates whether the approximately 500 women associated with UM exhibit health status significantly above the norm. As part of this investigation, questions for a newly developed menstrual attitudes questionnaire will also be evaluated.MethodsA quantitative cross-sectional survey of women in a UM cohort was designed with the help of three focus groups of women at three life stages: in menses, peri-menopausal, and menopausal. The menstrual attitudes portion of the survey incorporates the insights of these women regarding female health issues. The survey also includes 41 questions taken from the ALSWH. Focus groups generated additional questions about symptoms experienced and attitudes toward female health issues. ALSWH questions, including a range of health scales like the Short Form 36 (SF-36), Center for Epidemiologic Studies Depression Scale, Perceived Control Scale, Kessler Psychological Distress Scale, and the Multi-Item Summed Score for Perceived Stress, along with questions about experienced major health events, were investigated and incorporated if considered suitable. At the time of publication of this protocol, data collection has been completed.ResultsThe validity of the menstrual attitudes questionnaire will be evaluated with Cohen’s kappa. ALSWH respondents and UM participants will be compared, using unweighted regression or regression weighted or normalized by age, education, and interest in alternative treatments (to increase comparability), as appropriate. Analyses will determine whether UM-related variables (being a UM participant, length of UM participation, number of UM events attended) are associated with: differences in the number of major health events and health symptoms experienced; SF-36 physical and mental health scores; body mass index; and consumption of alcohol, tobacco, sugar, salt, caffeine, and dairy.ConclusionsIf women in the UM cohort are truly in substantially better health than the norm, further investigations may be worthwhile to see whether UM plays a causal role, and whether the women’s practices are generalizable.International Registered Report Identifier (IRRID)DERR1-10.2196/7993

Cox regression model with doubly truncated data.

Truncation is a well-known phenomenon that may be present in observational studies of time-to-event data. While many methods exist to adjust for either left or right truncation, there are very few methods that adjust for simultaneous left and right truncation, also known as double truncation. We propose a Cox regression model to adjust for this double truncation using a weighted estimating equation approach, where the weights are estimated from the data both parametrically and nonparametrically, and are inversely proportional to the probability that a subject is observed. The resulting weighted estimators of the hazard ratio are consistent. The parametric weighted estimator is asymptotically normal and a consistent estimator of the asymptotic variance is provided. For the nonparametric weighted estimator, we apply the bootstrap technique to estimate the variance and confidence intervals. We demonstrate through extensive simulations that the proposed estimators greatly reduce the bias compared to the unweighted Cox regression estimator which ignores truncation. We illustrate our approach in an analysis of autopsy-confirmed Alzheimer's disease patients to assess the effect of education on survival.

Liquid chromatography-electrospray ionization-tandem mass spectrometry method for quantitative estimation of new imiqualine leads with potent anticancer activities in rat and mouse plasma. Application to a pharmacokinetic study in mice

Imidazoquinoxaline derivatives (imiqualines) are a new series of anticancer compounds. Two lead compounds (EAPB0203 and EAPB0503) with remarkable in vitro and in vivo activity on melanoma and T-cell lymphomas have been previously identified. The modulation of the chemical structure of the most active compound, EAPB0503, has led to the synthesis of two compounds, EAPB02302 and EAPB02303, 7 and 40 times more active than EAPB0503 against A375 human melanoma cancer cell line, respectively. The aim of this study was to develop and validate a sensitive and accurate liquid chromatography-electrospray ionization-tandem mass spectrometry method to simultaneously quantify EAPB02303 and its potential active metabolite, EAPB02302, in rat and mouse plasma. Analytes were detected in multiple reaction monitoring acquisition mode using an electrospray ionization detector in positive ion mode. Following a liquid-liquid extraction with ethyl acetate, analytes and internal standard were separated by HPLC reversed-phase on a C18 RP18 Nucleoshell column (2.7μm, 4.6×100mm). The method was validated according to FDA and EMA Bioanalytical Method Validation guidelines. The robustness of the method was assessed by introducing small variations in nine nominal analytical parameters. Statistical interpretation was performed by mean of the Student’s t-test. Standard curves were generated via unweighted quadratic regression of calibrators (EAPB02303: 1.95–1000ng/mL, EAPB02302: 7.81–1000ng/mL in rat plasma; EAPB02303: 0.98–1000ng/mL, EAPB02302: 1.95–1000ng/mL in mouse plasma). From the analysis of QC samples, intra- and inter-assay precision and accuracy studies demonstrated %R.S.Ds. <12.5% and percent deviation from nominal concentration <7%. Matrix effects (mean matrix factors from 91.8-108.5% in rat plasma; and from 90.4-102.4% in mouse plasma) and stability assays (recoveries >87%) were acceptable and in accordance with the guidelines. No quantifiable carryover effect was observed. The LLOQs were 1.95ng/mL for EAPB02303 and 7.81ng/mL for EAPB02302 in rat plasma, and 0.98ng/mL and 1.95ng/mL for the two compounds in mouse plasma, respectively. This method was successfully implemented to support a mouse pharmacokinetic study following a single intraperitoneal administration of EAPB02303 in male C57Bl/6 mice. The obtained pharmacokinetic parameters of EAPB02303 would be useful to optimize the dosing and the rhythm of administration for subsequent preclinical in vivo activity studies.

Health-related quality of life among older patients following an emergency department visit and emergency department-to-home coaching intervention: A randomized controlled trial

Introduction Many older patients experience repeated emergency department visits and hospitalizations and inadequate links to primary care. This fragmented care can result in anxiety, uncertainty, and poor health outcomes. This study compares the impact of an emergency department-to-home coaching intervention to usual, post-emergency department care on patient-reported health-related quality of life measures: information support, anxiety, and physical function. Methods This was a randomized controlled trial. Seven hundred and forty-nine chronically ill older adults presenting to emergency departments were randomized into Intervention (emergency department-to-home coaching) or Usual Care groups. Participants completed baseline, in-person and follow-up, telephone surveys. Within- and between-group differences in health-related quality of life were assessed using unweighted linear regression and propensity-weighted difference-in-difference analyses. Three Patient Reported Outcomes Measurement System measures were assessed: social health (informational support), mental health (anxiety/emotional distress), and physical health (physical functioning). Results Usual Care participants experienced statistically significant declines in informational support in unweighted (−3.13) and weighted (−2.84) analyses not observed in the Intervention group (−0.91 and −1.45, respectively). Self-reported anxiety was lowest and physical function highest at the time of emergency department visit. Patient-reported anxiety increased and physical function declined statistically significantly in Intervention participants. Conclusion Among older emergency department patients, health-related quality of life was highest at the emergency department visit and declined following the encounter. The emergency department visit per se appears to provide needed information, and in the short term, reassurance about patients’ medical conditions. The coaching intervention blunts the fall in informational support observed after usual, post-emergency department care but may heighten patients’ anxiety and awareness of chronic health conditions.

Differences in the Prediction of Area Under the Curve for a Protease Inhibitor Using Trough Versus Peak Concentration: Assessment Using Published Pharmacokinetic Data for Indinavir.

In the present day antiretroviral therapy, Ctrough is a key tool for efficacy assessment. The present work explored the feasibility of using Ctrough or Cmax in the area under the concentration-time curve (AUC) prediction of indinavir. A simple unweighted linear regression model was developed to describe the relationship between Cmax versus AUC (r = 0.8101, P < 0.001) and Ctrough versus AUC (r = 0.8127, P < 0.001) for indinavir. The regression lines were used to predict the AUC values from literature Cmax or Ctrough data of indinavir in HIV and healthy subjects. The fold difference, defined as the quotient of the observed and predicted AUC values, was evaluated along with statistical comparison, including root mean square error (RMSE) prediction for the 2 models. The correlation between Cmax versus AUC and Ctrough versus AUC was established. Majority of the predicted values for Cmax versus AUC were within 0.75- to 1.5-fold differences. However, the Ctrough versus AUC model showed larger variability with approximately one-third of the predictions within 0.75- to 1.5-fold differences. The r value and %RMSE for observed versus predicted AUC for Ctrough (r = 0.5925, n = 65, P < 0.001, and RMSE: 67%) were inferior to the Cmax (r = 0.8773, n = 86, P < 0.001, and RMSE: 46%). In conclusion, Cmax versus AUC and Ctrough versus AUC relationships were established for indinavir showing the utility of a single concentration time point for therapeutic drug monitoring purpose. The Cmax model for indinavir may be more relevant for AUC prediction as determined by the statistical criteria.