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1.  Can Computer-Generated Evidence-Based Care Suggestions Enhance Evidence-Based Management of Asthma and Chronic Obstructive Pulmonary Disease? A Randomized, Controlled Trial 
Health Services Research  2005;40(2):477-498.
Objective
Translation of evidence-based guidelines into clinical practice has been inconsistent. We performed a randomized, controlled trial of guideline-based care suggestions delivered to physicians when writing orders on computer workstations.
Study Setting
Inner-city academic general internal medicine practice.
Study Design
Randomized, controlled trial of 246 physicians (25 percent faculty general internists, 75 percent internal medicine residents) and 20 outpatient pharmacists. We enrolled 706 of their primary care patients with asthma or chronic obstructive pulmonary disease. Care suggestions concerning drugs and monitoring were delivered to a random half of the physicians and pharmacists when writing orders or filling prescriptions using computer workstations. A 2 × 2 factorial randomization of practice sessions and pharmacists resulted in four groups of patients: physician intervention, pharmacist intervention, both interventions, and controls.
Data Extraction/Collection Methods
Adherence to the guidelines and clinical activity was assessed using patients' electronic medical records. Health-related quality of life, medication adherence, and satisfaction with care were assessed using telephone questionnaires.
Principal Findings
During their year in the study, patients made an average of five scheduled primary care visits. There were no differences between groups in adherence to the care suggestions, generic or condition-specific quality of life, satisfaction with physicians or pharmacists, medication compliance, emergency department visits, or hospitalizations. Physicians receiving the intervention had significantly higher total health care costs. Physician attitudes toward guidelines were mixed.
Conclusions
Care suggestions shown to physicians and pharmacists on computer workstations had no effect on the delivery or outcomes of care for patients with reactive airways disease.
doi:10.1111/j.1475-6773.2005.00368.x
PMCID: PMC1361152  PMID: 15762903
medical decision making; guidelines; quality improvement
2.  Issues of design and statistical analysis in controlled clinical acupuncture trials: An analysis of English-language reports from Western journals 
Statistics in medicine  2011;31(7):606-618.
Objective
To investigate major methods of design and statistical analysis in controlled clinical acupuncture trials published in the West during the past six years (2003–2009) and, based on this analysis, to provide recommendations that address methodological issues and challenges in clinical acupuncture research.
Method
PubMed was searched for acupuncture RCTs published in Western journals in English between 2003 and 2009. The keyword used was acupuncture.
Results
One hundred and eight qualified reports of acupuncture trials that included more than 30 symptoms/conditions were identified, analyzed, and grouped into efficacy (explanatory), effectiveness (pragmatically beneficial) and other (unspecified) studies. All were randomized controlled clinical trials (RCTs). In spite of significant improvement in the quality of acupuncture RCTs in the last 30 years, these reports show that some methodological issues and shortcomings in design and analysis remain. Moreover, the quality of the efficacy studies was not superior to that of the other types of studies. Research design and reporting problems include unclear patient criteria and inadequate practitioner eligibility, inadequate randomization and blinding, deficiencies in the selection of controls, and improper outcome measurements. Problems in statistical analysis included insufficient sample sizes and power calculations, inadequate handling of missing data and multiple comparisons, and inefficient methods for dealing with repeated-measure and cluster data, baseline value adjustment, and confounding issues.
Conclusion
Despite recent advancements in acupuncture research, acupuncture RCTs can be improved, and more rigorous research methods should be carefully considered.
doi:10.1002/sim.4034
PMCID: PMC3631592  PMID: 21341295
acupuncture; randomized controlled clinical trials; methodology design; statistical analysis
3.  Interval Estimation for the Difference in Paired Areas under the ROC Curves in the Absence of a Gold Standard Test 
Statistics in medicine  2009;28(25):3108-3123.
Summary
Receiver operating characteristic (ROC) curves can be used to assess the accuracy of tests measured on ordinal or continuous scales. The most commonly used measure for the overall diagnostic accuracy of diagnostic tests is the area under the ROC curve (AUC). A gold standard test on the true disease status is required to estimate the AUC. However, a gold standard test may sometimes be too expensive or infeasible. Therefore, in many medical research studies, the true disease status of the subjects may remain unknown. Under the normality assumption on test results from each disease group of subjects, using the expectation-maximization (EM) algorithm in conjunction with a bootstrap method, we propose a maximum likelihood based procedure for construction of confidence intervals for the difference in paired areas under ROC curves in the absence of a gold standard test. Simulation results show that the proposed interval estimation procedure yields satisfactory coverage probabilities and interval lengths. The proposed method is illustrated with two examples.
doi:10.1002/sim.3661
PMCID: PMC2812057  PMID: 19691022
Area under the ROC curve; EM algorithm; bootstrap method; gold standard test; maximum likelihood estimation
4.  Synthesis analysis of regression models with a continuous outcome 
Statistics in medicine  2009;28(11):1620-1635.
SUMMARY
To estimate the multivariate regression model from multiple individual studies, it would be challenging to obtain results if the input from individual studies only provide univariate or incomplete multivariate regression information. Samsa et al. (J. Biomed. Biotechnol. 2005; 2:113–123) proposed a simple method to combine coefficients from univariate linear regression models into a multivariate linear regression model, a method known as synthesis analysis. However, the validity of this method relies on the normality assumption of the data, and it does not provide variance estimates. In this paper we propose a new synthesis method that improves on the existing synthesis method by eliminating the normality assumption, reducing bias, and allowing for the variance estimation of the estimated parameters.
doi:10.1002/sim.3563
PMCID: PMC2952887  PMID: 19326397
synthesis analysis; meta-analysis; linear models
5.  Pseudo-empirical Likelihood-Based Method Using Calibration for Longitudinal Data with Drop-Out 
Summary
In observational studies, interest mainly lies in estimation of the population-level relationship between the explanatory variables and dependent variables, and the estimation is often undertaken using a sample of longitudinal data. In some situations, the longitudinal data sample features biases and loss of estimation efficiency due to non-random drop-out. However, inclusion of population-level information can increase estimation efficiency. In this paper we propose an empirical likelihood-based method to incorporate population-level information in a longitudinal study with drop-out. The population-level information is incorporated via constraints on functions of the parameters, and non-random drop-out bias is corrected by using a weighted generalized estimating equations method. We provide a three-step estimation procedure that makes computation easier. Some commonly used methods are compared in simulation studies, which demonstrate that our proposed method can correct the non-random drop-out bias and increase the estimation efficiency, especially for small sample size or when the missing proportion is high. In some situations, the efficiency improvement is substantial. Finally, we apply this method to an Alzheimer’s disease study.
doi:10.1111/rssc.12063
PMCID: PMC4288856  PMID: 25587200
Calibration; drop-out; empirical likelihood; longitudinal data
6.  Assessing Validity of a Depression Screening Instrument in the Absence of a Gold Standard 
Annals of epidemiology  2014;24(7):527-531.
Background
We evaluated the extent to which use of a hypothesized imperfect gold standard, the Composite International Diagnostic Interview (CIDI), biases the estimates of diagnostic accuracy of the Patient Health Questionnaire-9 (PHQ-9). We also evaluate how statistical correction can be used to address this bias.
Methods
The study was conducted among 926 adults where structured interviews were conducted to collect information about participants’ current major depressive disorder (MDD) using PHQ-9 and CIDI instruments. First, we evaluated the relative psychometric properties of PHQ-9 using CIDI as a gold standard. Next, we employed a Bayesian latent-class model to correct for the bias.
Results
In comparison with CIDI, the relative sensitivity and specificity of the PHQ-9 for detecting MDD at a cut point of ≥10 were 53.1% (95%CI: 45.4–60.8%) and 77.5% (95%CI: 74.5–80.5%), respectively. Using a Bayesian latent-class model to correct for the bias arising from the use of an imperfect gold standard increased the sensitivity and specificity of PHQ-9 to 79.8% (95% Bayesian credible interval (BCI): 64.9–90.8%) and 79.1% (95%BCI:74.7–83.7%), respectively
Conclusion
Our results provided evidence that assessing diagnostic validity of mental health screening instrument, where application of a gold standard might not be available, can be accomplished by using appropriate statistical methods.
doi:10.1016/j.annepidem.2014.04.009
PMCID: PMC4104527  PMID: 24935465
7.  A modified regression method to test publication bias in meta-analyses with binary outcomes 
Background
The tendency towards publication bias is greater for observational studies than for randomized clinical trials. Several statistical methods have been developed to test the publication bias. However, almost all existing methods exhibit rather low power or have inappropriate type I error rates.
Methods
We propose a modified regression method, which used a smoothed variance to estimate the precision of a study, to test for publication bias in meta-analyses of observational studies. A comprehensive simulation study is carried out, and a real-world example is considered.
Results
The simulation results indicate that the performance of tests varies with the number of included studies, level of heterogeneity, event rates, and sample size ratio between two groups. Neither the existing tests nor the newly developed method is particularly powerful in all simulation scenarios. However, our proposed method has a more robust performance across different settings. In the presence of heterogeneity, the arcsine-Thompson test is a suitable alternative, and Peters’ test can be considered as a complementary method when mild or no heterogeneity is present.
Conclusions
Several factors should be taken into consideration when employing asymmetry tests for publication bias. Based on our simulation results, we provide a concise table to show the appropriate use of regression methods to test for publication bias based on our simulation results.
doi:10.1186/1471-2288-14-132
PMCID: PMC4289575  PMID: 25516509
Meta-analysis; Observational studies; Publication bias; Smoothed variance; Weighted regression
8.  Validity of the Patient Health Questionnaire-9 for Depression Screening and Diagnosis in East Africa 
Psychiatry research  2013;210(2):10.1016/j.psychres.2013.07.015.
Depression is often underdiagnosed and undertreated in primary care settings, particularly in developing countries. This is, in part, due to challenges resulting from a lack of skilled mental health workers, stigma associated with mental illness, and lack of cross-culturally validated screening instruments. We conducted this study to evaluate the reliability and validity of the Patient Health Questionnaire-9 (PHQ-9) questionnaire as a screen for diagnosing major depressive disorder among adults in Ethiopia, the second most populous country in sub-Saharan Africa. A total of 926 adults attending outpatient departments in a major referral hospital in Ethiopia participated in this study. We assessed criterion validity and performance characteristics against an independent, blinded, and psychiatrist administered semi-structured Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview. Overall, the PHQ-9 items showed good internal (Cronbach's alpha=0.85) and test re-test reliability (intraclass correlation coefficient=0.92). A factor analysis confirmed a 1-factor structure. Receiver Operating Characteristics (ROC) analysis showed that a PHQ-9 threshold score of 10 offered optimal discriminatory power with respect to diagnosis of MDD via the clinical interview (sensitivity=86% and specificity=67%). The PHQ-9 appears to be a reliable and valid instrument that may be used to diagnose major depressive disorders among Ethiopian adults.
doi:10.1016/j.psychres.2013.07.015
PMCID: PMC3818385  PMID: 23972787
PHQ-9; Validation; Africa; Ethiopia; Depression
9.  Effect modification by gender and smoking status on the association between obesity and atopic sensitization in Chinese adults: a hospital-based case–control study 
BMC Public Health  2014;14:1105.
Background
There is an ongoing debate on the potential association between obesity and atopy. However, no previous studies have investigated whether this relationship depends on sex and smoking status in Chinese adults.
Methods
In this hospital-based, case–control study, we recruited 1150 atopic cases aged 18 years or older and 1245 healthy control participants during April 2009 and December 2012 in Harbin, China. We conducted structured questionnaire interviews, anthropometry measurements and serum allergen-specific immunoglobulin E (IgE) testing. Univariate and multivariate logistic regression models were used to explore the relationship between obesity and atopy risk stratified by sex and smoking status.
Results
There was an association between obesity and an increased risk of atopic sensitization after adjusting for age, educational, family history, smoking and alcohol consumption (OR: 2.61, 3.25; 95% CI: 1.57-4.33,1.91-5.56 in males and females, respectively). The association between BMI and allergic sensitization depended on smoking status. In both genders, the association of obesity with atopic sensitization risk was stronger in non-smokers than in current smokers. In males, ORs of atopic sensitization for obesity were 3.15 (95% CI, 1.46-6.68) for non-smokers and 2.22 (95% CI, 1.10-4.48) for current smokers. The corresponding ORs in females were 3.51 (95% CI, 1.98-6.24) and 2.22 (95% CI, 0.46-10.68) for non-smokers and current smokers, respectively. After excluding those subjects who with pre-existing allergic conditions, the same relationship still remained.
Conclusions
Obesity is positively and significantly associated with the risk of atopy in both men and women as well in both smokers and non-smokers in China. In addition, the relationship between obesity and atopic sensitization is stronger in non-smokers than in current smokers.
doi:10.1186/1471-2458-14-1105
PMCID: PMC4228147  PMID: 25344653
Obesity; Body mass index; Atopy; Adult
10.  Risk Factors of Stroke in Western and Asian Countries: A Systematic Review and Meta-analysis of Prospective Cohort Studies 
BMC Public Health  2014;14:776.
Background
There has been an increasing trend in the incidence of stroke worldwide in recent years, and the number of studies focusing on the risk factors for stroke has also increased every year. To comprehensively evaluate the risk factors of stroke identified in prospective Western and Asian cohort studies.
Methods
Population-based cohort studies on stroke were searched in databases (PubMed, EMBASE, Web of Science, Google Scholar, etc.), and the library of the Third Military Medical University was manually searched for relevant information. A meta-analysis of Western and Asian studies on risk factors was performed. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the final group of cohort studies.
Results
After screening, 22 prospective cohort studies were included in the analyses of this investigation. Two factors, smoking and alcohol consumption, showed statistically significant differences between Western and Asian populations, and the results were as follows (W/A): 2.05 (95% CI, 1.68 ~ 2.49)/1.27 (95% CI, 1.04 ~ 1.55) and 0.89 (95% CI, 0.76 ~ 1.04)/1.28 (95% CI, 1.07 ~ 1.53). The factor BMI = 18.5-21.9 kg/m2 showed statistically significant differences only in Western populations, 0.96 (95% CI, 0.93 ~ 0.99); the factor SBP = 120-139 mm Hg showed statistically significant differences only in Asian populations, 2.29 (95% CI, 1.04 ~ 5.09).
Conclusions
The prevalences of risk factors affect the stroke morbidity in Western and Asian populations, which may be biased by race. The meta-analysis of population-based studies suggests that different preventive measures should be adopted for Western and Asian population groups that are at high risk for stroke.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-776) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-776
PMCID: PMC4246444  PMID: 25081994
Stroke; Risk factors; Prospective study; Epidemiology; Systematic review; Public health
11.  Homogeneity tests of clustered diagnostic markers with applications to the BioCycle Study 
Statistics in medicine  2012;31(28):3638-3648.
Diagnostic trials often require the use of a homogeneity test among several markers. Such a test may be necessary to determine the power both during the design phase and in the initial analysis stage. However, no formal method is available for the power and sample size calculation when the number of markers is greater than two and marker measurements are clustered in subjects. This article presents two procedures for testing the accuracy among clustered diagnostic markers. The first procedure is a test of homogeneity among continuous markers based on a global null hypothesis of the same accuracy. The result under the alternative provides the explicit distribution for the power and sample size calculation. The second procedure is a simultaneous pairwise comparison test based on weighted areas under the receiver operating characteristic curves. This test is particularly useful if a global difference among markers is found by the homogeneity test. We apply our procedures to the BioCycle Study designed to assess and compare the accuracy of hormone and oxidative stress markers in distinguishing women with ovulatory menstrual cycles from those without.
doi:10.1002/sim.5391
PMCID: PMC4084872  PMID: 22733707
ROC curve; biomarker; homogeneity test; sample size
12.  Partial summary measures of the predictiveness curve 
In the evaluation of a biomarker for risk prediction, one can assess the performance of the biomarker in the population of interest by displaying the predictiveness curve. In conjunction with an assessment of the classification accuracy of a biomarker, the predictiveness curve is an important tool for assessing the usefulness of a risk prediction model. Inference for a single biomarker or for multiple biomarkers can be performed using summary measures of predictiveness curve. We propose two partial summary measures, the partial total gain and the partial proportion of explained variation, that summarize the predictiveness curve over a restricted range of risk. The methods we describe can be used to compare two biomarkers when there are existing thresholds for risk stratification. We describe inferencial tools for one and two-samples that are shown to have adequate power in a simulation study. The methods are illustrated by assessing the accuracy of a risk score for predicting the onset of Alzheimer's Disease.
doi:10.1002/bimj.201200146
PMCID: PMC3806283  PMID: 23508801
Biomarker; Classification; Prediction; Summary statistic
13.  Diagnostic Validity of the Composite International Diagnostic Interview (CIDI) Depression Module in an East African Population 
Objective
To evaluate the validity and reliability of the structured Composite International Diagnostic Interview (CIDI) in diagnosing current major depressive disorder (MDD) among East African adults.
Methods
A sample of 926 patients attending a major referral hospital participated in this diagnostic assessment study. We used a two stage-study design where participants were first interviewed using an Amharic version of the CIDI and a stratified random sample underwent a follow-up semi-structured clinical interview conducted by a psychiatrist, blinded to the screening results, using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) instrument. We tested construct validity by examining the association of the CIDI and World Health Organization Quality of Life (WHO-QOL) questionnaire. We calculated the psychometric properties of the CIDI using the SCAN diagnostic interview as a gold standard.
Results
We found that the Amharic version of the CIDI diagnostic interview has good internal reliability (Cronbach’s alpha= 0.97) among Ethiopian adults. Compared to the SCAN reference standard, the CIDI had fair specificity (72.2%) but low sensitivity (51.0%). Our study provided evidence for unidimensionality of core depression screening questions on the CIDI interview with good factor loadings on a major core depressive factor.
Conclusion
The Amharic language version of the CIDI had fair specificity and low sensitivity in detecting MDD compared with psychiatrist administered SCAN diagnosis. Our findings are generally consistent with prior studies. Use of fully structured interviews such as the CIDI for MDD diagnosis in clinical settings might lead to under detection of DSM-IV MDD.
PMCID: PMC4058648  PMID: 24922989
CIDI; Validation; Africa; Ethiopia; Depression; MDD
14.  Characterizing the effect of temperature fluctuation on the incidence of malaria: an epidemiological study in south-west China using the varying coefficient distributed lag non-linear model 
Malaria Journal  2014;13:192.
Background
Malaria transmission is strongly determined by the environmental temperature and the environment is rarely constant. Therefore, mosquitoes and parasites are not only exposed to the mean temperature, but also to daily temperature variation. Recently, both theoretical and laboratory work has shown, in addition to mean temperatures, daily fluctuations in temperature can affect essential mosquito and parasite traits that determine malaria transmission intensity. However, so far there is no epidemiological evidence at the population level to this problem.
Methods
Thirty counties in southwest China were selected, and corresponding weekly malaria cases and weekly meteorological variables were collected from 2004 to 2009. Particularly, maximum, mean and minimum temperatures were collected. The daily temperature fluctuation was measured by the diurnal temperature range (DTR), the difference between the maximum and minimum temperature. The distributed lag non-linear model (MDLNM) was used to study the correlation between weekly malaria incidences and weekly mean temperatures, and the correlation pattern was allowed to vary over different levels of daily temperature fluctuations.
Results
The overall non-linear patterns for mean temperatures are distinct across different levels of DTR. When under cooler temperature conditions, the larger mean temperature effect on malaria incidences is found in the groups of higher DTR, suggesting that large daily temperature fluctuations act to speed up the malaria incidence in cooler environmental conditions. In contrast, high daily fluctuations under warmer conditions will lead to slow down the mean temperature effect. Furthermore, in the group of highest DTR, 24-25°C or 21-23°C are detected as the optimal temperature for the malaria transmission.
Conclusion
The environment is rarely constant, and the result highlights the need to consider temperature fluctuations as well as mean temperatures, when trying to understand or predict malaria transmission. This work may be the first epidemiological study confirming that the effect of the mean temperature depends on temperature fluctuations, resulting in relevant evidence at the population level.
doi:10.1186/1475-2875-13-192
PMCID: PMC4050477  PMID: 24886630
15.  A Correlated Random Effects Model for Non-homogeneous Markov Processes with Nonignorable Missingness 
Life history data arising in clusters with prespecified assessment time points for patients often feature incomplete data since patients may choose to visit the clinic based on their needs. Markov process models provide a useful tool describing disease progression for life history data. The literature mainly focuses on time homogeneous process. In this paper we develop methods to deal with non-homogeneous Markov process with incomplete clustered life history data. A correlated random effects model is developed to deal with the nonignorable missingness, and a time transformation is employed to address the non-homogeneity in the transition model. Maximum likelihood estimate based on the Monte-Carlo EM algorithm is advocated for parameter estimation. Simulation studies demonstrate that the proposed method works well in many situations. We also apply this method to an Alzheimer's disease study.
doi:10.1016/j.jmva.2013.01.009
PMCID: PMC3697104  PMID: 23828666
Cluster; missing not at random; Markov non-homogeneous; random effects; transition intensity
16.  Japanese Encephalitis Risk and Contextual Risk Factors in Southwest China: A Bayesian Hierarchical Spatial and Spatiotemporal Analysis 
It is valuable to study the spatiotemporal pattern of Japanese encephalitis (JE) and its association with the contextual risk factors in southwest China, which is the most endemic area in China. Using data from 2004 to 2009, we applied GISmapping and spatial autocorrelation analysis to analyze reported incidence data of JE in 438 counties in southwest China, finding that JE cases were not randomly distributed, and a Bayesian hierarchical spatiotemporal model identified the east part of southwest China as a high risk area. Meanwhile, the Bayesian hierarchical spatial model in 2006 demonstrated a statistically significant association between JE and the agricultural and climatic variables, including the proportion of rural population, the pig-to-human ratio, the monthly precipitation and the monthly mean minimum and maximum temperatures. Particular emphasis was placed on the time-lagged effect for climatic factors. The regression method and the Spearman correlation analysis both identified a two-month lag for the precipitation, while the regression method found a one-month lag for temperature. The results show that the high risk area in the east part of southwest China may be connected to the agricultural and climatic factors. The routine surveillance and the allocation of health resources should be given more attention in this area. Moreover, the meteorological variables might be considered as possible predictors of JE in southwest China.
doi:10.3390/ijerph110404201
PMCID: PMC4024990  PMID: 24739769
Japanese encephalitis; contextual risk factors; meteorological factors; southwest China; Bayesian hierarchical model
17.  Covariate adjustment in estimating the area under ROC curve with partially missing gold standard 
Biometrics  2013;69(1):91-100.
Summary
In ROC analysis, covariate adjustment is advocated when the covariates impact the magnitude or accuracy of the test under study. Meanwhile, for many large scale screening tests, the true condition status may be subject to missingness because it is expensive and/or invasive to ascertain the disease status. The complete-case analysis may end up with a biased inference, also known as “verification bias”. To address the issue of covariate adjustment with verification bias in ROC analysis, we propose several estimators for the area under the covariate-specific and covariate-adjusted ROC curves (AUCx and AAUC). The AUCx is directly modelled in the form of binary regression, and the estimating equations are based on the U statistics. The AAUC is estimated from the weighted average of AUCx over the covariate distribution of the diseased subjects. We employ reweighting and imputation techniques to overcome the verification bias problem. Our proposed estimators are initially derived assuming that the true disease status is missing at random (MAR), and then with some modification, the estimators can be extended to the not-missing-at-random (NMAR) situation. The asymptotic distributions are derived for the proposed estimators. The finite sample performance is evaluated by a series of simulation studies. Our method is applied to a data set in Alzheimer's disease research.
doi:10.1111/biom.12001
PMCID: PMC3622116  PMID: 23410529
Alzheimer's disease; area under ROC curve; covariate adjustment; U statistics; verification bias; weighted estimating equations
18.  The temporal lagged association between meteorological factors and malaria in 30 counties in south-west China: a multilevel distributed lag non-linear analysis 
Malaria Journal  2014;13:57.
Background
The association between malaria and meteorological factors is complex due to the lagged and non-linear pattern. Without fully considering these characteristics, existing studies usually concluded inconsistent findings. Investigating the lagged correlation pattern between malaria and climatic variables may improve the understanding of the association and generate possible better prediction models. This is especially beneficial to the south-west China, which is a high-incidence area in China.
Methods
Thirty counties in south-west China were selected, and corresponding weekly malaria cases and four weekly meteorological variables were collected from 2004 to 2009. The Multilevel Distributed Lag Non-linear Model (MDLNM) was used to study the temporal lagged correlation between weekly malaria and weekly meteorological factors. The counties were divided into two groups, hot and cold weathers, in order to compare the difference under different climatic conditions and improve reliability and generalizability within similar climatic conditions.
Results
Rainfall was associated with malaria cases in both hot and cold weather counties with a lagged correlation, and the lag range was relatively longer than those of other meteorological factors. Besides, the lag range was longer in hot weather counties compared to cold weather counties. Relative humidity was correlated with malaria cases at early and late lags in hot weather counties.
Minimum temperature had a longer lag range and larger correlation coefficients for hot weather counties compared to cold weather counties. Maximum temperature was only associated with malaria cases at early lags.
Conclusion
Using weekly malaria cases and meteorological information, this work studied the temporal lagged association pattern between malaria cases and meteorological information in south-west China. The results suggest that different meteorological factors show distinct patterns and magnitudes for the lagged correlation, and the patterns will depend on the climatic condition. Existing inconsistent findings for climatic factors’ lags could be due to either the invalid assumption of a single fixed lag or the distinct temperature conditions from different study sites. The lag pattern for meteorological factors should be considered in the development of malaria early warning system.
doi:10.1186/1475-2875-13-57
PMCID: PMC3932312  PMID: 24528891
19.  Nonparametric ROC Based Evaluation for Survival Outcomes 
Statistics in medicine  2012;31(23):2660-2675.
SUMMARY
For censored survival outcomes, it can be of great interest to evaluate the predictive power of individual markers or their functions. Compared with alternative evaluation approaches, the time-dependent ROC (receiver operating characteristics) based approaches rely on much weaker assumptions, can be more robust, and hence are preferred. In this article, we examine evaluation of markers’ predictive power using the time-dependent ROC curve and a concordance measure which can be viewed as a weighted area under the time-dependent AUC (area under the ROC curve) profile. This study significantly advances from existing time-dependent ROC studies by developing nonparametric estimators of the summary indexes and, more importantly, rigorously establishing their asymptotic properties. It reinforces the statistical foundation of the time-dependent ROC based evaluation approaches for censored survival outcomes. Numerical studies, including simulations and application to an HIV clinical trial, demonstrate the satisfactory finite-sample performance of the proposed approaches.
doi:10.1002/sim.5386
PMCID: PMC3743052  PMID: 22987578
time-dependent ROC; concordance measure; inverse-probability-of-censoring weighting; marker evaluation; survival outcomes
20.  Joint Modeling of Transitional Patterns of Alzheimer's Disease 
PLoS ONE  2013;8(9):e75487.
While the experimental Alzheimer's drugs recently developed by pharmaceutical companies failed to stop the progression of Alzheimer's disease, clinicians strive to seek clues on how the patients would be when they visit back next year, based upon the patients' current clinical and neuropathologic diagnosis results. This is related to how to precisely identify the transitional patterns of Alzheimer's disease. Due to the complexities of the diagnosis of Alzheimer's disease, the condition of the disease is usually characterized by multiple clinical and neuropathologic measurements, including Clinical Dementia Rating (CDRGLOB), Mini-Mental State Examination (MMSE), a score derived from the clinician judgement on neuropsychological tests (COGSTAT), and Functional Activities Questionnaire (FAQ). In this research article, we investigate a class of novel joint random-effects transition models that are used to simultaneously analyze the transitional patterns of multiple primary measurements of Alzheimer's disease and, at the same time, account for the association between the measurements. The proposed methodology can avoid the bias introduced by ignoring the correlation between primary measurements and can predict subject-specific transitional patterns.
doi:10.1371/journal.pone.0075487
PMCID: PMC3779177  PMID: 24073268
21.  ROC Analysis in Biomarker Combination with Covariate Adjustment 
Academic radiology  2013;20(7):874-882.
Rational and Objectives
Receiver operating characteristic analysis (ROC) is often used to find the optimal combination of biomarkers. When the subject level covariates affect the magnitude and/or accuracy of the biomarkers, the combination rule should take into account of the covariate adjustment. The authors propose two new biomarker combination methods that make use of the covariate information.
Materials and Methods
The first method is to maximize the area under covariate-adjusted ROC curve (AAUC). To overcome the limitations of the AAUC measure, the authors further proposed the area under covariate standardized ROC curve (SAUC), which is an extension of the covariate-specific ROC curve. With a series of simulation studies, the proposed optimal AAUC and SAUC methods are compared with the optimal AUC method that ignores the covariates. The biomarker combination methods are illustrated by an example from Alzheimer's disease research.
Results
The simulation results indicate that the optimal AAUC combination performs well in the current study population. The optimal SAUC method is flexible to choose any reference populations, and allows the results to be generalized to different populations.
Conclusions
The proposed optimal AAUC and SAUC approaches successfully address the covariate adjustment problem in estimating the optimal marker combination. The optimal SAUC method is preferred for practical use, because the biomarker combination rule can be easily evaluated for different population of interest.
doi:10.1016/j.acra.2013.03.009
PMCID: PMC3682803  PMID: 23747153
Biomarker combination; covariate adjustment; AUC; covariate standardization
22.  Generalized Partially Linear Models for Incomplete Longitudinal Data In the Presence of Population-Level Information 
Biometrics  2013;69(2):386-395.
Summary
In observational studies, interest often lies in estimation of the population-level relationship between the explanatory variables and dependent variables, and the estimation is often done using longitudinal data. Longitudinal data often feature sampling error and bias due to non-random drop-out. However, inclusion of population-level information can increase estimation efficiency. In this paper we consider a generalized partially linear model for incomplete longitudinal data in the presence of the population-level information. A pseudo-empirical likelihood-based method is introduced to incorporate population-level information, and non-random drop-out bias is corrected by using a weighted generalized estimating equations method. A three-step estimation procedure is proposed, which makes the computation easier. Several methods that are often used in practice are compared in simulation studies, which demonstrate that our proposed method can correct the non-random drop-out bias and increase the estimation efficiency, especially for small sample size or when the missing proportion is high. We apply this method to an Alzheimer's disease study.
doi:10.1111/biom.12015
PMCID: PMC3715115  PMID: 23413768
Auxiliary; drop-out; longitudinal data; partially linear model; population-level information; pseudo-empirical likelihood
23.  A semiparametric separation curve approach for comparing correlated ROC data from multiple markers 
In this article we propose a separation curve method to identify the range of false positive rates for which two ROC curves differ or one ROC curve is superior to the other. Our method is based on a general multivariate ROC curve model, including interaction terms between discrete covariates and false positive rates. It is applicable with most existing ROC curve models. Furthermore, we introduce a semiparametric least squares ROC estimator and apply the estimator to the separation curve method. We derive a sandwich estimator for the covariance matrix of the semiparametric estimator. We illustrate the application of our separation curve method through two real life examples.
doi:10.1080/10618600.2012.663303
PMCID: PMC3466820  PMID: 23074360
Confidence band; Empirical distribution function; Least squares
24.  Marginal methods for clustered longitudinal binary data with incomplete covariates 
Many analyses for incomplete longitudinal data are directed to examining the impact of covariates on the marginal mean responses. We consider the setting in which longitudinal responses are collected from individuals nested within clusters. We discuss methods for assessing covariate effects on the mean and association parameters when covariates are incompletely observed. Weighted first and second order estimating equations are constructed to obtain consistent estimates of mean and association parameters when covariates are missing at random. Empirical studies demonstrate that estimators from the proposed method have negligible finite sample biases in moderate samples. An application to the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) demonstrates the utility of the proposed method.
doi:10.1016/j.jspi.2012.04.006
PMCID: PMC3690662  PMID: 23805025
Association; Generalized estimating equation; Longitudinal data; Missing covariates
25.  A Scan Statistic for Binary Outcome Based on Hypergeometric Probability Model, with an Application to Detecting Spatial Clusters of Japanese Encephalitis 
PLoS ONE  2013;8(6):e65419.
As a useful tool for geographical cluster detection of events, the spatial scan statistic is widely applied in many fields and plays an increasingly important role. The classic version of the spatial scan statistic for the binary outcome is developed by Kulldorff, based on the Bernoulli or the Poisson probability model. In this paper, we apply the Hypergeometric probability model to construct the likelihood function under the null hypothesis. Compared with existing methods, the likelihood function under the null hypothesis is an alternative and indirect method to identify the potential cluster, and the test statistic is the extreme value of the likelihood function. Similar with Kulldorff’s methods, we adopt Monte Carlo test for the test of significance. Both methods are applied for detecting spatial clusters of Japanese encephalitis in Sichuan province, China, in 2009, and the detected clusters are identical. Through a simulation to independent benchmark data, it is indicated that the test statistic based on the Hypergeometric model outweighs Kulldorff’s statistics for clusters of high population density or large size; otherwise Kulldorff’s statistics are superior.
doi:10.1371/journal.pone.0065419
PMCID: PMC3681795  PMID: 23785424

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