Association between multiple-heavy-metal exposures and systemic immune inflammation in a middle-aged and elderly Chinese general population.

BACKGROUND: Exposure to heavy metals alone or in combination can promote systemic inflammation. The aim of this study was to investigate potential associations between multiple plasma heavy metals and markers of systemic immune inflammation. METHODS: Using a cross-sectional study, routine blood tests were performed on 3355 participants in Guangxi, China. Eight heavy metal elements in plasma were determined by inductively coupled plasma mass spectrometry. Immunoinflammatory markers were calculated based on peripheral blood WBC and its subtype counts. A generalised linear regression model was used to analyse the association of each metal with the immunoinflammatory markers, and the association of the metal mixtures with the immunoinflammatory markers was further assessed using weighted quantile sum (WQS) regression. RESULTS: In the single-metal model, plasma metal Fe (log10) was significantly negatively correlated with the levels of immune-inflammatory markers SII, NLR and PLR, and plasma metal Cu (log10) was significantly positively correlated with the levels of immune-inflammatory markers SII and PLR. In addition, plasma metal Mn (log10 conversion) was positively correlated with the levels of immune inflammatory markers NLR and PLR. The above associations remained after multiple corrections. In the mixed-metal model, after WQS regression analysis, plasma metal Cu was found to have the greatest weight in the positive effects of metal mixtures on SII and PLR, while plasma metals Mn and Fe had the greatest weight in the positive effects of metal mixtures on NLR and LMR, respectively. In addition, blood Fe had the greatest weight in the negative effects of the metal mixtures for SII, PLR and NLR. CONCLUSION: Plasma metals Cu and Mn were positively correlated with immunoinflammatory markers SII, NLR and PLR. While plasma metal Fe was negatively correlated with immunoinflammatory markers SII, NLR, and PLR.

Association between the dietary antioxidant index and relative telomere length of leucocytes in the Chinese population.

Dietary antioxidant indices (DAI) may be potentially associated with relative telomere length (RTL) of leucocytes. This study aimed to investigate the relationship between DAI and RTL. A cross-sectional study involving 1656 participants was conducted. A generalised linear regression model and a restricted cubic spline model were used to assess the correlation of DAI and its components with RTL. Generalised linear regression analysis revealed that DAI (ß = 0·005, P = 0·002) and the intake of its constituents vitamin C (ß = 0·043, P = 0·027), vitamin E (ß = 0·088, P < 0·001), Se (ß = 0·075, P = 0·003), and Zn (ß = 0·075, P = 0·023) were significantly and positively correlated with RTL. Sex-stratified analysis showed that DAI (ß = 0·006, P = 0·005) and its constituents vitamin E (ß = 0·083, P = 0·012), Se (ß = 0·093, P = 0·006), and Zn (ß = 0·092, P = 0·034) were significantly and positively correlated with RTL among females. Meanwhile, among males, only vitamin E intake (ß = 0·089, P = 0·013) was significantly and positively associated with RTL. Restricted cubic spline analysis revealed linear positive associations between DAI and its constituents' (vitamin E, Se and Zn) intake and RTL in the total population. Sex-stratified analysis revealed a linear positive correlation between DAI and its constituents' (vitamin E, Se and Zn) intake and RTL in females. Our study found a significant positive correlation between DAI and RTL, with sex differences.

The effect of a tailored message package for reducing antibiotic use among respiratory tract infection patients in rural Anhui, China: a cluster randomized controlled trial protocol.

BACKGROUND: Antibiotics are over-used for patients with respiratory tract infections (RTIs) in primary care, especially in the rural areas of China. METHODS: A cluster randomized controlled trial (RCT) will be carried out to estimate the effectiveness of a tailored message package for educating patients to reduce antibiotic use for symptomatic respiratory tract infections (RTIs). In the intervention group, patients will receive 12 short messages in 12 consecutive days. The whole process of the message design, modification, translation (of substitution variables), and sending will be facilitated by a user-friendly mini-computer program. The primary measure for assessment is the reduction in number of days in which antibiotics are used by patients with symptomatic RTIs. The secondary measures include (1) patients' knowledge about and attitude toward antibiotics; (2) patients' quality of life (EQ-5D-5L) and symptom severity and duration; (3) times of re-visits to clinics and antibiotics re-prescription for the same RTI episode; and (4) times of re-occurrence of RTIs and related health service seeking and antibiotics consumption. DISCUSSION: This study will determine the efficacy of a 12-message intervention to educate patients to reduce excessive antibiotic use in rural China. TRIAL REGISTRATION: ISRCTN29801086 . Registered on 23 September 2022.

Effects of COVID-19 on Global Financial Markets: Evidence from Qualitative Research for Developed and Developing Economies.

The research aims to prioritize the pandemic's impact on the financial markets of developed and developing economies using a multi-criteria decision-making approach. The results revealed that COVID-19's pandemic effects on financial markets differ between developed and developing nations. COVID-19 pandemic affects developed countries' financial markets more through supply reduction, demand reduction, and economic instability. Regarding developing nations, confidence and expectations, changes in consumption patterns, and the bandwagon effect are the three most significant impacts of COVID-19 pandemic on financial markets. The best decisions to lower the effect of COVID-19 pandemic on developed nations' financial markets are the declaration of the stimulus package and support of small-and-medium-sized enterprises. Contrastingly, in developing countries, support for vulnerable households and declaration of the stimulus package are the best decisions to combat COVID-19's negative impact on their financial markets. As practical policy implications for lowering COVID-19's negative impact on financial markets, the promotion of new financing instruments, reconstruction of the relationship between public and private sectors, and support of vulnerable households and enterprises are highly recommended.

La recherche vise à hiérarchiser l'impact de la pandémie sur les marchés financiers des économies développées et en développement en utilisant une approche décisionnelle à plusieurs critères. Les résultats ont révélé que les effets du COVID-19 sur les marchés financiers diffèrent entre les nations développées et en développement. Le COVID-19 affecte davantage les marchés financiers des pays développés par la réduction de l'offre, la réduction de la demande et l'instabilité économique. En ce qui concerne les pays en développement, la confiance et les attentes, les changements dans les habitudes de consommation et l'effet boule de neige sont les trois impacts les plus significatifs causé par le COVID-19 sur les marchés financiers. Les meilleures décisions pour réduire l'effet du COVID-19 sur les marchés financiers des pays développés ont été la déclaration de plans de relance et le soutien aux petites et moyennes entreprises. En revanche, dans les pays en développement, le soutien aux ménages vulnérables et la déclaration de plans de relance apparaissent comme les meilleures décisions pour combattre l'impact négatif du COVID-19 sur leurs marchés financiers. En ce qui concerne les implications politiques pratiques pour réduire l'impact négatif du COVID-19 sur les marchés financiers, la promotion de nouveaux instruments de financement, la reconstruction de la relation entre les secteurs public et privé, et le soutien des ménages et des entreprises les plus vulnérables sont fortement recommandés.

Differentiated Effects and Determinants of Home Blood Pressure Telemonitoring: Three-Year Cohort Study in Jieshou, Anhui, China.

BACKGROUND: Home blood pressure telemonitoring (HBPT) is witnessing rapid diffusion worldwide. Contemporary studies documented mainly short-term (6-12 months) effects of HBPT, and there are limited data about its uptake. OBJECTIVE: The aim of this study was to explore the 3-year use and determinants of HBPT, and the interactions with systolic and diastolic blood pressure (SBP/DBP) and overall blood pressure (BP) control rate. METHODS: HBPT records were obtained from a 3-year cohort of 5658 patients with hypertension in Jieshou, Anhui, China, and data from a structured household survey of a random sample (n=3005) of the cohort. The data analysis comprised (1) timeline trajectories of the rates of monthly active HBPT and mean SBP/DBP for overall and subgroups of patients with varied start-month SBP/DBP; and (2) multivariable linear, logistic, and percentile regression analyses using SBP/DBP, BP control rate, and yearly times of HBPT as the dependent variable, respectively. RESULTS: HBPT was followed by mixed changes in mean monthly SBP/DBP for varied patient groups. The magnitude of changes ranged from -43 to +39 mmHg for SBP and from -27 to +15 mmHg for DBP. The monthly rates of active HBPT all exhibited a rapid and then gradually slower decline. When controlled for commonly reported confounders, times of HBPT in the last year were found to have decreasing correlation coefficients for SBP/DBP (from 0.16 to -0.35 and from 0.11 to -0.35, respectively) and for BP control rate (from 0.53 to -0.62). CONCLUSIONS: HBPT had major and "target-converging" effects on SBP/DBP. The magnitude of changes was much greater than commonly reported. BP, variation in BP, and time were the most important determinants of HBPT uptake. Age, education, duration of hypertension, family history, and diagnosis of hypertension complications were also linked to the uptake but at weaker strength. There is a clear need for differentiated thinking over the application and assessment of HBPT, and for identifying and correcting/leveraging potential outdated/new opportunities or beliefs.

Evaluating an oral health programme for the prevention of dental decay among school-aged children in China: protocol for a mixed-methods study based on the RE-AIM framework.

INTRODUCTION: The objective of the Comprehensive Intervention of Oral Disease for Children (CIODC) in China is to prevent dental decay for school-aged children and provide free prevention services in pilot areas beginning in 2008. It is a potentially affordable, acceptable and effective prevention strategy to use for more school-aged children in the future. There is a shortage of robust evidence regarding the cost-effectiveness, feasibility and scalability of prevention strategies for dental decay for school-aged children in China. This study aims to provide a comprehensive evaluation, including an economic evaluation and process evaluation, to better understand how and why the public health programme may be effective and economical. METHODS AND ANALYSIS: Mixed methods will be used in this study. Cost-effectiveness analysis (CEA) will be conducted from a societal perspective, based on a modelling study over 6 years (from age 7 to 12) in terms of the incremental cost-effectiveness ratios per dental decay averted. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework informed the process evaluation. An estimated 48-80 semistructured interviews with service providers, patient parents/caregivers and decision-makers under the logic model will be used in the progress evaluation to describe the feasibility and sustainability of CIODC. ETHICS AND DISSEMINATION: The study has all necessary ethical approvals from the Ethics Committee of Anhui Medical University (number 2021H030). All participants will provide informed consent prior to participation. Findings will be disseminated through conference presentations and scientific publications in peer-reviewed journals.

Stated preferences for family doctor contract services: a survey of the rural elderly in Anhui Province, China.

OBJECTIVE: A number of factors contribute to the utilisation of family doctor contract services (FDCS) in China. This study aims to measure the preferences of the elderly for the FDCS and identify the key factors (and their relative importance) that may guide policymakers in more accurately providing the FDCS. PARTICIPANTS AND METHODS: A discrete choice experiment was performed to elicit the preferences for FDCS among the rural elderly in China. Attributes and levels were established based on qualitative methods. Four attributes were included: service type, service package, physician's reputation and annual contract costs. A D-efficient design was used to create a set of profiles that represented FDCS. The survey was conducted face to face using a sample of participants aged 60 and above in rural areas of Anhui Province. The data were analysed using a latent class logit (LCL) model. RESULTS: A total of 545 valid questionnaires were included in the analysis. The average age of the participants was 69.44 (SD 5.80). Two latent classes were identified with the LCL model. All four attributes proved statistically significant at the level of both the population mean and the two classes. The rural elderly showed a preference for FDCS with a relatively good reputation, lower annual contract costs, the basic service with the add-on of chronic disease service and home visit. Age, gender, education, self-reported health status and the number of chronic diseases were found to be associated with latent class membership. CONCLUSION: In this study, the physician's reputation had the largest impact on the rural elderly's choice of FDCS. Policy recommendations included the need to strengthen family doctor team training, devote greater attention to improving the family doctor's medical skills and service approaches, and increased FDCS efficiency for the care of the rural elderly.

Antibiotic Stewardship in Retail Pharmacies and the Access-Excess Challenge in China: A Policy Review.

In China, efforts to restrict excessive antibiotic consumption may prevent sufficient access to these life-saving drugs among the most deprived in society because of the weak primary health care system. This makes antibiotic stewardship in the retail pharmacy sector a particular challenge. We conducted an analysis to examinate policies on antibiotic sales in retail pharmacies in China and how tensions between 'excess' and 'access' are managed. The analysis was guided by the Walt and Gilson health policy analysis triangle to systematically analyse policies based on the content of policies, contexts, governance processes, and actors. Nine research studies and 25 documents identified from national and international sources were extracted, grouped into categories, and examined within and across records and categories. As of 2020, eight key policies have been introduced in China that focus on two areas: dispending prescribed medicines or antimicrobials with a prescription and having a licensed pharmacist present in the retail pharmacies, with approaches having changed over time. Inappropriate sales of antibiotics are still common in retail pharmacies, which can be linked to the lack of consistency and enforcement of published policies, the profit-driven nature of retail pharmacies, and the displacement of the demand for antibiotics from clinical into less regulated settings.

Cluster randomised controlled trial to assess a tailored intervention to reduce antibiotic prescribing in rural China: study protocol.

INTRODUCTION: Up to 80% of patients with respiratory tract infections (RTI) attending healthcare facilities in rural areas of China are prescribed antibiotics, many of which are unnecessary. Since 2009, China has implemented several policies to try to reduce inappropriate antibiotic use; however, antibiotic prescribing remains high in rural health facilities. METHODS AND ANALYSIS: A cluster randomised controlled trial will be carried out to estimate the effectiveness and cost effectiveness of a complex intervention in reducing antibiotic prescribing at township health centres in Anhui Province, China. 40 Township health centres will be randomised at a 1:1 ratio to the intervention or usual care arms. In the intervention group, practitioners will receive an intervention comprising: (1) training to support appropriate antibiotic prescribing for RTI, (2) a computer-based treatment decision support system, (3) virtual peer support, (4) a leaflet for patients and (5) a letter of commitment to optimise antibiotic use to display in their clinic. The primary outcome is the percentage of antibiotics (intravenous and oral) prescribed for RTI patients. Secondary outcomes include patient symptom severity and duration, recovery status, satisfaction, antibiotic consumption. A full economic evaluation will be conducted within the trial period. Costs and savings for both clinics and patients will be considered and quality of life will be measured by EuroQoL (EQ-5D-5L). A qualitative process evaluation will explore practitioner and patient views and experiences of trial processes, intervention fidelity and acceptability, and barriers and facilitators to implementation. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Biomedical Research Ethics Committee of Anhui Medical University (Ref: 20180259); the study has undergone due diligence checks and is registered at the University of Bristol (Ref: 2020-3137). Research findings will be disseminated to stakeholders through conferences and peer-reviewed journals in China, the UK and internationally. TRIAL REGISTRATION NUMBER: ISRCTN30652037.

The impact of COVID-19 on primary health care and antibiotic prescribing in rural China: qualitative study.

BACKGROUND: In China, the primary health care (PHC) system has been designated responsible for control and prevention of COVID-19, but not treatment. Suspected COVID-19 cases presenting to PHC facilities must be transferred to specialist fever clinics. This study aims to understand the impact of COVID-19 on PHC delivery and on antibiotic prescribing at a community level in rural areas of central China. METHODS: Qualitative semi-structured interviews were conducted with 18 PHC practitioners and seven patients recruited from two township health centres and nine village clinics in two rural residential areas of Anhui province. Interviews were transcribed verbatim and analysed thematically. RESULTS: PHC practitioners reported a major shift in their work away from seeing and treating patients (due to government-mandated referral to specialist Covid clinics) to focus on the key public health roles of tracing, screening and educating in rural areas. The additional work, risk, and financial pressure that PHC practitioners faced, placed considerable strain on them, particularly those working in village clinics. Face to face PHC provision was reduced and there was no substitution with consultations by phone or app, which practitioners attributed to the fact that most of their patients were elderly and not willing or able to switch. Practitioners saw COVID-19 as outside of their area of expertise and very different to the non-COVID-19 respiratory tract infections that they frequently treated pre-pandemic. They reported that antibiotic prescribing was reduced overall because far fewer patients were attending rural PHC facilities, but otherwise their antibiotic prescribing practices remained unchanged. CONCLUSIONS: The COVID-19 pandemic had considerable impact on PHC in rural China. Practitioners took on substantial additional workload as part of epidemic control and fewer patients were seen in PHC. The reduction in patients seen and treated in PHC led to a reduction in antibiotic prescribing, although clinical practice remains unchanged. Since COVID-19 epidemic control work has been designated as a long-term task in China, rural PHC clinics now face the challenge of how to balance their principal clinical and increased public health roles and, in the case of the village clinics, remain financially viable.

A quantitative trait rare variant nonparametric linkage method with application to age-at-onset of Alzheimer's disease.

To analyze pedigrees with quantitative trait (QT) and sequence data, we developed a rare variant (RV) quantitative nonparametric linkage (QNPL) method, which evaluates sharing of minor alleles. RV-QNPL has greater power than the traditional QNPL that tests for excess sharing of minor and major alleles. RV-QNPL is robust to population substructure and admixture, locus heterogeneity, and inclusion of nonpathogenic variants and can be readily applied outside of coding regions. When QNPL was used to analyze common variants, it often led to loci mapping to large intervals, e.g., >40 Mb. In contrast, when RVs are analyzed, regions are well defined, e.g., a gene. Using simulation studies, we demonstrate that RV-QNPL is substantially more powerful than applying traditional QNPL methods to analyze RVs. RV-QNPL was also applied to analyze age-at-onset (AAO) data for 107 late-onset Alzheimer's disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with whole-genome sequence data. When AAO of AD was analyzed regardless of APOE ε4 status, suggestive linkage (LOD = 2.4) was observed with RVs in KNDC1 and nominally significant linkage (p < 0.05) was observed with RVs in LOAD genes ABCA7 and IQCK. When AAO of AD was analyzed for APOE ε4 positive family members, nominally significant linkage was observed with RVs in APOE, while when AAO of AD was analyzed for APOE ε4 negative family members, nominal significance was observed for IQCK and ADAMTS1. RV-QNPL provides a powerful resource to analyze QTs in families to elucidate their genetic etiology.

A Rare Variant Nonparametric Linkage Method for Nuclear and Extended Pedigrees with Application to Late-Onset Alzheimer Disease via WGS Data.

To analyze family-based whole-genome sequence (WGS) data for complex traits, we developed a rare variant (RV) non-parametric linkage (NPL) analysis method, which has advantages over association methods. The RV-NPL differs from the NPL in that RVs are analyzed, and allele sharing among affected relative-pairs is estimated only for minor alleles. Analyzing families can increase power because causal variants with familial aggregation usually have larger effect sizes than those underlying sporadic diseases. Differing from association analysis, for NPL only affected individuals are analyzed, which can increase power, since unaffected family members can be susceptibility variant carriers. RV-NPL is robust to population substructure and admixture, inclusion of nonpathogenic variants, as well as allelic and locus heterogeneity and can readily be applied outside of coding regions. In contrast to analyzing common variants using NPL, where loci localize to large genomic regions (e.g., >50 Mb), mapped regions are well defined for RV-NPL. Using simulation studies, we demonstrate that RV-NPL is substantially more powerful than applying traditional NPL methods to analyze RVs. The RV-NPL was applied to analyze 107 late-onset Alzheimer disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with WGS data, and statistically significant linkage (LOD ≥ 3.8) was found with RVs in PSMF1 and PTPN21 which have been shown to be involved in LOAD etiology. Additionally, nominally significant linkage was observed with RVs in ABCA7, ACE, EPHA1, and SORL1, genes that were previously reported to be associated with LOAD. RV-NPL is an ideal method to elucidate the genetic etiology of complex familial diseases.

Pathways to optimising antibiotic use in rural China: identifying key determinants in community and clinical settings, a mixed methods study protocol.

INTRODUCTION: This study aims to investigate patterns of antibiotic treatment-seeking, describe current levels of and drivers for antibiotic use for common infections (respiratory tract and urinary tract infections) and test the feasibility of determining the prevalence and epidemiology of antimicrobial resistance (AMR) in rural areas of Anhui province, in order to identify potential interventions to promote antibiotic stewardship and reduce the burden of AMR in China. METHODS AND ANALYSIS: We will conduct direct observations, structured and semistructured interviews in retail pharmacies, village clinics and township health centres to investigate treatment-seeking and antibiotic use. Clinical isolates from 1550 sputum, throat swab and urine samples taken from consenting patients at village and township health centres will be analysed to identify bacterial pathogens and ascertain antibiotic susceptibilities. Healthcare records will be surveyed for a subsample of those recruited to the study to assess their completeness and accuracy. ETHICS AND DISSEMINATION: The full research protocol has been reviewed and approved by the Biomedical Ethics Committee of Anhui Medical University (reference number: 20170271). Participation of patients and doctors is voluntary and written informed consent is sought from all participants. Findings from the study will be disseminated through academic routes including peer-reviewed publications and conference presentations, via tailored research summaries for health professionals, health service managers and policymakers and through an end of project impact workshop with local and regional stakeholders to identify key messages and priorities for action.

The relationship between demands for lung cancer screening and the constructs of health belief model: a cross-sectional survey in Hefei, China.

The aim of investigation is to explore the relationship between demands for lung cancer screening (LCS) and the constructs derived from the health belief model (HBM) in Hefei. The study collected data about socio-demographics, health beliefs in and demands for LCS during early June to later July 2015. By constructing a LCS demands HBM constructs, it calculated indices of demands for LCS (DSI) and HBM constructs, which include perceived risk (PR) and seriousness (PS) of the cancers; and perceived effectiveness (PE), benefits (PB) and difficulties (PD) of the screening. It also performed descriptive and multivariate regression analysis of the demands and the HBM constructs. The amount of 823 respondents participated and completed the survey. 6.4% of them had ever undertaken LCS, whereas 60.1% of them expressed willingness to accept the service of LCS if it is free. In multiple regression analysis which used weights in calculating the HBM construct indices, education displayed significant positive associations with DSI (p = .044), and most of HBM constructs indices (PSI, PRI, PBI, and PDI) were statistically significant with DSI (p < .05). HBM-based constructs regarding LCS have important effects on demands for the service, and may provide effective paths to cancer screening promotion.

SEQSpark: A Complete Analysis Tool for Large-Scale Rare Variant Association Studies Using Whole-Genome and Exome Sequence Data.

Massively parallel sequencing technologies provide great opportunities for discovering rare susceptibility variants involved in complex disease etiology via large-scale imputation and exome and whole-genome sequence-based association studies. Due to modest effect sizes, large sample sizes of tens to hundreds of thousands of individuals are required for adequately powered studies. Current analytical tools are obsolete when it comes to handling these large datasets. To facilitate the analysis of large-scale sequence-based studies, we developed SEQSpark which implements parallel processing based on Spark to increase the speed and efficiency of performing data quality control, annotation, and association analysis. To demonstrate the versatility and speed of SEQSpark, we analyzed whole-genome sequence data from the UK10K, testing for associations with waist-to-hip ratios. The analysis, which was completed in 1.5 hr, included loading data, annotation, principal component analysis, and single variant and rare variant aggregate association analysis of >9 million variants. For rare variant aggregate analysis, an exome-wide significant association (p < 2.5 × 10-6) was observed with CCDC62 (SKAT-O [p = 6.89 × 10-7], combined multivariate collapsing [p = 1.48 × 10-6], and burden of rare variants [p = 1.48 × 10-6]). SEQSpark was also used to analyze 50,000 simulated exomes and it required 1.75 hr for the analysis of a quantitative trait using several rare variant aggregate association methods. Additionally, the performance of SEQSpark was compared to Variant Association Tools and PLINK/SEQ. SEQSpark was always faster and in some situations computation was reduced to a hundredth of the time. SEQSpark will empower large sequence-based epidemiological studies to quickly elucidate genetic variation involved in the etiology of complex traits.

The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data.

Whole-genome and exome sequence data can be cost-effectively generated for the detection of rare-variant (RV) associations in families. Causal variants that aggregate in families usually have larger effect sizes than those found in sporadic cases, so family-based designs can be a more powerful approach than population-based designs. Moreover, some family-based designs are robust to confounding due to population admixture or substructure. We developed a RV extension of the generalized disequilibrium test (GDT) to analyze sequence data obtained from nuclear and extended families. The GDT utilizes genotype differences of all discordant relative pairs to assess associations within a family, and the RV extension combines the single-variant GDT statistic over a genomic region of interest. The RV-GDT has increased power by efficiently incorporating information beyond first-degree relatives and allows for the inclusion of covariates. Using simulated genetic data, we demonstrated that the RV-GDT method has well-controlled type I error rates, even when applied to admixed populations and populations with substructure. It is more powerful than existing family-based RV association methods, particularly for the analysis of extended pedigrees and pedigrees with missing data. We analyzed whole-genome sequence data from families affected by Alzheimer disease to illustrate the application of the RV-GDT. Given the capability of the RV-GDT to adequately control for population admixture or substructure and analyze pedigrees with missing genotype data and its superior power over other family-based methods, it is an effective tool for elucidating the involvement of RVs in the etiology of complex traits.