Pooling Projects Research Articles

Spline Analysis of Biomarker Data Pooled from Multiple Matched/Nested Case-Control Studies.

Simple SummaryThis paper presents methods to pool continuous biomarker measurements from multiple studies to estimate the dose–response curves that allow for the nonlinear association between biomarker values and disease risks in matched/nested case–control studies. The approach can be easily applied to pooling projects of cancer studies and user-friendly software for implementing the method can be found on the corresponding author’s website.Pooling biomarker data across multiple studies enables researchers to obtain precise estimates of the association between biomarker measurements and disease risks due to increased sample sizes. However, biomarker measurements often vary significantly across different assays and laboratories; therefore, calibration of the local laboratory measurements to a reference laboratory is necessary before pooling data. We propose two methods for estimating the dose–response curves that allow for a nonlinear association between the continuous biomarker measurements and log relative risk in pooling projects of matched/nested case–control studies. Our methods are based on full calibration and internalized calibration methods. The full calibration method uses calibrated biomarker measurements for all subjects, even for people with reference laboratory measurements, while the internalized calibration method uses the reference laboratory measurements when available and otherwise uses the calibrated biomarker measurements. We conducted simulation studies to compare these methods, as well as a naive method, where data are pooled without calibration. Our simulation and theoretical results suggest that, in estimating the dose–response curves for biomarker-disease relationships, the internalized and full calibration methods perform substantially better than the naive method, and the full calibration approach is the preferred method for calibrating biomarker measurements. We apply our methods in a pooling project of nested case–control studies to estimate the association of circulating Vitamin D levels with risk of colorectal cancer.

Approaches to outcome and covariate harmonization--the perfect as the “enemy of the good”

S21: When the Answer is “Big(ger) Data” in Environmental Epidemiology: What are the Questions?, Room 315, Floor 3, August 26, 2019, 1:30 PM - 3:00 PM As discussed in other talks in this session, pooling multiple generally similar studies allows more flexibility in data analysis compared to meta-analysis methods but requires careful attention to details of harmonization. Though the design of pooling projects may consider similarities in available data when selecting cohorts for inclusion, it is nearly inevitable that harmonization of exposures, outcomes, and covariates pose specific challenges. This talk will discuss approaches to harmonization for cohort studies, acknowledging the tradeoffs with each choice made. Even when cohorts use the same methods and tools to collect data, there are differences in cohort design including differences in time periods data were collected, differences in locations of participants, and meaningful differences in how environmental exposures differ over time and space. Harmonization of outcome measures may pose additional challenges, particularly due to changes over time in both standard definitions of health endpoints and data collection methods. For example, blood pressure may be measured, taken from medical records, a self-reported value or self-reported as “high”. It may be reported at baseline only, or reported during follow-ups. Also, standard definitions of high blood pressure have changed over time. When considering how to harmonize all of these aspects must be considered. Most existing pooling projects have harmonized covariates by attempting to create unified variables; is this sufficient? What other considerations should we be taking into account, particularly in environmental epidemiology? Are there other methodological approaches that can be considered? An open discussion of the advantages and disadvantages to different approaches to harmonization will help guide future pooling projects.

Proceedings of the fourth international molecular pathological epidemiology (MPE) meeting.

An important premise of epidemiology is that individuals with the same disease share similar underlying etiologies and clinical outcomes. In the past few decades, our knowledge of disease pathogenesis has improved, and disease classification systems have evolved to the point where no complex disease processes are considered homogenous. As a result, pathology and epidemiology have been integrated into the single, unified field of molecular pathological epidemiology (MPE). Advancing integrative molecular and population-level health sciences and addressing the unique research challenges specific to the field of MPE necessitates assembling experts in diverse fields, including epidemiology, pathology, biostatistics, computational biology, bioinformatics, genomics, immunology, and nutritional and environmental sciences. Integrating these seemingly divergent fields can lead to a greater understanding of pathogenic processes. The International MPE Meeting Series fosters discussion that addresses the specific research questions and challenges in this emerging field. The purpose of the meeting series is to: discuss novel methods to integrate pathology and epidemiology; discuss studies that provide pathogenic insights into population impact; and educate next-generation scientists. Herein, we share the proceedings of the Fourth International MPE Meeting, held in Boston, MA, USA, on 30 May-1 June, 2018. Major themes of this meeting included 'integrated genetic and molecular pathologic epidemiology', 'immunology-MPE', and 'novel disease phenotyping'. The key priority areas for future research identified by meeting attendees included integration of tumor immunology and cancer disparities into epidemiologic studies, further collaboration between computational and population-level scientists to gain new insight on exposure-disease associations, and future pooling projects of studies with comparable data.

Biliary tract cancer incidence and trends in the United States by demographic group, 1999-2013.

Biliary tract cancers (BTCs) are rare but deadly cancers (gallbladder cancer [GBC], intrahepatic cholangiocarcinoma [ICC], extrahepatic cholangiocarcinoma [ECC], and ampulla of Vater cancer [AVC]). A recent US study reported increasing GBC incidence among people younger than 45 years and blacks; however, it did not examine trends for other biliary tract sites. This study characterized demographic differences in BTC incidence rates and time trends by anatomic site. Population-based North American Association of Central Cancer Registries data were used to calculate age-adjusted incidence rates, incidence rate ratios (IRRs), and estimated annual percent changes (eAPCs) for 1999-2013 by site and demographic group. For sites with significant differences in eAPC by age group, IRRs were compared by age group. GBC incidence rates declined among women (eAPC, -0.5%/y; P=.01) and all racial/ethnic groups except for non-Hispanic blacks, among whom rates increased (1.8%/y; P<.0001). Although GBC rates increased among 18- to 44-year-olds (eAPC, 1.8%/y; P=.01), they decreased among people 45 years old or older (-0.4%/y; P=.009). Sex (P<.0001) and racial/ethnic differences (P=.003 to .02) in GBC incidence were larger for younger people than older people. During this period, ICC (eAPC, 3.2%/y; P<.0001) and ECC rates (1.8%/y; P=.001) steadily increased across sex and racial/ethnic groups. Although AVC incidence rates increased among younger adults (eAPC, 1.8%/y; P=.03) but not older adults (-0.20%/y; P=.30), sex and racial/ethnic IRRs did not differ by age. Differential patterns of BTC rates and temporal trends have been identified by anatomic site and demographic groups. These findings highlight the need for large pooling projects to evaluate BTC risk factors by anatomic site.

Abstract P225: The Associations of Dietary and Biomarkers of Linoleic Acid Intake and All-cause and Cardiovascular Mortality: A Systematic Review and Meta-analysis

Background: Previous studies on intake of linoleic acid (LA), a predominant n-6 fatty acid, and risk of mortality from all-cause and cardiovascular disease (CVD) have generated inconsistent results. We performed a systematic review and meta-analysis of prospective cohort studies to summarize the evidence regarding the relation of LA and all-cause and CVD mortality. Methods: We searched MEDLINE and EMBASE databases through June 2017 for prospective cohort studies reporting association of LA (assessed by dietary survey or biomarker in blood or adipose tissue) with all-cause and CVD mortality. In addition, unpublished data from pooling projects were included. We pooled the multivariate-adjusted Hazards ratios (HRs) using random-effect meta-analysis, which allowed for between-study heterogeneity. Results: 27 studies covering 37 prospective cohorts were identified; these included 274,565 individuals with dietary assessment (34,597 all-cause and 10,636 CVD deaths) and 54,794 individuals with biomarker measurements (6,767 all-cause and 5,311 CVD deaths). Comparing the highest category with the lowest, dietary LA intake was associated with a 14% lower risk of all-cause mortality (95% confidence interval [CI], 2%-25%, I 2 =71%) and a 20% lower risk of CVD mortality (95% CI, 13%-26%, I 2 =0). Baseline health status (i.e. general population, CVD/high risk for CVD, or cancer) might be a main source of heterogeneity for the association of dietary LA intake with all-cause mortality. As for biomarkers, 1 SD increment in LA was associated with a 9% lower risk of all-cause mortality (95% CI, 4%-14%, I 2 =61%) and a 10% lower risk of CVD mortality (95% CI, 5%-14%, I 2 =13%). Heterogeneity was presented across tissue types and between genders. Conclusions: In prospective cohort studies, LA intake, assessed by either dietary survey or biomarkers, was inversely associated with all-cause and CVD mortality in a dose-response manner. These data support the current recommendations on polyunsaturated fat intake for prevention of CVD and early death.

Review Article: The Role of Molecular Pathological Epidemiology in the Study of Neoplastic and Non-neoplastic Diseases in the Era of Precision Medicine.

Molecular pathology diagnostics to subclassify diseases based on pathogenesis are increasingly common in clinical translational medicine. Molecular pathological epidemiology (MPE) is an integrative transdisciplinary science based on the unique disease principle and the disease continuum theory. While it has been most commonly applied to research on breast, lung, and colorectal cancers, MPE can investigate etiologic heterogeneity in non-neoplastic diseases, such as cardiovascular diseases, obesity, diabetes mellitus, drug toxicity, and immunity-related and infectious diseases. This science can enhance causal inference by linking putative etiologic factors to specific molecular biomarkers as outcomes. Technological advances increasingly enable analyses of various -omics, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, microbiome, immunomics, interactomics, etc. Challenges in MPE include sample size limitations (depending on availability of biospecimens or biomedical/radiological imaging), need for rigorous validation of molecular assays and study findings, and paucities of interdisciplinary experts, education programs, international forums, and standardized guidelines. To address these challenges, there are ongoing efforts such as multidisciplinary consortium pooling projects, the International Molecular Pathological Epidemiology Meeting Series, and the Strengthening the Reporting of Observational Studies in Epidemiology-MPE guideline project. Efforts should be made to build biorepository and biobank networks, and worldwide population-based MPE databases. These activities match with the purposes of the Big Data to Knowledge (BD2K), Genetic Associations and Mechanisms in Oncology (GAME-ON), and Precision Medicine Initiatives of the United States National Institute of Health. Given advances in biotechnology, bioinformatics, and computational/systems biology, there are wide open opportunities in MPE to contribute to public health.

The Age-Specific Quantitative Effects of Metabolic Risk Factors on Cardiovascular Diseases and Diabetes: A Pooled Analysis

BackgroundThe effects of systolic blood pressure (SBP), serum total cholesterol (TC), fasting plasma glucose (FPG), and body mass index (BMI) on the risk of cardiovascular diseases (CVD) have been established in epidemiological studies, but consistent estimates of effect sizes by age and sex are not available.MethodsWe reviewed large cohort pooling projects, evaluating effects of baseline or usual exposure to metabolic risks on ischemic heart disease (IHD), hypertensive heart disease (HHD), stroke, diabetes, and, as relevant selected other CVDs, after adjusting for important confounders. We pooled all data to estimate relative risks (RRs) for each risk factor and examined effect modification by age or other factors, using random effects models.ResultsAcross all risk factors, an average of 123 cohorts provided data on 1.4 million individuals and 52,000 CVD events. Each metabolic risk factor was robustly related to CVD. At the baseline age of 55–64 years, the RR for 10 mmHg higher SBP was largest for HHD (2.16; 95% CI 2.09–2.24), followed by effects on both stroke subtypes (1.66; 1.39–1.98 for hemorrhagic stroke and 1.63; 1.57–1.69 for ischemic stroke). In the same age group, RRs for 1 mmol/L higher TC were 1.44 (1.29–1.61) for IHD and 1.20 (1.15–1.25) for ischemic stroke. The RRs for 5 kg/m2 higher BMI for ages 55–64 ranged from 2.32 (2.04–2.63) for diabetes, to 1.44 (1.40–1.48) for IHD. For 1 mmol/L higher FPG, RRs in this age group were 1.18 (1.08–1.29) for IHD and 1.14 (1.01–1.29) for total stroke. For all risk factors, proportional effects declined with age, were generally consistent by sex, and differed by region in only a few age groups for certain risk factor-disease pairs.ConclusionOur results provide robust, comparable and precise estimates of the effects of major metabolic risk factors on CVD and diabetes by age group.

Shedding Light on Serum Vitamin D Concentrations and the Risk of Rarer Cancers

Cancer is a broad term for many disparate diseases with different etiologies, commonly classified by affected organ site. This review summarizes the published evidence from prospective cohort studies examining the associations between vitamin D, measured as serum 25-hydroxyvitamin D (25OHD) concentrations, and the risk of rarer cancer sites including pancreatic, non-Hodgkin lymphoma, ovarian, endometrial, kidney, gastric and esophageal cancer. Overall, evidence from prospective cohort studies provides little support for a protective association between adequate or higher serum 25OHD concentrations and risk of these rarer cancer sites. Additionally, controversy persists concerning a potential increased risk of pancreatic cancer associated with serum 25OHD levels >100 nmol/L due to conflicting results reported by two large prospective pooling projects. Keywords: 25-hydroxyvitamin D, Bladder cancer, Cancer, Cohort, Endometrial cancer, Esophageal cancer, Gastric cancer, Kidney cancer, Nested case-control study, Non-Hodgkin lymphoma, Ovarian cancer, Pancreatic cancer, Prospective studies, Vitamin D

Shedding Light on Serum Vitamin D Concentrations and the Risk of Rarer Cancers

Cancer is a broad term for many disparate diseases with different etiologies, commonly classified by affected organ site. This review summarizes the published evidence from prospective cohort studies examining the associations between vitamin D, measured as serum 25-hydroxyvitamin D (25OHD) concentrations, and the risk of rarer cancer sites including pancreatic, non-Hodgkin lymphoma, ovarian, endometrial, kidney, gastric and esophageal cancer. Overall, evidence from prospective cohort studies provides little support for a protective association between adequate or higher serum 25OHD concentrations and risk of these rarer cancer sites. Additionally, controversy persists concerning a potential increased risk of pancreatic cancer associated with serum 25OHD levels > 100 nmol/L due to conflicting results reported by two large prospective pooling projects.

Characteristics of land value variation and the urban land market in Kathmandu, Nepal1

This paper examines the characteristics of the urban land market in Kathmandu, the capital city of Nepal, in two stages by analysing land value variation in 2002 and 2009. In the first stage, it captures the characteristics of urban spatial structure, using the extended land value gradient model which includes not only the distance from the city centre but also zoning, road accessibility and planning variables as the determinants of land values. The estimates show that urban growth in Kathmandu has recently been characterized by neither centralization nor suburbanization with little shift in urban land demand between central and peripheral areas. Instead, land values have increased significantly across all urban areas, indicating the possibility of overall excess demand for urban plots. Correspondingly, in the second stage whether the supply is sufficient in urban land market is tested using two methods. First, by investigating the data on land pooling projects, urban land value after the project turns out to be greater than the sum of agricultural land value before the project and rural-to-urban conversion costs. Second, the actual or physical distance of urban-rural boundary turns out to be shorter than the theoretical or economic distance derived from the estimates of the extended gradient model. Both results confirm that urban land supply is in a shortage in Kathmandu.

Implementation experiences of land pooling projects in Kathmandu Valley

To facilitate planned development through adequate supply of serviced plots for housing, a full fledged and more positive approach called the land pooling scheme was initiated in 1988 in the Kathmandu Valley. Today, the valley has managed to implement 11 projects after hard negotiations with the landowners. However, no review has been made so far as to what extent they were able to meet the overall planning objectives. This paper makes an attempt to assess the overall implementation experiences of land pooling projects in the valley. At the beginning, the paper introduces: the urban land management challenges, the concept of land pooling and the international experiences, the Nepalese context of urban land development, and the land pooling projects of Kathmandu Valley. The paper then makes an assessment of the implementation experiences: strengths and weaknesses, and finally, concludes by making recommendations to improve the performance of the future land pooling projects to achieve the urban planning objectives mentioned above.

Land Pooling for Resubdivision and New Subdivision in Western Australia

Abstract. Land pooling is a technique for the unified subdivision of separate private landholdings in urban‐fringe areas. Pooling projects are self‐financing and the costs and profits of each project are shared between the participating landowners. It provides local governments with a powerful tool for implementing their municipal land use plans and for ensuring an adequate supply of urban land. Local governments in Western Australia began using land pooling in 1951, first to redesign and service old, undeveloped subdivision estates (development projects), then to install special infrastructure works in new suburban areas, and later for the progressive development of their municipalities. By 1982 a total of 56 pooling projects ranging from 1.5 to 250 hectares had been undertaken in metropolitan Perth. The technique and its use in the state of Western Australia are described and discussed and improvements 3re proposed. A case history of a typical pooling project is presented in the appendix. The West Australian experience shows that land pooling could be adopted to improve urban development and land supply for housing in the U.S.A. and Canada, and in other mixed‐economy countries.