Controlling unmeasured confounders in non-randomized controlled studies is challenging. Negative control theory is based on the theoretical concept that the test result of negative controls must be negative. Setting appropriate negative control incorporates the specificity of association into population studies for the identification and control of unmeasured confounders. This paper explains the principles to control unmeasured confounders using negative control theory from a statistical perspective. A detailed introduction of derived methods based on negative control theory is also introduced, including adjusted standardized mortality ratio method, calibrating P-value method, generalized difference-in-difference model and double negative control method. The reasonable application of those derived methods is also comprehensively summarized based on representative case studies. Negative control is an important statistical design to identify, revise and control unmeasured confounders and a valuable method for comparative effectiveness research based on real-world data.
Humans ; Confounding Factors, Epidemiologic ; Research Design ; Comparative Effectiveness Research ; Bias

BACKGROUND: Age-related musculoskeletal diseases are becoming increasingly burdensome in terms of both individual quality of life and medical cost. We intended to establish a large population-based cohort study to determine environmental, lifestyle, and genetic risk factors of musculoskeletal and other age-related diseases, and to clarify the association between vitamin D status and such diseases. METHODS: We targeted 34,802 residents aged 40-74 years living in areas of northern Niigata Prefecture, including Sekikawa Village, Awashimaura Village, and Murakami City (Murakami region). The baseline questionnaire survey, conducted between 2011 and 2013, queried respondents on their lifestyle and environmental factors (predictors), and self-reported outcomes. Plasma 25-hydroxyvitamin D (25[OH]D) concentration, an indicator of vitamin D status, was determined with the Liaison® 25OH Vitamin D Total Assay. The primary outcome of this study was osteoporotic fracture; other outcomes included age-related diseases including knee osteoarthritis, perception of chronic pain, dementia, and long-term care insurance use. Mean ages of men and women were 59.2 (SD = 9.3, N = 6907) and 59.0 (SD = 9.3, N = 7457) years, respectively. From the blood samples provided by 3710 men and 4787 women, mean 25(OH)D concentrations were 56.5 (SD = 18.4) nmol/L (22.6 ng/mL) and 45.4 (SD = 16.5) nmol/L (18.2 ng/mL), respectively. DISCUSSION Follow-up surveys are planned every 5 years for 15 years, and incident cases of our targeted diseases will be followed at hospitals and clinics in and nearby the cohort area. We anticipate that we will be able to clarify the association between vitamin D status and multiple disease outcomes in a Japanese population.
Aged ; Aging ; Cohort Studies ; Epidemiologic Research Design ; Female ; Humans ; Incidence ; Japan ; epidemiology ; Male ; Middle Aged ; Musculoskeletal Diseases ; epidemiology ; prevention & control ; Predictive Value of Tests ; Quality of Life ; Risk Factors ; Vitamin D ; analogs & derivatives ; blood

One of the commonly accepted merits of cohort studies (CSs) refers to the exposure precedes outcome superior to other observational designs. We use Directed Acyclic Graphs to construct a causal graph among research populations under CSs. We notice that the substitution of research population in place of a susceptible one can be used for effect estimation. Its correctness depends on the outcome-free status of the substituted population and the performance of both screening and diagnosis regarding the outcomes under study at baseline. The temporal precedence of exposure over outcome occurs theoretically, despite the opposite happens in realities. Correct effect estimate is affected by both the suitability of population substitution and the validities of outcome identification and exclusion.
Causality ; Cohort Studies ; Confounding Factors, Epidemiologic ; Epidemiologic Methods ; Mass Screening ; Research Design

Confounding affects the causal relation among the population. Depending on whether the confounders are known, measurable or measured, they can be divided into four categories. Based on Directed Acyclic Graphs, the strategies for confounding control can be classified as (1) the broken-confounding-path method, which can be further divided into single and dual broken paths, corresponding to exposure complete intervention, restriction and stratification, (2) and the reserved-confounding-path method, which can be further divided into incomplete exposure intervention (in instrumental variable design and non-perfect random control test), mediator method and matching method. Among them, random control test, instrumental variable design or Mendelian randomized design, mediator method can meet the requirements for controlling all four types of confounders, while the restriction, stratification and matching methods are only applicable to known, measurable and measured confounders. Identifying the mechanisms of confounding control is a prerequisite for obtaining correct causal effect estimates, which will be helpful in research design.
Causality ; Confounding Factors, Epidemiologic ; Humans ; Models, Statistical ; Random Allocation ; Randomized Controlled Trials as Topic ; Research Design

Clinical epidemiology is defined as a method for investigating the distribution and determinants of diseases and for applying this knowledge in their prevention, and simply means application of epidemiological methods for medical research. In evidence-based medicine, randomized controlled trials (RCT) are the gold standard for assessing efficacy and safety of the intervention, while it is commonly impractical because of many limitations, such as ethical/legal problems and weak external-validity. High internal-validity of RCT permits to assess the direct efficacy of intervention without interference with bias and confounder; however, it has less generalizability or applicability to the real-life practice. Evidence-based practical guidelines are developed for patient management and decision making in real-life practice; paradoxically, the evidence of the guidelines does not come from real life, but from strict trial life. To overcome these limitations, pragmatic clinical trials for assessing the effectiveness of intervention in real-life practice or high-quality observational studies would be the best alternatives or could add more strong evidence. This article provides an overview of clinicoepidemiological research designs in the field of childhood allergic diseases and their strength/weakness.
Bias (Epidemiology) ; Child ; Decision Making ; Epidemiologic Methods ; Epidemiology ; Evidence-Based Medicine ; Humans ; Hypersensitivity ; Pragmatic Clinical Trial ; Pragmatic Clinical Trials as Topic ; Research Design*

OBJECTIVES: To evaluate the utility of using a web-based sample size calculator in the preparation of a research proposal.

METHODS: EpiTools, a free web-based calculator for sample size determination, was used in various study designs.

RESULTS: Computations of sample size needed for several simple epidemiologic study designs were calculated using different assumptions. The calculator was straightforward to use and user- friendly. The results were calculated quickly. Comparison of the computed sample size using different assumptions may be done to assist in evaluating research project feasibility. The input data and output of the sample size calculation may be transformed into a report for inclusion in the written research proposal.

CONCLUSION: The EpiTools web-based calculators is a convenient tool for sample size determination in the design of research protocols in relatively simple study designs. It may be used in evaluating the feasibility of the computed sample size needed by the study design.

Academic Dissertations as Topic ; Epidemiologic Research Design ; Molecular Epidemiology

OBJECTIVES: On September 2, 2010 and November 25, 2011, the Korean Research Project on Integrated Exposure Assessment to Hazardous Materials for Food Safety (KRIEFS) organized two international symposia in Seoul, Korea. KRIEFS, established by the Korean Food and Drug Administration in March 2010, envisioned these international symposia as means to obtain advanced experiences from other countries and to reflect on and refine the KRIEFS's survey design and methods. METHODS: For the first symposium KRIEFS invited human biomonitoring (HBM) experts from Germany, the US, and Canada. The visiting HBM experts shared the details of their national studies while the KRIEFS discussed study design, as well as the methods, results and policymaking processes of the KRIEFS project. The second symposium was organized to share the survey design and results on endocrine disruptors from Taiwan. RESULTS: The Speaker from Germany introduced the German Environmental Survey and shared their experiences in HBM design, such as the process of developing reference values, and discussed the new HBM plan in Germany and the European Union. The Representative from Canada shared insights from national HBM approach. In the case of the US, the speaker focused on risk communication with subjects in epidemiological studies. In the second international symposium, the speaker shared the experience of endocrine disruptors'studies from Taiwan. CONCLUSIONS: KRIEFS was able to better understand previous nationwide HBM research designs, policy making process, and risk communication with research subjects.
Canada ; Cohort Studies ; Endocrine Disruptors ; Epidemiologic Studies ; European Union ; Food Safety ; Germany ; Hazardous Substances ; Humans ; Korea ; Policy Making ; Reference Values ; Research Design ; Research Subjects ; United States Food and Drug Administration

Air Pollution ; prevention & control ; Epidemiologic Research Design

OBJECTIVES: Formative research can serve as a means of obtaining important information for designing an epidemiologic study, but descriptions of this approach in the epidemiologic literature are lacking. The objective of this paper is to describe the use of three formative research techniques in designing a survey of home care and hospice nurses. METHODS: We conducted two focus groups, seven key informant interviews, and approximately fifteen hours of direct observation among home care and hospice nurses recruited by word of mouth in North Carolina in 2006. RESULTS: We used information obtained from the formative research to decide which survey design would likely be most successful with this population (mail survey, as opposed to Internet survey or in-person interviews), which measure to use for the denominator of the blood exposure incidence rates (number of visits, as opposed to patient-time), and which items and response options to include in the questionnaire, as well as to identify specific survey techniques that would likely increase the response rate (emphasizing the regional focus of the study; sending the questionnaire to the home address). CONCLUSION: When particular information for planning a study is unavailable from the literature or the investigator's experience, formative research can be an effective means of obtaining that information.
Data Collection ; Epidemiologic Studies ; Focus Groups ; Home Care Services ; Hospices ; Incidence ; Internet ; Mouth ; North Carolina ; Research Design ; Surveys and Questionnaires