Journal of Preventive Medicine

Introduction
Although in infectious diseases, transmissibility of the disease from one person to another is a proven principle, it is less understood in most chronic diseases. An important hypothesis in the field of transmission in chronic diseases is that humans pass their genes to their children. Genetic epidemiology studies on immigrants, studies on familial aggregation, studies on twins, and child adoption studies, explain the role of genetic factors in the occurrence of a disease in contrast to environmental factors. Examining familial aggregation is the first step in identifying the hereditary causes of diseases, which compares the prevalence of a specific disease in people of a given family and community, and is considered as a prerequisite for more specialized investigations. In these studies, scholars investigate the causes of diseases by using indirect evidence or phenotype and without using specialized tests of DNA. Although due to the importance of determining the genetic causes of diseases for the early diagnosis of diseases in high-risk people as well as preventing the occurrence and progression of diseases, familial aggregation studies are carried out on a large scale, but we found no any review study in the field of definition and different methods of its implementation. Therefore, this study aims to review the principles, concepts, and various methods of familial aggregation analysis to provide coherent information in this field.

Methods
This is a systematic review study. A search was first conducted in international databases including Google Scholar, Cochrane Library, Medline/PubMed and national databases including IranMedex, Magiran, SID, and the website of international genetic epidemiology society (https://www.geneticepi.org) for the related studies published until March, 2021 using the keywords “familial” OR “family” and “aggregation”. To find more studies, the articles were also searched manually. The primary outcome of this study is to explain and provide comprehensive and clear explanations for familial aggregation and its methods. All familial aggregation studies were included in the review. Those published in a language other than English or Persian were excluded from the review. After removing the duplicates, to evaluate the inclusion and exclusion criteria, the titles, abstracts, and full texts of the articles were independently evaluated by two researchers. Information including the first author’s name, country of study, year of study, a definition for familial aggregation, phenotype, the comparison group, and conclusion were extracted.

Results
Based on the initial search, 461197 articles were found, of which 67 were found from the national databases, 31.13% from PubMed, 68.74% from Google Scholar and 13% from Cochrane Library. 138,581 articles were excluded due to being duplicate and 322,600 articles were excluded by examining their titles and abstracts due to investigating family aggregation in certain diseases and not providing an explanation about the methods. Then, the full text of the remaining 16 articles was read; 3 articles due to being irrelevant and 6 articles due to having incomplete and insufficient information about the methods of conducting family aggregation studies were excluded. Finally, 7 eligible articles were selected. 
The selected articles had been published from 2000 to 2014; of which 71% were published during 2000-2010 and 29% after 2010. Four articles (57%) explained the implementation method by using the comparison group, one article (14.28%) based on the phenotypes, and two articles based on both methods. Based on the study design, two articles were case-control, cohort, and cross-sectional, 3 articles were case-control and cohort, and one article was only case-control.

Discussion
The present study is the first systematic review of the definitions, principles, and methods of family aggregation. Family aggregation study is done when the desired disease and phenotype in family members is more than the expected rate of that disease in the population. Based on the results of the reviewed studies, the presence of family aggregation in different phenotypes indicates that any environmental and genetic factors or their interaction may play a role in the occurrence of the disease, but it cannot determine the role of these factors separately. Case-control studies are more useful in cases where the phenotype is rare. Recall biases and misclassification of cases and controls due to recall problems are lower in case-control studies that investigate genetic factors. In this design, cases are selected from the disease registration systems or based on medical records and controls are selected based on the determined criteria from among the study population. Having the desired phenotype in the proband is defined as a outcome and the phenotype status in relatives is defined as exposure. In cohort studies, people with the desired phenotype are considered as the exposed group and people without the studied phenotype are considered as the non-exposed group, and their family members are followed up and finally the occurrence of the phenotype is examined and compared.

Ethical Considerations

Compliance with ethical guidelines
This article has been approved by the Ethics Committee of Tabriz University of Medical Sciences (Code: IR.TBZMED.REC.1400.614). In this study, the samples used in existing studies are not used, and no human samples or hospital records that require informed consent have been used.

Funding
The financial resources of this study were provided by the research center for the management and prevention of traffic accident injuries, Tabriz University of Medical Sciences.

Authors' contributions
Initial idea, design, evaluation accuracy, data extracted from articles and revision of the first draft: Saeed Dastgiri; Searching for sources, extracting the required data from the articles and preparing the first draft: Elham Davtalab Esmaeili.

Conflicts of interest
The authors declared no conflict of interest.

Acknowledgements
The authors would like to express their gratitude to the Research Center for the Management and Prevention of Traffic Accidents and the Tabriz University of Medical Sciences, which provided a suitable platform for searching in domestic and international electronic sources.
 

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