Strength

The main strength of multigenerational cohorts is the long-term follow-up of a cohort with a repeated collection of various data from multidisciplinary topics, making it possible to understand how different risk factors affect one’s disease susceptibility not just in one period of life but also cumulative over time even across generations. Also, the multigenerational cohort study design has statistical strengths regarding its accuracy, various levels of data, separating genetic and environmental factors, and direct haplotype assessment. ^{Reference Stolk, Rosmalen and Postma25} Then, this type of study design provides extraordinary opportunities to study social characteristics such as socioeconomic mobility, partner preferences, and generation similarities, and also offers practical benefits in efficiency and a relatively high response rate. Furthermore, the broad age range of participants included in the multigenerational cohorts allows for early detection of events before it’s too late, hence broadening insights into time-dependent effects, and can examine how various exposures affect disease development at different ages.

Weakness

A major problem of multigenerational cohort studies is the loss of follow-up of the cohort over time which is nearly inevitable for studies that are designed to consecutively recruit more than two generations. ^{Reference Arshad, Karmaus, Zhang and Holloway8} Due to the long-term follow-up and attrition of the cohort, multigenerational cohort studies are likely to have incomplete measurements across generations and missing informative data. Also, the poor quality of some cohorts was mostly caused by the practical difficulties when collecting data across multiple generations. Another significant disadvantage of this study design is the generalizability of research findings. The participants of these cohorts are usually recruited from one location with certain ethnic people, and this cohort’s socioeconomic status and common exposures may differ greatly from other cohorts.

Opportunity

Multigenerational cohort studies are important for understanding the DOHaD. Only a small part of the familial clustering of phenotypes can be explained by traditional genetics, which implies the necessity to investigate additional underlying causes and mechanisms. ^{Reference Manolio, Collins and Cox27} Although environmental and behavioral factors are also highly related to families, ^{Reference Taouk and Schulkin28–Reference Karatsoreos, Thaler, Borgland, Champagne, Hurd and Hill30} recent studies in epigenetics indicate potential routes of multigenerational effects may be plausible. ^{Reference Youngson and Whitelaw31,Reference Heindel, McAllister, Worth and Tyson32} Multigenerational cohort studies also provide unique possibilities for researchers to identify pre-conceptional influences on the next generation and the interaction between genetic and environmental factors. ^{Reference Taouk and Schulkin28} Additionally, various topics can be involved and many scientific questions can be addressed in one multigenerational cohort with comprehensive data collected in this cohort.

Threat

Conducting multigenerational human cohort studies is difficult. Retrospective cohort studies are vulnerable to recall bias, ^{Reference McGee, Weisskopf, Kioumourtzoglou, Coull and Haneuse33} and prospective cohort studies are hard to conduct as well since they require long-term follow-up and a large financial investment. And both these two kinds of cohorts are prone to miss data which is the common disadvantage of long-term cohorts. ^{Reference Harville, Kruse and Zhao34} Even if the data is collected regularly, the critical periods of events or disease development usually can’t be identified under the analysis of general statistical methods. The independent effects are also difficult to determine due to inevitable measurement errors. ^{Reference Hallqvist, Lynch, Bartley, Lang and Blane35} Furthermore, the explanation of research findings of multigenerational human cohort studies is complicated. Although it is easy and common to attribute to maternal inheritance, various epigenetic and transgenerational effects have been demonstrated to be paternal inheritance. ^{Reference Zambrano, Martínez-Samayoa and Bautista36}

Interpretation

For decades, evidence demonstrating that inherent properties can be transmitted across more than two generations has changed our knowledge of genetics and disease susceptibility theories. ^{Reference Fitz-James and Cavalli37,Reference Bošković and Rando38} Pioneering research on humans revealed that exposure to smoking, famine, endocrine disruptors, or trauma could influence two to three generations’ offspring, which prompted a significant change in people’s view of heredity. ^{Reference Accordini, Calciano and Johannessen39–Reference Greenblatt-Kimron, Shrira, Rubinstein and Palgi44} However, multigenerational cohort studies conducted on humans were limited, especially for transgenerational inheritance studies. ^{Reference Arshad, Karmaus, Zhang and Holloway8,Reference Stegemann and Buchner45} Particularly, only a few studies begin at an early-life stage and sustain long term. Although child–mother pairs are usually recruited for birth cohort studies, ^{Reference Géa-Horta, Silva Rde, Fiaccone, Barreto and Velásquez-Meléndez46–Reference Dearth-Wesley, Gordon-Larsen, Adair, Zhang and Popkin48} and grown-up children from existing cohorts may be recruited in other new cohorts, ^{Reference Kannel, Feinleib, McNamara, Garrison and Castelli49–Reference Dougan, Willett and Michels51} rarely are cohorts that include integrated and completed three-generation data. ^{Reference Harville, Breckner, Shu, Cooper and Bazzano14}

Although there’s limited evidence of intergenerational and transgenerational inheritance for humans at present, some outstanding findings need to be noticed. For instance, a Swedish study found that providing proper nutrition to paternal grandparents when they were ten years old could decrease cardiovascular diseases and diabetes mellitus risk ^{Reference Kaati, Bygren and Edvinsson52} and extend lifespan ^{Reference Bygren, Kaati and Edvinsson53} of their grandchildren. There were also studies claimed that grandparents’ obesity condition might have an impact on grandchildren’s obesity either directly by grandparents to shape grandchildren’s behavioral decisions or indirectly by their parents. ^{Reference Li, Adab and Cheng54,Reference Kanmiki, Fatima and Mamun55} Golding et al. demonstrated that when both grandmother and mother had smoked, compared to mothers who had not smoked, the smoking ones’ female descendant had declined in height, weight, and fat/lean/bone mass. ^{Reference Golding, Northstone, Gregory, Miller and Pembrey56} And the Framingham Heart Study demonstrated that grandparents who had hypertension in early life could increase the hypertension risk among grandchildren after adjusting for parental confounding factors. ^{Reference Niiranen, McCabe and Larson57} In addition, studies revealed that coronary heart disease, birth weight, body mass index, and major depressive disorder have intergenerational inheritance and can transmit across three generations. ^{Reference Emanuel, Filakti, Alberman and Evans58–Reference Weissman, Berry and Warner62}