Historical cohort studies and the early origins of disease hypothesis: making sense of the evidence

Abstract

The hypothesis that early-life growth patterns contribute to non-communicable diseases initially emerged from historical cohort studies, consistently associating low birth weight and infant weight gain with later disease risk. Cohort studies offer crucial life-course data on disease aetiology, but also suffer from important limitations, including the difficulty of adjusting for confounding factors and the challenge of interpreting data on early growth. Prospective randomised trials of infant diet appear to provide evidence in direct contradiction to cohort studies, associating faster early growth with disease risk. The present article attempts to resolve this contradiction on two grounds. First, insufficient attention has been directed to inconsistency of outcomes between cohort studies and prospective trials. Cohort studies can assess actual mortality, whereas prospective trials investigate proxies for disease risk. These proxies are often aspects of phenotype that reflect the 'normalisation' of metabolism in response to growth, and not all those displaying normalisation in adolescence and early adulthood may go on to develop disease. Second, a distinction is made between 'metabolic capacity', defined as organ development that occurs in early life, and 'metabolic load', which is imposed by subsequent growth. Disease risk is predicted to be greatest when there is extreme disparity between metabolic capacity and metabolic load. Whereas cohort studies link disease risk with poor metabolic capacity, prospective trials link it with increased metabolic load. Infancy is a developmental period in which nutrition can affect both metabolic capacity and metabolic load; this factor accounts for reported associations of both slow and fast infant growth with greater disease risk. Early origins of disease hypothesis: Historical cohort studies: Conflicts in evidence:Phenotypic inductionDuring the 20th century the burden of disease in industrialised countries shifted dramatically from infectious to non-infectious diseases as a result of changes in sanitation, hygiene, living conditions and nutrition (1) . In 1880 infectious, parasitic and respiratory diseases accounted for approximately 50% of all deaths in England and Wales, whereas cancers and diseases of the circulatory system accounted for <10%. By 1990 the corresponding percentages had altered to 17 and 70 (1) . The modern killers became known as 'lifestyle' diseases, attributed to behavioural factors such as diet, sedentary behaviour and tobacco smoking, although both genetic factors and broader environmental factors such as pollution were also acknowledged to be important. Public health campaigns to reduce the prevalence of CVD and associated diseases such as type 2 diabetes, hypertension and stroke focused on dietary change (decreased consumption of fat, salt and refined carbohydrate, increased consumption of fruit, vegetables, vitamins and minerals), reductions in smoking and alcohol consumption and the promotion of leisure-time physical activity. Within the last two d...

Infant Growth and the Occurrence of Developmental Defects of Enamel in 12-Year-Olds

“…This result appears to be similar to reports by other investigators in medicine, i.e. rapid infant growth is related to certain health problems [Rikkonen et al, 2008;Wells, 2009], while from a dental perspective preterm/low-birthweight children have a significantly higher prevalence of enamel defects in either primary and/or permanent teeth [Nelson et al, 2010;Jacobsen et al, 2014]. The lack of an association between poor growth and DDE in secondary school children, found in this study, may be due to the fact that the subsample was drawn from a randomized stratified sampling procedure.…”

“…It is also hypothesized that rapid infant growth exacerbates metabolic load, whereas poor infant growth constrains metabolic capacity. Both effects can be influenced by nutritional status and growth patterns during infancy, which ultimately affect health later in life [Wells, 2009]. However, permanent incisors and first molars commence formation at approximately 5 months of embryogenesis, with mineralization beginning at birth and continuing for 3 or 4 years post partum.…”

Body composition indices of a load–capacity model: gender- and BMI-specific reference curves

“…The fundamental concept of the two indices is that the metabolic load in an individual is not given by a specific amount of the two individual components but by their contribution relative to one another. Adapted from Wells (20,21) Statistical methods Analyses were conducted utilising the DXA data sets released by NHANES on the Centers for Disease Control and Prevention website (http://www.cdc.gov/nchs/about/ major/nhanes/dxx/dxa.htm). Age was entered into the models as the independent variable.…”

“…In addition, the relationship between skeletal muscle and adipose tissue changes with increasing adiposity and it is modified by gender and assessment of regional body composition (16) . A new conceptual approach to chronic disease risk has focused on the contribution of two contrasting traits: (i) 'metabolic capacity', which refers to the organs and tissues that maintain homeostasis; and (ii) 'metabolic load', which derives from other body components or from behaviours (dietary intake, sedentary behaviour) that collectively challenge the maintenance of homeostasis (20,21) . The original model focused on the fact that many homeostatic organs are strongly influenced by fetal growth, indicating that metabolic capacity is powerfully shaped by developmental experience.…”

The hunt for the epiallele

“…To study pure epialleles, an isogenic environment offers a means with which to increase the power to detect non-genetic events, and this has been successfully performed in inbred mouse strains [Pogribny et al, 2009] and studies of disease-discordant monozygotic twins [Javierre et al, 2010]. Identification of environmentally induced epialleles in human cohorts should also take careful note of potential confounding factors when considering their aetiological role [Wells, 2009].…”