Heterogeneity identified at birth and blood pressure in adulthood.

OBJECTIVE: In the developmental programming literature, the association of birth weight and blood pressure later in life is modest at best. This article reexamines this issue using Covariate Density Defined mixture of regressions (CDDmr) to determine if a latent variable, based on birth weight, and known to influence infant mortality, provides a stronger indicator of developmental programming. METHODS: CDDmr identifies two latent components in the birth weight distribution, generally interpreted in the infant mortality literature as "compromised" and "normal" fetal development. The data are taken from the 1958 British National Child Development Study. RESULTS: In the 1958 cohort, the "compromised" component consists of about 10% of the birth weight distribution. Compared to "normal" births, the mean systolic blood pressure at age 45 of "compromised" births is 20.3 (females) and 26.4 (males) mm Hg higher than "normal" births. The relative risks of stage-I-II systolic hypertension (>140 mm Hg) of "compromised" births compared to "normal" births are 10.7 (females) and 4.2 (males). The relative risks of stage-II systolic hypertension (>160 mm Hg) are considerably higher, 241.6 (females) and 74.3 (males). In general, the highest blood pressures are observed in "compromised" births with birth weights within the normal (about 3.0-3.5 kg) birth weight range. Results for diastolic blood pressure are similar. CONCLUSIONS: These associations are much stronger than those identified using conventional methods. CDDmr is likely to be useful for studying the dynamics of developmental programming particularly in large cohort studies where birth weight is often the only indicator of programming available. Am. J. Hum. Biol. 28:545-554, 2016. © 2016 Wiley Periodicals, Inc.

The effect of intra-uterine growth restriction on blood lipids and response to exercise training.

OBJECTIVES: To determine if a small body size at birth is associated with an unfavorable metabolic profile and a reduced response to exercise training in young adults. METHODS: Thirty-six college students, all singletons born to term, participated. Subjects were defined as either high ponderal index (HIGHPI) or low ponderal index (LOWPI). LOWPI was defined as below the 10th percentile of the PI-for-gestational age distribution. HIGHPI was defined as greater than the 10th percentile. Subject groups were matched pair-wise on age, sex, BMI, and pretraining physical activity level. Subjects completed an 8-week aerobic exercise program. Pre- and post-training measurements included a blood lipid profile. RESULTS: The LOWPI group, when compared to the HIGHPI group, exhibited higher total (183.6 mg dl(-1) vs. 150.9, P = 0.04) and LDL cholesterol (114.8 mg dl(-1) vs. 80.2, P = 0.019) values prior to exercise training. After training, these values decreased in the LOWPI group, eliminating the group difference. Various blood lipid ratios were more favorable for the HIGHPI group, both before and after training. The inclusion of maternal smoking as a covariate attenuated group differences for pretraining TChol, pre-training TG:HDL, and post-training HDL cholesterol. CONCLUSIONS: An 8-week exercise program corrected some, but not all, of the differences in blood lipid values between the LOWPI and HIGHPI group. The persistent group difference in blood lipid ratios suggests a higher long-term risk of chronic disease in the LOWPI group independent of lifestyle intervention.

Maternal education, birth weight, and infant mortality in the United States.

This research determines whether the observed decline in infant mortality with socioeconomic level, operationalized as maternal education (dichotomized as college or more, versus high school or less), is due to its "indirect" effect (operating through birth weight) and/or to its "direct" effect (independent of birth weight). The data used are the 2001 U.S. national African American, Mexican American, and European American birth cohorts by sex. The analysis explores the birth outcomes of infants undergoing normal and compromised fetal development separately by using covariate density defined mixture of logistic regressions (CDDmlr). Among normal births, mean birth weight increases significantly (by 27-108 g) with higher maternal education. Mortality declines significantly (by a factor of 0.40-0.96) through the direct effect of education. The indirect effect of education among normal births is small but significant in three cohorts. Furthermore, the indirect effect of maternal education tends to increase mortality despite improved birth weight. Among compromised births, education has small and inconsistent effects on birth weight and infant mortality. Overall, our results are consistent with the view that the decrease in infant death by socioeconomic level is not mediated by improved birth weight. Interventions targeting birth weight may not result in lower infant mortality.

Low ponderal index is associated with decreased muscle strength and fatigue resistance in college-aged women.

Poor fetal growth is associated with decrements in muscle strength likely due to changes during myogenesis. We investigated the association of poor fetal growth with muscle strength, fatigue resistance, and the response to training in the isolated quadriceps femoris. Females (20.6 years) born to term but below the 10th percentile of ponderal index (PI)-for-gestational-age (LOWPI, n=14) were compared to controls (HIGHPI, n=14), before and after an 8-week training. Muscle strength was assessed as grip-strength and as the maximal isometric voluntary contraction (MVC) of the quadriceps femoris. Muscle fatigue was assessed during knee extension exercise. Body composition and the maximal oxygen consumption (VO(2)max) were also measured. Controlling for fat free mass (FFM), LOWPI versus HIGHPI women had ~11% lower grip-strength (P=0.023), 9-24% lower MVC values (P=0.042 pre-trained; P=0.020 post-trained), a higher rate of fatigue (pre- and post-training), and a diminished training response (P=0.016). Statistical control for FFM increased rather than decreased strength differences between PI groups. The PI was not associated with VO(2)max or measures of body composition. Strength and fatigue decrements strongly suggest that poor fetal growth affects the pathway of muscle force generation. This could be due to neuromotor and/or muscle morphologic changes during development e.g., fiber number, fiber type, etc. Muscle from LOWPI women may also be less responsive to training. Indirectly, results also implicate muscle as a potential mediator between poor fetal growth and adult chronic disease, given muscle's direct role in determining insulin resistance, type II diabetes, physical activity, and so forth.

Racial disparities in infant mortality: what has birth weight got to do with it and how large is it?

BACKGROUND: It has been hypothesized that birth weight is not on the causal pathway to infant mortality, at least among "normal" births (i.e. those located in the central part of the birth weight distribution), and that US racial disparities (African American versus European American) may be underestimated. Here these hypotheses are tested by examining the role of birth weight on racial disparities in infant mortality. METHODS: A two-component Covariate Density Defined mixture of logistic regressions model is used to decompose racial disparities, 1) into disparities due to "normal" versus "compromised" components of the birth cohort, and 2) further decompose these components into indirect effects, which are associated with birth weight, versus direct effects, which are independent of birth weight. RESULTS: The results indicate that a direct effect is responsible for the racial disparity in mortality among "normal" births. No indirect effect of birth weight is observed despite significant disparities in birth weight. Among "compromised" births, an indirect effect is responsible for the disparity, which is consistent with disparities in birth weight. However, there is also a direct effect among "compromised" births that reduces the racial disparity in mortality. This direct effect is responsible for the "pediatric paradox" and maybe due to differential fetal loss. Model-based adjustment for this effect indicates that racial disparities corrected for fetal loss could be as high as 3 or 4 fold. This estimate is higher than the observed racial disparities in infant mortality (2.1 for both sexes). CONCLUSIONS: The results support the hypothesis that birth weight is not on the causal pathway to infant mortality among "normal" births, although birth weight could play a role among "compromised" births. The overall size of the US racial disparities in infant mortality maybe considerably underestimated in the observed data possibly due to racial disparities in fetal loss.

Maternal age and infant mortality: a test of the Wilcox-Russell hypothesis.

It has been argued (e.g., the Wilcox-Russell hypothesis) that (low) birth weight is a correlate of adverse birth outcomes but is not on the "causal" pathway to infant mortality. However, the US national policy for reducing infant mortality is to reduce low birth weight. If these theoretical views are correct, lowering the rate of low birth weight may have little effect on infant mortality. In this paper, the authors use the "covariate density defined mixture of logistic regressions" method to formally test the Wilcox-Russell hypothesis that a covariate which influences birth weight, in this case maternal age, can influence infant mortality directly but not indirectly through birth weight. The authors analyze data from 8 populations in New York State (1985-1988). The results indicate that among the populations examined, 1) maternal age significantly influences the birth weight distribution and 2) maternal age also affects infant mortality directly, but 3) the influence of maternal age on the birth weight distribution has little or no effect on infant mortality, because the birth-weight-specific mortality curve shifts accordingly to compensate for changes in the birth weight distribution. These results tend to support the Wilcox-Russell hypothesis for maternal age.

What do we know about the agricultural demographic transition?

The Agricultural Revolution accompanied, either as a cause or as an effect, important changes in human demographic systems. The consensus model is that fertility and mortality increased and health declined with the adoption of agriculture, compared to those for hunter-gatherers. Analysis of the agricultural transition relies primarily on archaeological and paleodemographic data and is thus subject to the errors associated with such data. The assumptions needed to use these data can profoundly affect the inferences that are drawn. While it is clear that, in general, population growth accompanied the agricultural transition, it is not as clear exactly how fertility and mortality changed or whether the transition caused a decline in health. Although the model of the agricultural demographic transition as outlined here may be correct, researchers should remain aware of the underlying assumptions and be open to future empirical evidence.

Modeling the pediatric paradox: birth weight by gestational age.

The "pediatric paradox" of African versus European American infant mortality is often observed with respect to birth weight, but rarely to gestational age, even though the two measures are biologically related. This paper models the pediatric paradox by birth weight and gestational age simultaneously, using Covariate Density Defined mixture of logistic regressions (CDDmlr) fitted to 1985-1988 New York State births. The model controls for unobserved heterogeneity and isolates the pediatric paradox in the "compromised" subpopulation. The paradox is not limited to low birth weights and/or short gestational ages, but surrounds the normal birth range. Nevertheless, the pediatric paradox is only observed in the marginal distribution of birth weight and not the marginal distribution of gestational age. These results are consistent with the hypothesis that higher fetal losses in the "compromised" subpopulation may be responsible for the pediatric paradox and that African versus European American infant mortality differentials are underestimated.

Multiple mortality optima due to heterogeneity in the birth cohort: a continuous model of birth weight by gestational age-specific infant mortality.

Birth weight and gestational age are both important predictors of infant survival. Covariate Density Defined mixture of logistic regressions (CDDmlr), a method that accounts for unobserved heterogeneity, has been applied to birth outcomes using birth weight alone. This paper investigates a CDDmlr model of birth outcomes that includes birth weight and gestational age. Applications to four birth cohorts, composed of all non-Hispanic singleton African/European American female/male live births in New York State from 1985-1988, are presented. Multiple birth weight by gestational age optimal (minimal) mortalities are observed in the birth weight by gestational age-specific mortality surface. Multiple optima have not been mentioned in the published literature, but they do appear in some published plots of birth weight by gestational age mortality. It is possible that misreporting of gestational age contributes to this phenomenon, but it cannot completely explain the locations of the local optima. The global optimum is associated with a "normal" fetal development subpopulation, while the local optima are due to a subpopulation that accounts for most low birth weight, intrauterine growth retarded, pre-term, post-term, and small for gestational age births, as well as, births with misestimated gestational ages. These two subpopulations have significantly different birth weight by gestational age-specific mortality surfaces. Consequently, the presence of multiple optima can be attributed to heterogeneity in the birth cohort. Comparisons of CDDmlr based on birth weight by gestational age and birth weight alone might statistically identify births with "erroneous" gestational age.

Are modern environments really bad for us?: revisiting the demographic and epidemiologic transitions.

It is a common assumption that agriculture and modernization have been detrimental for human health. The theoretical argument is that humans are adapted to hunter-gatherer lifestyles, and that the agricultural and "modern" environments are novel and hence likely to be detrimental. In particular, changes in nutrition, and population size and distribution with the adoption of agriculture, are considered to increase the risk of infectious disease mortality. Similarly, changes due to modern lifestyles, notably changes in nutrition, smoking, exercise, and stress, are thought to be associated with an increased risk of degenerative disease mortality in the industrial environment. This paper reviews the available literature on the history and prehistory of total mortality (the demographic transition) and cause of death (the epidemiologic transition), and finds that neither agriculture nor modernization is associated with increases in mortality, i.e., declines in health. First, mortality does not appear to have increased during the transition to agriculture, or during the early phases of the industrial revolution. Clearly, infectious diseases have declined with modernization. Second, the empirical data, when uncorrected for misclassification of cause of death, do suggest an increase in degenerative disease mortality, at least until the mid 20th century, when these causes of death clearly began to decline. All studies that correct for misclassification of cause of death, however, find that the general decline in degenerative disease mortality began much earlier, perhaps as early as the 1850s in the developed countries. This is about the same time that infectious disease mortality began to decline in these countries. The exception is neoplasms, which increased with modernization until quite recently. Part of the increase in neoplasms may be attributable to increases in smoking during the course of modernization. Nevertheless, the overall risk of degenerative disease mortality appears to have declined with modernization. The fact that the decline in the risk of infectious disease mortality, and the decline in risk of degenerative disease mortality, are largely coordinated suggests that the causes of both declines may be related. Historical trends in morbidity, and potential causes of the decline in infectious and degenerative disease mortality, are briefly considered.

Pediatric paradox: heterogeneity in the birth cohort.

Comparisons of birth-weight-specific infant mortality indicate that low-birth-weight African American infants have lower mortality than low-birth-weight European American infants despite higher infant mortality overall-the "pediatric paradox." One explanation is heterogeneity in birth weight. Analyses of African American and European American births suggest that birth cohorts consist of two heterogeneous subpopulations. One appears to account for normal births, whereas the other may consist of compromised births. Estimates of infant mortality indicate that the compromised subpopulation has higher overall mortality but lower birth-weight-specific mortality. We attribute lower birth-weight-specific infant mortality in the compromised subpopulation to higher rates of fetal loss. Compared to European American birth cohorts, African American birth cohorts have (1) higher birth-weight-specific mortality in the normal subpopulation, (2) larger compromised subpopulations, and (3) lower birth-weight-specific mortality in the compromised subpopulation. Consequently, the pediatric paradox is attributable to greater rates of compromised pregnancies and higher fetal losses among African Americans.

Has the transition to agriculture reshaped the demographic structure of prehistoric populations? New evidence from the Levant.

This paper presents the demographic changes that followed the transition from a hunting-gathering way of life (Natufian) to an agricultural, food-producing economy (Neolithic) in the southern Levant. The study is based on 217 Natufian (10,500-8,300 BC) skeletons and 262 Neolithic (8,300-5,500 BC) skeletons. Age and sex identification were carried out, and life tables were constructed. A five-parameter competing hazard model developed by Siler ([1979] Ecology 60:750-757) was used to smooth life-table data. No indication of increased mortality with the advent of agriculture was noted. On the contrary, both life expectancy at birth (24.6 vs. 25.5 years) and adults' mean age at death (31.2 vs. 32.1 years) increased slightly from the Natufian to the Neolithic period (assuming stationary populations). Yet the transition to agriculture affected males and females differently: mean age at death in the Natufian was higher for adult females compared to adult males, while in the Neolithic, it was the reverse. One interpretation given to the distribution of female ages at death is that with the onset of the Neolithic period, maternal mortality increased as a result of a concomitant increase in fertility. If the adoption of agriculture in the Levant increased the rate of population growth at the beginning of the Neolithic, expectation of life may have increased dramatically.

The evolution of human phenotypic plasticity: age and nutritional status at maturity.

Several evolutionary optimal models of human plasticity in age and nutritional status at reproductive maturation are proposed and their dynamics examined. These models differ from previously published models because fertility is not assumed to be a function of body size or nutritional status. Further, the models are based on explicitly human demographic patterns, that is, model human life-tables, model human fertility tables, and, a nutrient flow-based model of maternal nutritional status. Infant survival (instead of fertility as in previous models) is assumed to be a function of maternal nutritional status. Two basic models are examined. In the first the cost of reproduction is assumed to be a constant proportion of total nutrient flow. In the second the cost of reproduction is constant for each birth. The constant proportion model predicts a negative slope of age and nutritional status at maturation. The constant cost per birth model predicts a positive slope of age and nutritional status at maturation. Either model can account for the secular decline in menarche observed over the last several centuries in Europe. A search of the growth literature failed to find definitive empirical documentation of human phenotypic plasticity in age and nutritional status at maturation. Most research strategies confound genetics with phenotypic plasticity. The one study that reports secular trends suggests a marginally insignificant, but positive slope. This view tends to support the constant cost per birth model.

Modeling birthweight and gestational age distributions: additive vs. multiplicative processes.

Researchers have traditionally employed Gaussian distributions to model quantitative biological traits. Recently, mixtures of Gaussian distributions have begun to be used as well. However, there are many alternatives to the Gaussian distribution. From a theoretical perspective, the lognormal distribution is as applicable as the Gaussian (both are justified on the basis of the Central Limit Theorem). Here, the utility of mixtures of Gaussians and lognormals for describing birthweight and gestational age distributions are compared. This is carried out within the context of the hybrid-lognormal distribution, in which the Gaussian and lognormal are special cases. The data consists of African American births (1985-1988) and European American births (1988) in the state of New York. The results suggest that of the conventional distributions, a mixture of two Gaussians generally provides the best fit to birthweight and gestational age. However, in the case of birthweight a two-component hybrid-lognormal fits better than any of the simpler models. This may be due to a feature of the hybrid-lognormal distribution that can be interpreted as maternal constraints on fetal development.

Birth-weight-specific infant and neonatal mortality: effects of heterogeneity in the birth cohort.

Birth-weight-specific infant mortality is examined using a novel statistical procedure, parametric mixtures of logistic regressions. The results indicate that birth cohorts are composed of two or more subpopulations that are heterogeneous with respect to infant mortality. One subpopulation appears to account for the "normal" process of fetal development, while the other, which accounts for the majority of births at both low and high birth weights, may represent fetuses that were "disturbed" during development. Surprisingly, estimates of neonatal and infant mortality indicate that the "disturbed" subpopulation has lower birth-weight-specific mortality, although overall crude mortality rates are higher for this subpopulation. It is hypothesized that this is due to high rates of fetal loss among the "disturbed" subpopulation, resulting in a highly selected group at birth. The heterogeneity identified in the birth cohort could be responsible for recent decelerations in the decline in infant mortality, and might be the cause of unexplained ethnic differences in birth-weight-specific infant mortality. The novel statistical methodology developed here has broad application within human biology. In particular, it could be used in any context where parametric mixture modeling is applied, such as complex segregation analysis.

Variability of gestational age distributions by sex and ethnicity: An analysis using mixture models.

As an antecedent of birthweight and in its own right, gestational age is an important proximate determinant of infant mortality. Recent analyses using mixture models of birthweight distributions suggest that substantial heterogeneity occurs within a birth cohort even when controlling for sex and ethnicity. This article extends the mixture model analysis to gestational age. The results indicate that, like birthweight, human gestational age distributions are heterogeneous, consisting of two, or perhaps more, subpopulations with separate means and variances. The possibility that birthweight and gestational age both identify the same underlying subpopulations cannot be rejected. Statistical analyses of the sex and ethnic differences indicate that, like birthweight, gestational age distributions vary significantly between the sexes and among ethnic groups. However, the pattern, and even the direction, of the variation often differs between the two indicators of birth outcome. The results suggest that a multivariate mixture model that combines birthweight and gestational age might be a useful extension of the univariate mixture models. Am. J. Hum. Biol. 12:181-191, 2000. Copyright 2000 Wiley-Liss, Inc.