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close this bookEffects of Improved Nutrition in Early Childhood : The institute of Nutrition of Central America and Panama (INCAP) Follow-up Study; Proceedings of an IDECG workshop, July 1990, Bellagio, Italy, Supplement of The Journal of Nutrition (International Dietary Energy Consultative Group - IDECG, 1994, 198 pages)
close this folderMalnutrition and human function: A comparison of conclusions from the INCAP and nutrition CRSP studies(¹,²)
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LINDSAY H. ALLEN³

Department of Nutrition, University of California at Davis, Davis, CA 95616

¹ Presented in the symposium on Nutrition in Early Childhood and its Long-Term Functional Significance, FASEB, April 6, 1992, Anaheim, CA. Published as a supplement to The Journal of Nutrition. Guest editors for this supplement publication were Reynaldo Martorell, The Rollins School of Public Health of Emory University, Atlanta, GA and Nevin Scrimshaw, The United Nations University, Boston, MA.

² The Nutrition CRSP was supported by USAID grants no. DAN1309-G-SS1070-00 and DAN-1309-A-00-9090-00.

³ To whom correspondence should be addressed: Department of Nutrition, University of California, Davis, Meyer Hall, Room 3135, Davis, CA 95616.

ABSTRACT

The overall objective of both the Institute of Nutrition of Central America and Panama (INCAP) studies and the Nutrition Collaborative Research Support Program (CRSP) was to determine if marginal malnutrition affects human function. The conclusions from the two studies were consistent, notably that growth stunting occurs early in life and is accompanied by functional impairments. These consequences of early malnutrition persist later in life. The comparison of INCAP and Nutrition CRSP results also illustrates that the Cuatemalan children were more malnourished and stunted than those in Kenya, Mexico or Egypt and that this greater degree of stunting occurs before 18 months of age. Even the Atole did not bring the average size of supplemented children in Guatemala up to those of the unsupplemented children in the CRSP populations. It is also likely that their functional potential was not realized fully by supplementation. The CRSP studies provide evidence of multiple micronutrient deficiencies associated with poor growth and function and it is probable that these associations exist in Guatemala as well. The overall conclusion is that our attention should be directed to determining the adequacy of micronutrient status in the perinatal period and to the development of approaches that prevent early growth failure. J. Nutr. 125: 1119S-1126S, 1995.

INDEXING KEY WORDS:

· malnutrition
· function
· energy
· growth
· micronutrients
· human

The Institute of Nutrition of Central America and Panama (INCAP) studies described in the preceding articles and the Nutrition Collaborative Research Support Program (CRSP) are two of the largest field investigations of marginal malnutrition ever conducted. Such studies are inherently difficult to design, conduct and control so that the interpretation of their results is always open to question. Because the INCAP and CRSP research had similar goals and measured many of the same outcomes and possible confounding variables, a comparison of the results can extend the generalizability of the conclusions and add new insights into their interpretation. There is no doubt that the general conclusions from the two studies are in agreement and are useful for developing appropriate nutrition policy. However, some important unanswered questions also emerge from this comparison.

Comparison of hypotheses tested

Both projects had the main goal of testing whether marginal malnutrition affects human function. The major hypothesis addressed by the original design of the INCAP longitudinal study (1969-77) was that improved nutrition results in accelerated physical growth and mental development of preschool-aged children; in the follow-up study the hypothesis was extended to apply to the same children at adolescence or adulthood (Martorell et al. 1995a). The major CRSP hypothesis was that marginal malnutrition affects function, namely growth, cognitive performance/behavior, morbidity, reproduction and social competence (Calloway et al. 1988).

Comparison of study designs

There are marked similarities and differences between the studies. The INCAP project was located in rural Guatemala and the Nutrition CRSP was located in rural Kenya and Mexico and a periurban area of Egypt. The CRSP was conducted in three locations to test the generalizability of the results across different staple diets, environments and cultures. Nevertheless, the CRSP investigators worked together closely to ensure that the types of data collected and the research methods were as similar as possible across the three projects. In general, based on anthropometry and dietary information, the nutritional status of the populations was poorest in Kenya, where famines occurred during the project, intermediate in Mexico and best in Egypt. The CRSP results discussed in this article are described in detail elsewhere (Allen et al. 1992a, Allen 1993, Calloway et al. 1992, Kirksey et al. 1992, Neumann et al. 1992).

The original INCAP study was a controlled intervention design, providing energy and protein supplements for pregnant women and children under seven years of age (Martorell et al. l995a). When this project was designed it was the current belief that protein would be the critical growth-limiting nutrient. INCAP analyses have tended to focus on comparisons of Atole and Fresco groups and to analyses of the relationship between supplement intake, often expressed as energy, and outcomes (Habicht et al. 1995). The Nutrition CRSP was a nonintervention observational study in which the intent was to describe relationships between intake and function of several household members consuming their usual diet. When the CRSP was designed, in the late 1970s and early 1980s, it was believed that inadequate energy (food) intake was the dietary problem most likely to limit growth and other human functions (National Research Council, 1977). Thus, energy intake was the main independent variable. However, because energy intake was assessed by frequent measurements of food intake, the consumption of other nutrients and food intake patterns were also used as independent variables during subsequent data analyses.

Pregnant and lactating women, and children were subjects in both studies. The INCAP project was longitudinal, originally studying children for up to 7 y of age and, in the follow-up, adolescents and adults. The CRSP only followed each type of "target" subject for 1 y, or slightly longer for most pregnant or lactating women. CRSP subjects also included schoolers, adult males and nonpregnant nonlactating women.

Many similar functional outcomes of nutritional status were measured, including maternal and child anthropometry and cognitive development and behavior. Morbidity and socioeconomic and demographic data were used as potential confounding variables. The INCAP follow-up study included work capacity measures (Haas et al. 1995) whereas the CRSP has information on the observed activity patterns of some preschoolers and adults. In general, the CRSP focused more on food intake data, measuring 2 days of intake per month during the year of study, on each individual as well as at the household level. Dietary variables constructed during data analysis included micronutrient intakes, estimates of mineral bioavailability and food patterns. Hematological and biochemical measures, included to examine potential confounding effects of vitamin and mineral (primarily iron) deficiency in functional tests, provided an indication of the status of some micronutrients.

Patterns of growth stunting

The INCAP longitudinal study (1969-77), similar to many previous and subsequent studies in developing countries, showed that growth stunting occurred very early in life. The follow-up study was relatively unique in that it followed the same individuals in late adolescence and adulthood, so proving that this early growth failure persisted (Martorell et al. 1995b). The CRSP does not have equivalent longitudinal data across childhood and adolescence because each individual was followed for only 1 year. However, because infants, preschoolers and schoolers were studied from the same sample of households, it is reasonable to compare growth at these ages and make some inference about the longitudinal development of the CRSP children.

One of the most important conclusions from the INCAP follow-up is that size (length) at 3 y of age is a strong predictor of adolescent size (Martorell et al. 1992; Rivera et al. 1995). The situation seems to be similar in the Nutrition CRSP. Figure 1 shows the length/height Z-scores of the target children in each country, in each target age group. At birth, infants were slightly shorter than reference values (Hamill et al. 1979) in all three countries. The most rapid period of growth failure started at ~3-4 mo after birth. Growth stunting relative to the reference values essentially was complete before 18 mo, the age at which Observations were started on preschoolers; length Z-scores actually improved slightly between 18 and 30 mo of age. In Egypt, height Z-scores improved slightly for schoolers, but comparison with crosssectional data on adolescents in the same households and with the adult target subjects suggests that in none of the three CRSP locations will there be a significant change in height status during adolescence. The INCAP followup supports this assumption, because growth in adolescence occurred at a rate similar to that of adolescents in the United States (Martorell et al. 1995b). The pattern for weight Z-scores in the CRSP was similar to that for height, although these were higher than those for height at all ages.

Because both height and weight were stunted, weight-for-height was relatively normal at all ages. Weight-for-height was also relatively normal in Guatemala, in both initial (Martorell et al. 1982) and follow-up studies (Rivers et al. 1995).


FIGURE 1 Height Z-scores of target children in the Nutrition CRSP compared with the Guatemalan children. E = Egypt; M = Mexico; K = Kenya; GS = Guatemalans supplemented with Atole; GNS = Guatemalans supplemented with Fresco. CRSP children were 30 mo old and Guatemalans were 36 ma old. A Z-score of zero represents the NCHS reference value at each age.

Growth-stunting predicts impaired function

INCAP studies indicate that short size was associated with adverse cognitive and behavioral outcomes in infancy and childhood (Lasky et al. 1981) and that this association persisted to adulthood (Martorell et al. 1992). It is somewhat difficult to compare specific outcomes across the studies because there were differences among tests and many of the scores were grouped or scaled differently during analysis. However, it is clear that short stature also predicted poorer outcomes in the Nutrition CRSP. Most of the associations between height and these functional outcomes in both the INCAP and CRSP subjects were identified in multivariate analyses that controlled for variables such as socioeconomic status, years of schooling and parental and household factors.

CRSP preschoolers who were taller, in Kenya and Mexico but not Egypt, had better cognitive and behavioral performance. In Mexico, the taller preschoolers performed better on the Bayley Mental examination (Allen et al. 1992a). They played, verbalized and interacted more frequently and were crying or doing nothing (apathetic) less often (Allen et al. l992a, Scanlon 1989). In Kenya, less-stunted preschoolers had higher scores on the Bayley Mental and Motor tests and played and verbalized more (Sigman et al. 1989a). In general, similar associations were seen with weight but not with weight-for-height.

In schoolers, cognitive scores and verbal comprehension, behavior and school performance tended to be even more strongly correlated with height and weight (Allen et al. 1992a, Oh 1990, Sigman et al. 1989b). Although schoolers' size was probably predominantly determined by the second year of life, we assume that longer exposure to an inadequate diet and performance deficits already obvious in the preschool period created cumulative deficits in the children's performance.

The nutritional causes of growth stunting

Both the CRSP and INCAP data provide very strong evidence that early growth stunting predicts both current and later functional performance of individuals. Certainly, it can no longer be argued that small size is an adaptation to malnutrition, reducing the lifelong need for food but unaccompanied by ill health or poor function (Heckler 1980).

This moves us to the need for a new research agenda, which is to understand the reasons why growth stunting occurs in developing countries and the extent to which poor dietary patterns and specific nutrient deficiencies are responsible. A comparison of the INCAP and CRSP results provides some insight into this question, although not nearly enough.

Comparing the height Z-scores of the CRSP and INCAP preschoolers illustrates the relative degree of early malnutrition across projects Fig. 1). The closest ages for which published data are available for comparison are 30 mo in the CRSP populations and 36 mo in the Guatemalan children. This comparison illustrates the important point that the Guatemalan children were substantially shorter than in the other three countries, even after supplementation with Atole. Thus, it is likely that the Guatemalan children were by far the most malnourished group.

These differences in nutritional status should be attributable to differences in dietary patterns or nutrient intake. The dietary patterns across the three Nutrition CRSP countries are described in Table 1 (Calloway et al. 1992). Mexico and, to a substantial extent, Kenya is similar to Guatemala in that maize and beans supply a large proportion of the dietary energy. Egypt uses more wheat and rice. Animal product and fat consumption is low in all three locations, especially in Kenya and Mexico, where intakes of these dietary constituents are most similar to those in Guatemala.

TABLE 1 Foods consumed by Egyptian, Mexican and Kenyan children'


Preschoolers

Schoolers


Egypt

Mexico

Kenya

Egypt

Mexico

Kenya


(n = 96)

(n = 591

(n = 100)

(n = 63)

(n = 84)

(n = 138)


kcal/d²

kcal/d

Maize

169

551

369

291

1185

877

Wheat

292

75

24

358

97

26

Rice

126

26

41

187

28

29

Legumes

43

80

83

62

201

121

Dairy

59

66

59

72

40

35

Meat, egg

85

60

6

111

76

11

Fats

162

98

29

221

126

41

¹ From analyses by Calloway et al. (1992).
² To obtain kilojoules, multiply kilocalories by 4.184.

The energy intakes of the children in the four locations are shown in Table 2. For the CRSP projects the values represent average energy intakes between 18 and 30 mo of age (Beaton et al. 1992). For the Guatemalan children the data are an average of intakes between 15 and 36 mo, from the home diets of the Fresco group and excluding the small amount of energy provided by this supplement (Martorell et al. 1982).

TABLE 2 Energy and protein intakes of preschoolers in the four countries ¹


Egypt

Mexico

Kenya

Guatemala

Energy,

kj/d

5,003 ± 1237

4,640 ± 1095

3,540 ± 748

3,322 ± 895

Protein,

g/d

36 ± 10

33 ± 8

23 ± 5

21 ± 6

1 Values are means ± SD. Data for CRSP locations are from Beaton et al. (1992). Values for Guatemala are calculated from Martorell et al. (1982).

Clearly, there is a gradation of energy intake across the projects. The CRSP analyses showed that energy intake was adequate for the Egyptian and Mexican preschoolers. In Kenya, where food shortages occurred during the project, energy intakes averaged less than recommended levels. The Guatemalan children consumed even less energy from their home diets than the Kenyan children.

Protein intakes followed a similar pattern because the correlation between protein and energy intake is very high in these populations. In the CRSP, the calculated probability of digestible protein and essential amino acid intakes being inadequate was essentially zero (Beaton 1992).et al. 1992). In Guatemala, protein intake is likely to be adequate for those children consuming adequate amounts of energy, but not otherwise (Town and Viteri 1981).

Because energy intake was inadequate for some Kenyan and Guatemalan children, an energy supplement, such as the Atole used as one of the INCAP supplements, would be expected to benefit the growth of the Guatemalan children and, to a lesser extent, the Kenyan children. Intervention with dietary energy would not be expected to improve the linear growth of the Egyptian or Mexican groups. This is supported by the fact that in both Kenya (Neumann et al. 1992) and Guatemala (Martorell et al. 1982) the children's energy intake during the preceding 12 mo was a predictor of their height at 30 mo (Kenya) and 36 mo (Guatemala) and of functional outcomes. In Egypt (Kirksey et al. 1992) and Mexico (Allen et al. 1992b), where food shortage was not seen, dietary energy intake was not associated with growth or other functions.

Micronutrient deficiencies

Several lines of evidence suggest that micronutrient (mineral and/or vitamin) deficiencies may explain at least some of the early growth failure. As summarized in Table 3, there was a high predicted prevalence of inadequate vitamin and mineral intakes in all three CRSP countries (Callowly et al. 1992, Murphy et al. 1992). The estimates of mineral adequacy were based on algorithms that took into consideration the high intake of phytate (especially in Mexico) and the low consumption of animal products and ascorbic acid. The Guatemalan diet is also high in fiber and phytate and low in ascorbic acid and animal products.

TABLE 3 Predicted prevalence of children with inadequate nutrient intakes¹


Kenya

Egypt

Mexico

Kenya

Egypt

Mexico


n = 96)

(n = 59)

(n = 100)

(n = 63)

(n = 84)

(n = 138)


%

%

Thiamin

1.4

5.9

0.0

0.0

7.4

0.0

Riboflavin

20.4

51.7

1.9

16.3

83.4

1.6

Vitamin B-12

3.2

8.0

44.2

23.6

38.3

86.9

Vitamin C

3.1

62.7

1.2

1.6

34.6

0.0

Vitamin A

2.2

19.5

0.4

9.2

24.4

0.6

Vitamin E

21.5

91.8

85.1

4.5

86.0

43.5

Iron

65.3

88.5

36.2

70.4

87.3

31.4

Zinc

9.8

25.2

57.0

3.5

9.2

29.5

1 From analyses by Calloway et al. (1992) and Murphy et al. (1992). Intakes of niacin, folate, vitamin B-6 and copper were adequate in all three locations. For vitamin A, iron, zinc and copper comparisons are against FAO/WHO basal requirements, i.e., that needed to prevent clinically detectable signs of functional impairment. The prevalence of low intakes would have been substantially higher if based on normative requirements.

There was a very high prevalence of anemia and iron deficiency (low ferritin) in all three CRSP studies. For Egypt, Mexico and Kenya, respectively, low hemoglobin was present in 73, 62 and 74%, and iron deficiency (low ferritin) was present in 38,45 and 40% of preschoolers (Murphy et al. l 992). There is a strong possibility that the Guatemalan children were also iron deficient based on the similarity of their diet to that of the Mexican children, the poor absorption of iron from maize (Martinez-Torres et al.1987) and the high prevalence of iron-deficiency anemia in Central America (DeMaeyer and Adiels-Tegman 1985). Habicht et al. (1973) reported that anemia was not found in 1971 in unsupplemented 2-y olds; however, information about iron deficiency without anemia was not provided. Finally, iron supplements have improved the cognitive (mental) performance of rural Guatemalan children in other studies (Lozoff et al. 1985).

Preschoolers' growth in Mexico and Kenya was related positively to the amount of animal products consumed in their usual diet (Allen et al. l992b, Neumann et al. 1992); animal products supply more nutrients, such as available iron and zinc, and vitamin A and are markers for a diet that is generally of higher quality and lower in fiber and phytate (Allen et al. 1992a). Animal product consumption, as well as other indicators of a better quality diet, also predicted a number of cognitive and behavioral outcomes in children in all three countries.

Micronutrient content of the INCAP supplements

The comparative data presented in Figure 1 also illustrates the important point that even the Guatemalan children supplemented with Atole did not attain the average size of those in any of the CRSP countries and that the supplement failed to prevent all but a very small amount of their growth faltering. Because even the smaller degree of growth stunting of CRSP children was associated with functional deficits, it is reasonable to assume that even those Guatemalan individuals who benefited from the Atole supplement still suffered from a substantial amount of functional impairment.

INCAP's Atole supplement was designed to provide additional energy and protein. It consisted of (g/180 mL) Incaparina,, a vegetable protein mixture (13.5), dry skim milk (21.6) and sugar (9.0) (Martoreal et al. 1995a). The Fresco, which contained only sugar, provided only one third as much energy and no protein. The Atole contained calcium and phosphorus whereas the Fresco did not. Because the Atole ingredients also contained micronutrients, the concentrations of several vitamins and minerals were matched in the two supplements with the aim of preventing differences in these from confounding the interpretation of the results. However, between birth and 2 y of age, the children unexpectedly drank about four times as much Atole as Fresco and twice as much between birth and 3 y (Schroeder et al. 1992). This means, as presented for the 0-2-y age period in Table 4, that there was a difference in the actual micronutrient intake between the two groups. Estimated intakes of four micronutrients (zinc, vitamin B-6, folacin and vitamin B-12) not originally considered in the formulation have been calculated here from the dry skim milk in the Atole. Data are not available for the micronutrient composition of the incaparina. The 1989 RDA values are used (NRC, 1989).

TABLE 4 Nutrients in INCAP supplemento consumed by children 1-2 y


Percent RDA per cup

Percent RDA supplemented





Energy

13

6

12

6

Protein

72

0

66

0

Calcium

50

0

46

0

Phosphorus

40

0

37

0

Iron

54

50

50

21

Ascorbic acid

10

0

9

0

Thiamin

157

157

143

71

Riboflavin

188

188

175

133

Niacin

150

150

189

86

Vitamin A

300

300

275

125

Zinc¹

10

0

9

0

Vitamin B-6¹

7

0

7

0

Folacin¹

21

0

19

0

Vitamin B-12¹

124

0

114

0

1 Calculated contribution from the skim milk in Atole.

The difference between the micronutrients consumed in the two supplements raises two concerns. First, it is impossible to be certain that the greater benefits of the Atole supplement on postpartum growth and development are attributable to its energy content alone. [We note that this was not true for the relationship between energy supplementation of the pregnant woman and birth weight, where this association remained significant when the amount of supplement was controlled for (Habicht et al. l995).] Second, the supplements failed to improve the intake of some micronutrients substantially. Notably, neither supplement contributed much zinc, which may be growth limiting in this population, or ascorbic acid, which might have improved iron absorption and subsequently growth, or vitamin B-6, which might have improved infant cognitive development. Although this is speculation, there is no doubt that even the Atole did not supply enough of some nutrient(s) to prevent growth stunting during the first 2 y after birth.

The nutritional implications of early growth stunting

Figure 2 compares children's average length growth rates between 18 and 30 mo of age for the three CRSP projects, the INCAP study (Martorell and Klein 1980) and the National Center for Health Statistics (NCHS) reference population (Hamilll et al. 1979). The rate of increase in the four poorer countries was less than that of the reference children so that some growth failure was still occurring during this period. However, given that the Guatemalan children were so much shorter than CRSP children at 30-36 mo (Fig. 1), it is remarkable that even the Guatemalans supplemented with Fresco were growing at least as fast as children in Egypt and Kenya, and those supplemented with Atole grew as rapidly as children in all three CRSP locations. The pattern for weight was similar, the Atole-supplemented Guatemalans growing faster than the Mexicans or Kenyans during this period (Fig. 3). This means that the greater degree of growth failure of the Guatemalan children occurred before the age of 18 mo (see Martorell et al. 1995b). Infants in all four countries were breast-fed, the majority receiving almost all of


FIGURE 2 Rate of length growth of NCHS reference, Nutrition CRSP and Guatemalan children. E = Egypt; M = Mexico; K = Kenya; GS = Guatemalans supplemented with Atole; GNS = Guatemalans supplemented with Fresco. Values are for the 18-30-mo age period for all groups. their nutrients from breast milk through at least the first 8 mo of life. Guatemalan infants consumed an average of ~10% of their energy requirements from Atole between 3 and 12 mo of age (Schroeder et al. 1995), most of this presumably toward the end of the first year. Some children still received small amounts of breast milk beyond 18 mot Considering that the most rapid growth failure occurred within a few months of birth in all the population samples, the conclusion must be that either maternal milk or weaning foods failed to supply the nutrients needed by the children.


FIGURE 3 Rate of weight growth of NCHS reference, Nutrition CRSP and Guatemalan children. E = Egypt; M = Mexico; K = Kenya; GS = Guatemalans supplemented with Atole; GNS = Guatemalans supplemented with Fresco. Values are for the 18-30-mo age period for all groups.

The CRSP found some evidence that the poor micronutrient status of the mothers had an adverse effect on breast milk composition. The concentrations of water soluble vitamins in breast milk are especially responsive to maternal dietary intake. In Egypt, breast milk concentrations of vitamin B-6 were only about one half those in milk of nonsupplemented American women and predicted the behavior of the infants at 6 mo of age (McCullough et al. 1990). The milk content of this vitamin was not analyzed in Kenya or Mexico. The only other vitamin measured in breast milk was vitamin B-12 in Kenya and Mexico. The content was deficient in the milk of all the Kenyan mothers (Neumann et al. 1992) and in 62% of the milk samples in Mexico (Black et al. 1994). More data are needed concerning whether the micronutrient content of maternal milk is adequate to support infant growth and development in regions where dietary quality is poor.

The INCAP and Nutrition CRSP studies show that growth failure occurs very early in life in marginally malnourished populations. They leave little doubt that early malnutrition usually causes permanent growth stunting and associated functional deficits. However, we still do not know why it occurs or which nutrients are growth limiting. In Kenya and Guatemala, where there was a shortage of food, inadequate energy intake probably explains some, but not all, of the growth failure. However, the energy provided by the INCAP Atole supplement was not very effective at preventing growth stunting and children given this supplement were still smaller than the average CRSP child at ~30 mo of age.

It is highly probable that, as in the Nutrition CRSP, micronutrient deficiencies played a role in the failure of Guatemalan children to grow adequately. In preschoolers and schoolers this can be attributed in part to their low intake of animal products and the poor bioavailability of minerals from dietary constituents. But the growth failure occurs during the first few months after birth when breast milk provides all or by far the majority of infant's nourishment. It is also evident from these comparisons that the greater severity of growth stunting in the Guatemalan children can be attributed to their nutritional status before the age of 18 mo; between 18 and 30 mo they grew as well or faster than the CRSP children.

For many compelling reasons nutritionists support breast milk as the sole food for infants during the first 4-6 mo of life. Certainly, however, breast milk was not adequate to support optimal growth of either the CRSP or the INCAP infants. Although the introduction of supplementary foods and infant morbidity (especially subclinical) cannot be ruled out definitively as causes of the inadequate growth, in none of the four locations have these explained more than a small proportion of the growth faltering. Further attention should be paid to the possibility that maternal micronutrient deficiencies result in infants having stores at birth and/or intakes from breast milk that are inadequate to support optimal growth and development in such environments. Efforts should now be focused on understanding when to intervene, how to intervene and what nutrients to provide to prevent early growth stunting and its associated persistent functional deficits.

ACKNOWLEDGMENTS

The author is indebted to her coprincipal investigators in the Mexico Nutrition CRSP, Gretel H. Pelto of the University of Connecticut and Adolfo Chavez who headed the research team at the Instituto Nacional de la NutriciĆ³n in Mexico City. Thanks are also due to the principal investigators of the Egypt and Kenya projects, the team at Berkeley and the INCAP investigators, who produced the data discussed here and made helpful comments on this paper.