Stunting and the Prediction of Lung Volumes Among Tibetan Children and Adolescents at High Altitude

Charles A Weitz; Ralph M Garruto

doi:10.1089/ham.2015.0036

. 2015 Dec 1;16(4):306–317. doi: 10.1089/ham.2015.0036

Stunting and the Prediction of Lung Volumes Among Tibetan Children and Adolescents at High Altitude

Charles A Weitz ^1,^✉, Ralph M Garruto ²

PMCID: PMC4685485 PMID: 26397381

Abstract

Weitz, Charles A., and Ralph M. Garruto. Stunting and the prediction of lung volumes among Tibetan children and adolescents at high altitude. High Alt Biol Med 16:306–317, 2015.—This study examines the extent to which stunting (height-for-age Z-scores ≤ −2) compromises the use of low altitude prediction equations to gauge the general increase in lung volumes during growth among high altitude populations. The forced vital capacity (FVC) and forced expiratory volume (FEV₁) of 208 stunted and 365 non-stunted high-altitude Tibetan children and adolescents between the ages of 6 and 20 years are predicted using the Third National Health and Nutrition Examination Survey (NHANESIII) and the Global Lung Function Initiative (GLF) equations, and compared to observed lung volumes. Stunted Tibetan children show smaller positive deviations from both NHANESIII and GLF prediction equations at most ages than non-stunted children. Deviations from predictions do not correspond to differences in body proportions (sitting heights and chest circumferences relative to stature) between stunted and non-stunted children; but appear compatible with the effects of retarded growth and lung maturation that are likely to exist among stunted children. These results indicate that, before low altitude standards can be used to evaluate the effects of hypoxia, or before high altitude populations can be compared to any other group, it is necessary to assess the relative proportion of stunted children in the samples. If the proportion of stunted children in a high altitude population differs significantly from the proportion in the comparison group, lung function comparisons are unlikely to yield an accurate assessment of the hypoxia effect. The best solution to this problem is to (1) use stature and lung function standards based on the same low altitude population; and (2) assess the hypoxic effect by comparing observed and predicted values among high altitude children whose statures are most like those of children on whom the low altitude spirometric standard is based—preferably high altitude children with HAZ-scores ≥ −1.

Key Words: : FVC, FEV1, Global Lung Function Initiative, growth, NHANESIII

Introduction

In addition to being shorter, children who are growth retarded (or “stunted”) also exhibit body proportions that differ from children who are growing normally (Tanner et al., 1982; Bogin, 1999). Perhaps the most recognized difference in body proportions associated with stunting is shorter leg length, which produces longer sitting-height-to-stature ratios (Bogin et al., 2002; Frisancho, 2007). Secular changes and between-population differences in sitting-height-to-stature ratios are known to influence lung volumes (Braun et al., 2013; Quanjer et al., 2015), suggesting that similar differences are likely to exist within populations when stunted children are compared to non-stunted children (Ong et al., 1998).

Additional variation in lung volumes may result from another consequence of stunting: larger chest circumferences relative to stature (Malina et al., 1975; Ounstead et al., 1986; Post and Victora, 2001; Vercellotti and Piperata, 2012). At high altitude, indigenous populations tend to be short (Frisancho and Baker, 1970; Weitz et al., 2000) and linear growth stunting is relatively common among children, both in the Andes (de Meer et al., 1993) and in Tibet (Harris et al., 2001; Argnani et al., 2008; Dang et al., 2008).

In addition, high altitude populations exhibit high sitting-height-to-stature ratios (Stinson, 2009), large chest dimensions relative to stature (Stinson, 1985; Greksa, 1986; Droma et al., 1991), and large lung volumes (Frisancho, 1969, Greksa et al, 1987; Wu and Kaiser, 2006). The large thorax sizes and large lung volumes of high altitude populations have been attributed to developmental and/or genetic effects on thorax growth in a hypoxic environment (Frisancho et al., 1997; Brutsaert et al., 1999), and sitting-height-to-stature ratios may also have a genetic component (Stinson, 2009).

However, the extent to which stunting may cause differences in body proportions among high altitude children, and whether such differences are associated with differences in lung volumes has not been studied. Using a large cross-sectional study of Tibetan children between the ages of 6 and 20 years, this article explores (1) whether body proportions vary between stunted versus non-stunted high altitude children, and (2) whether differences in body proportions that may be associated with stunting alter the deviations between the lung volumes of high altitude children and those predicted based on low altitude standards. If such an alteration exists, it may limit the value of using low altitude standards to assess the effect of hypoxia on lung volumes of indigenous high altitude populations.

Materials and Methods

This study was conducted at three towns located between 3200 m and 4300 m in Qinghai Province, western China between 1990 and 1995. Details of the study and the participating populations have been previously published (Weitz et al., 2000). The human subjects' protocol for this study was reviewed and approved by the Temple University Institutional Review Board and by the Qinghai Bureau of Public Health. Informed consent was obtained from participants and their parents in each of the study towns.

All individuals included in this analysis were determined to have two Tibetan parents. Birthplaces and birth dates (in terms of the Western calendar) of participants were determined from school records or other official forms of identification. Most participants were born and raised in the study towns between 3200 m and 4300 m. A few of the participating individuals (2.7% of the sample) were born at hospitals in towns between 2300 m and 3000 m, and then were brought back up to the study towns as neonates. Otherwise, no migrants are included in the study. Interviews conducted at the time of the study indicate that the overwhelming majority of Tibetans remained year-round in the towns in which the study was conducted. Only about 8% of the participants made trips to nearby high-altitude towns located at or above 3200 m in the year prior to the study. None of these visits lasted more than 4 weeks, and all participants had returned to the study town at least 3 months prior to the time at which the lung function tests took place.

Pediatricians and other health care professionals from collaborating Chinese institutions routinely assessed the health status of prospective participants. Individuals who were identified as suffering from chronic illnesses have not been included in the analysis. A total of 666 males and females of Tibetan descent, between the ages of 6 and 20 years, participated in tests of pulmonary function.

Forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV₁) were determined using a Jones Pulmonaire 10 MS Spirometer (Jones Medical Instrument Company, Oak Brook, Illinois). This is a bellows instrument that met American Thoracic Society (ATS) standards for range and accuracy in the measurement of both FVC and FEV₁, and for resistance and back pressure that existed at the time of the study:1990 through 1995 (American Thoracic Society, 1987). All tests were performed by the same researcher using the same instrument. Volumes were standardized to BTPS prior to analysis; and FEV₁/FVC ratios were subsequently calculated.

The spirometer was calibrated according to manufacturer specifications prior to each individual's tests. The spirometric tests performed by each individual followed procedures recommended by the ATS at the time the study was conducted (American Thoracic Society, 1987). Only individuals who were able to perform three technically acceptable tests in which FVC did not vary by more than 5% were included in the analysis. Analysis is based on the highest of the three acceptable tests. Acceptable tests were performed by 342 boys and 231 girls between the ages of 6 and 20 years.

Anthropometric measurements were taken on each individual, following standard guidelines. Height was converted to Height-for-Age Z-scores (HAZ), using the lambda, mu, and sigma (LMS) transformation technique based on the US Center for Disease Control growth charts from 2000 as reference (Kuczmarski et al., 2002). Conversion to standard deviation units provides a better indication of stature growth retardation than direct anthropometric measurements (Cameron et al., 2005). It also makes possible direct comparisons of relative stature retardation across different ages.

In this study, three HAZ categories are identified: (1) Individuals whose stature was equal to or less than 2 standard deviations below the US CDC means for children and adolescents of the same age (i.e., HAZ ≤ −2); (2) individuals whose stature was between 1 and 2 standard deviations below the US CDC means for children and adolescents of the same age (i.e., < −1 HAZ > −2); and (3) individuals whose stature was equal to or greater than 1 standard deviation below the US CDC means for children and adolescents of the same age (i.e., HAZ ≥ −1). Figure 1 shows the proportion of girls and boys who are stunted (i.e., HAZ ≤ −2) at each age between 6 and 20 years. The overall proportion of stunted Tibetan children in this study (208/573 = 36%) is comparable to rates of over 50% among children ages 7 and younger (Haris et al., 2001) and rates of 28% among children ages 8 through 14 years (Argnani et al., 2008) reported in other studies of Tibetans.

FIG. 1. — The percentage of growth-stunted Tibetan children and adolescents (HAZ < −2) by age. HAZ, Height-for-Age Z-scores.

Statistics

Two strategies are used to determine the extent to which body proportions may be altered by differences in stature. First, regression analysis based on data for all ages is used to compare the relationship between siting height and stature and the relationship between chest circumference and stature among the three HAZ categories. Second, analysis of variance is used to compare the sitting-height-to-stature ratios, chest-circumference-to-stature ratios, and chest-circumference-to-sitting-height ratios of the three HAZ categories by 2-year age groups between 6 and 17 years and for a 3-year group that included 18 through 20 years olds.

To determine the extent to which HAZ status may affect the degree to which lung volumes of Tibetan children deviate from low altitude standards, observed FEV and FEV₁ are compared to values predicted by equations generated from the third National Health and Nutrition Examination Survey (NHANESIII) for Caucasians (Hankinson et al., 1999), and to values predicted by recently-developed equations generated by the Global Lung Function Initiative (GLF) for North East Asians (Quanjer et al., 2012). Lung volumes tend to be larger among Caucasian than other groups (Hankinson et al., 1999), and thus using NHANESIII Caucasian standards provides a conservative estimate of the differences that might exist between low altitude populations and high altitude Tibetans.

Using GLF North East Asian standards provides comparisons with ethnic groups most like Tibetans. Residuals (differences between observed values and those predicted by the two low altitude standards) are analyzed to determine whether, and at what ages, HAZ status may affect deviations from low altitude predictions. ANOVA is used to determine whether residuals for the three HAZ categories differ significantly among pre-pubescent, peri-pubescent and post-pubescent children. All statistical analyses were conducted using PASW statistical software, version 21; and all analyses were conducted separately by sex.

Results

Differences in body proportions

Tables 1 and 2 show the means and standard deviations of stature, sitting height and chest circumference of boys and girls respectively, according to age group and HAZ category. In all age groups, children with HAZ-scores ≥ −1 are significantly taller and have greater sitting height and chest circumference sizes than children with HAZ-scores between −1 to −2 or with HAZ-scores ≤ −2. Figure 2A and B shows the relationship between sitting height and stature by HAZ category for Tibetan boys and girls between the ages of 6 and 20 years. All HAZ categories show the same linear relationship across the entire age range.

Table 1.

Means and Standard Deviations of Stature, Sitting Height, and Chest Circumference by Age and Height-for-Age Z-Scores for Tibetan Boys

Age	HAZ	N	Stature (cm)	Sitting height (cm)	Chest circumference (cm)
6 and 7	≥−1	10	117.4 (3.3)	64.7 (2.3)	56.4 (2.2)
	−1 to −2	10	114.5 (4.5)	63.4 (2.7)	55.2 (2.5)
	≤ −2	10	109.3 (4.8)^***	61.2 (3.2)^*	53.9 (3.1)
	F		9.566^c	3.987^a	2.222^NS
8 and 9	≥−1	7	131.3 (2.3)	72.1 (1.9)	61.5 (2.8)
	−1 to −2	17	123.2 (3.0)^***	66.7 (2.5)^***	58.2 (1.6)^***
	≤ −2	24	117.4 (4.3)^***	65.0 (2.0)^***	58.1 (2.0)^***
	F		42.377^c	28.737^c	8.704^c
10 and 11	≥−1	6	138.5 (2.9)	73.3 (1.0)	63.7 (2.3)
	−1 to −2	21	133.4 (3.1)^*	71.6 (2.0)^*	62.0 (2.5)
	≤ −2	19	126.8 (3.8)^***	69.0 (2.0)^***	60.7 (2.4)^*
	F		34.001^c	15.082^c	3.933^a
12 and 13	≥−1	7	155.0 (1.3)	81.9 (1.8)	72.1 (2.2)
	−1 to −2	24	144.3 (4.7)^***	76.7 (2.9)^***	67.0 (3.2)^***
	≤ −2	26	137.3 (3.5)^***	72.9 (2.2)^***	64.6 (2.6)^***
	F		62.319^c	41.350^c	19.904^c
14 and 15	≥−2	6	169.3 (5.1)	89.2 (4.1)	79.9 (2.8)
	−1 to −2	26	157.4 (3.2)^**	82.1 (2.9)^**	75.5 (3.8)^*
	≤ −2	28	146.1 (6.3)^***	77.1 (3.5)^***	69.6 (4.4)^***
	F		66.731^c	38.828^c	23.874^c
16 and 17	≥−1	17	170.5 (3.2)	89.4 (3.3)	83.0 (3.4)
	−1 to −2	20	164.3 (2.5)^***	87.7 (2.0)	81.5 (3.2)
	≤ −2	12	156.0 (4.6)^***	82.8 (3.7)^***	77.9 (4.7)^**
	F		65.757^c	18.593^c	6.903^b
18–20	≥−1	16	173.1 (3.0)	91.2 (2.6)	85.0 (4.0)
	−1 to −2	26	165.4 (2.2)^***	88.4 (2.2)^**	82.6 (3.7)
	≤ −2	10	159.2 (2.5)^***	85.0 (2.5)^***	80.5 (3.8)^*
	F		99.812^c	21.023^c	4.498^a

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^{^a}

p < 0.05; ^bp < 0.01; ^cp < 0.001; ^NSnot significant.

Difference relative to HAZ ≥ −1, ^*p < 0.05; ^**p < 0.01; ^***p < 0.001. HAZ, Height-for-Age Z-scores.

Table 2.

Means and Standard Deviations of Stature, Sitting Height, and Chest Circumference by Age and Height-for-Age Z-Scores for Tibetan Girls

Age	HAZ	N	Stature (cm)	Sitting height (cm)	Chest circumference (cm)
6 and 7	≥−1	6	120.5 (4.9)	64.8 (3.1)	56.0 (3.0)
	−1 to −2	17	114.1 (3.7)^**	63.1 (2.3)	53.7 (2.4)
	≤ −2	10	109.9 (3.2)^***	61.0 (1.9)^*	53.1 (1.7)
	F		14.609^c	5.205^a	3.134^NS
8 and 9	≥−1	6	131.3 (3.2)	70.2 (1.6)	59.0 (1.1)
	−1 to −2	18	124.4 (3.5)^***	68.3 (2.0)	58.3 (2.2)
	≤ −2	18	118.1 (3.0)^***	64.9 (2.6)^***	54.8 (2.7)^***
	F		41.883^c	17.026^c	13.177^c
10 and 11	≥−1	10	142.8 (4.4)	76.2 (2.6)	63.4 (2.6)
	−1 to −2	11	132.5 (4.1)^***	70.8 (2.4)^***	60.6 (3.2)
	≤ −2	13	125.1 (3.4)^***	68.1 (1.8)^***	58.7 (2.2)^***
	F		57.449^c	36.428^c	8.426^c
12 and 13	≥−1	7	153.2 (3.4)	81.2 (1.8)	69.5 (1.8)
	−1 to −2	9	146.5 (3.0)^**	78.1 (1.7)	66.8 (3.1)
	≤ −2	16	137.4 (4.5)^***	73.5 (3.0)^***	63.8 (4.6)^**
	F		43.926^c	22.174^c	5.927^b
14 and 15	≥−2	7	156.7 (1.1)	82.3 (2.5)	75.1 (4.4)
	−1 to −2	12	152.1 (1.9)^**	80.4 (2.1)	74.8 (3.8)
	≤ −2	11	145.6 (4.0)^***	76.7 (3.1)^***	70.1 (3.4)^*
	F		36.886^c	11.303^c	4.227^a
16 and 17	≥−1	11	159.6 (1.7)	83.6 (2.7)	77.2 (5.5)
	−1 to −2	11	153.2 (1.3)^***	82.0 (1.6)	77.5 (4.3)
	≤ −2	4	146.7 (2.7)^***	78.9 (2.1)^**	77.0 (3.4)
	F		95.316^c	7.203^b	0.022^NS
18–20	≥−1	15	161.5 (4.6)	86.4 (3.1)	81.9 (5.8)
	−1 to −2	12	153.3 (2.1)^***	82.5 (2.4)^**	77.8 (4.5)
	≤ −2	7	147.0 (3.2)^***	79.6 (3.6)^***	78.7 (3.4)
	F		41.362^c	13.419^c	2.522^NS

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^{^a}

p < 0.05; ^bp < 0.01; ^cp < 0.001; ^NSnot significant.

Difference relative to HAZ ≥ −1, ^*p < 0.05; ^**p < 0.01; ^***p < 0.001.

FIG. 2. — Relationship between sitting height and stature among Tibetan boys **(A)** and Tibetan girls **(B)** in three HAZ categories. Age group means are shown, along with regressions based on individual data.

Thus, at any stature, sitting height does not differ among stunted versus non-stunted children. However, age-related increases in stature are greater than age-related increases in sitting height. Thus, in most age groups, the average sitting-height-to-stature ratios of stunted children (HAZ-scores ≤ −2) are higher than for non-stunted children (HAZ-scores between −2 and −1 or HAZ-scores ≥ −1). This is apparent in Table 3 (for boys) and Table 4 (for girls). Differences are statistically significant among 8–11-year-old boys, 6- and 7-year-old girls, and 16- and 17-year-old girls.

Table 3.

Means and Standard Deviations of Sitting-Height-to-Stature, Chest-Circumference-to-Stature, and Chest-Circumference–Sitting-Height Ratios by Age and Height-for-Age Z-Scores for Tibetan Boys

Age	HAZ	N	Sitting height/stature	Chest circ/stature	Chest circ/sitting height
6 and 7	≥−1	10	55.1 (1.3)	48.1 (1.3)	87.2 (4.9)
	−1 to −2	10	55.4 (1.9)	48.2 (2.0)	86.0 (2.9)
	≤ −2	10	56.1 (1.3)	49.4 (2.3)	87.4 (3.5)
	F		2.692^NS	1.406^NS	0.198^NS
8 and 9	≥−1	7	54.9 (1.0)	46.8 (1.8)	85.3 (3.9)
	−1 to −2	17	54.1 (1.5)	47.2 (1.2)	87.4 (3.5)
	≤ −2	24	55.4 (1.6)	49.5 (1.5)	89.4 (2.9)
	F		3.877^a	16.599^c	4.491^a
10 and 11	≥−1	6	53.0 (1.3)	46.1 (1.1)	86.9 (3.4)
	−1 to −2	21	53.6 (1.0)	46.5 (1.5)	86.6 (2.8)
	≤ −2	19	54.5 (1.0)	47.9 (2.2)	87.9 (3.7)
	F		5.595^b	4.026^a	0.799^NS
12 & 13	≥−1	7	52.9 (1.0)	46.5 (1.2)	88.1 (2.8)
	−1 to −2	24	53.2 (1.2)	46.5 (1.9)	87.4 (4.0)
	≤ −2	26	53.1 (1.3)	47.1 (1.7)	88.8 (3.7)
	F		0.186^NS	1.005^NS	0.809^NS
14 and 15	≥−2	6	52.6 (1.5)	47.2 (1.6)	89.8 (4.8)
	−1 to −2	26	52.2 (1.2)	48.0 (2.3)	92.1 (5.0)
	≤ −2	28	52.8 (1.0)	47.7 (2.7)	90.3 (4.8)
	F		1.914^NS	0.308^NS	1.106^NS
16 and 17	≥−1	17	52.4 (1.4)	48.7 (1.9)	92.8 (4.0)
	−1 to −2	20	53.4 (0.9)	49.6 (2.3)	93.0 (4.3)
	≤ −2	12	53.1 (1.1)	49.9 (2.5)	94.1 (5.0)
	F		3.052^NS	1.373^NS	0.318^NS
18–20	≥−1	16	52.7 (1.4)	49.1 (2.2)	93.2 (4.6)
	−1 to −2	26	53.4 (1.2)	49.9 (2.4)	93.6 (4.8)
	≤ −2	10	53.4 (1.2)	50.6 (2.7)	94.8 (5.8)
	F		1.797^NS	1.245^NS	0.328^NS

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^{^a}

p < 0.05; ^bp < 0.01; ^cp < 0.001; ^NSnot significant.

Table 4.

Means and Standard Deviations of Sitting-Height-to-Stature, Chest-Circumference-to-Stature, and Chest-Circumference–Sitting-Height Ratios by Age and Height-for-Age Z-Scores for Tibetan Girls

Age	HAZ	N	Sitting height/stature	Chest circ/stature	Chest circ/sitting height
6 and 7	≥−1	6	53.8 (1.5)	46.5 (2.1)	86.4 (3.6)
	−1 to −2	17	55.3 (1.2)	47.1 (2.2)	85.2 (3.8)
	≤ −2	10	55.5 (1.2)	48.3 (1.0)	87.1 (1.9)
	F		3.919^a	2.101^NS	1.061^NS
8 and 9	≥−1	6	53.5 (1.4)	45.0 (1.1)	84.1 (3.1)
	−1 to −2	18	54.9 (1.4)	46.9 (1.9)	85.4 (3.8)
	≤ −2	18	55.0 (1.8)	46.4 (2.0)	84.5 (4.1)
	F		2.160^NS	2.442^NS	0.380^NS
10 and 11	≥−1	10	53.3 (0.9)	44.4 (1.7)	83.2 (2.9)
	−1 to −2	11	53.5 (1.8)	45.7 (1.9)	85.5 (3.6)
	≤ −2	13	54.5 (1.4)	47.0 (2.2)	86.2 (3.5)
	F		2.379^NS	4.972^a	2.362^NS
12 and 13	≥−1	7	53.0 (1.3)	45.4 (1.6)	85.7 (2.9)
	−1 to −2	9	53.3 (1.4)	45.6 (2.3)	85.6 (5.0)
	≤ −2	16	53.5 (1.3)	46.4 (2.4)	86.8 (4.0)
	F		0.314^NS	0.744^NS	0.335^NS
14 and 15	≥−2	7	52.5 (1.5)	47.9 (3.9)	91.4 (5.7)
	−1 to −2	12	52.9 (1.1)	49.2 (2.1)	93.0 (4.6)
	≤ −2	11	52.7 (1.5)	48.1 (1.7)	91.4 (3.9)
	F		0.178^NS	0.730^NS	0.258^NS
16 and 17	≥−1	11	52.4 (1.3)	48.4 (3.7)	92.4 (7.4)
	−1 to −2	11	53.5 (0.9)	50.6 (2.9)	94.5 (5.1)
	≤ −2	4	53.8 (1.4)	52.4 (1.6)	97.5 (2.6)
	F		3.325^a	2.834^NS	1.102^NS
18–20	≥−1	15	53.5 (1.3)	50.8 (3.9)	95.0 (7.8)
	−1 to −2	12	53.8 (1.3)	50.7 (3.1)	94.3 (5.7)
	≤ −2	7	54.2 (1.8)	53.5 (2.0)	98.8 (5.4)
	F		0.546^NS	1.917^NS	1.138^NS

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^{^a}

p < 0.05; ^bp < 0.01; ^cp < 0.001; ^NSnot significant.

Figure 3A and B shows the relationship between chest circumference and stature for Tibetan boys and girls between the ages of 6 and 20 years in the three HAZ categories. While not shown, the relationship between chest circumference and sitting height follows the same pattern. In all three HAZ categories, the relationship is curvilinear; but both the intercept and the increase in chest circumference relative to stature differ significantly between HAZ categories.

FIG. 3. — Relationship between chest circumference and stature among Tibetan boys **(A)** and Tibetan girls **(B)** in three HAZ categories. Age group means are shown, along with regressions based on individual data.

Tables 3 (boys) and 4 (girls) show that prior to 11 years, increases in stature are greater than increases in chest circumference—causing stunted children (HAZ-scores ≤ −2) to exhibit greater average chest-circumference-to-stature ratios than non-stunted children (HAZ-scores between −2 and −1 or HAZ-scores ≥ −1). Differences are statistically significant among 8–11-year-old boys and 10–11yearold girls. Beginning at age 12, stunted children show more rapid increases in chest circumference relative to stature than non-stunted children. Thus, at statures between 135 cm and 155 cm for boys and at statures between 135 cm and 150 cm for girls, stunted children (HAZ-scores ≤ −2) exhibit greater chest circumferences than non-stunted children (HAZ-scores between −2 and −1 or HAZ-scores ≥ −1).

But the same stature is attained at older ages among stunted compared to non-stunted children; and the maximum stature attained by stunted children is significantly below that of non-stunted children. In addition, the curvilinear relationship between chest circumference and sitting height is more similar for boys than for girls. Thus, at the same age, stunted and non-stunted boys show similar ratios of chest circumference to stature or to sitting height (see Table 3). The greater curvilinear increase in chest circumference relative to stature among stunted girls results in greater average chest-circumference-to-stature and chest-circumference-to-sitting height ratios compared to non-stunted girls at ages 16–17 and 18–20; but the differences are not quite statistically significant (see Table 3).

Differences in lung volumes

Mean stature-adjusted FVC and FEV₁ values obtained at 3200 m, 3800 m, and 4300 m were compared by age using ANOVA (with p < 0.05 as the confidence level for statistical significance). No significant altitude differences in mean, stature-adjusted FVC or FEV₁ values were found at any age among Tibetan males. Among Tibetan females, statistically-significant altitude differences in mean, stature-adjusted FVC and FEV₁ values occurred only among 10- and 13-year olds. At these two ages, girls at 3800 m have significantly higher FVC and FEV1 values than girls at the other two altitudes. The lack of statistically significant altitude differences at any age among males, and the presence of statistically significant altitude differences at only two ages among females, makes it reasonable to combine samples from different altitudes into a single data set for analysis.

Figure 4A–D shows mean FVC and FEV₁ values by age groups among Tibetan boys and girls in the three HAZ categories. Supplementary Tables 1 and 2 show means of FVC, FEV₁ and FEV₁/FVC values, along with the results of an ANOVA comparing children in the three HAZ categories at each age (Supplementary material is available online at www.liebertpub.com/ham).

FIG. 4. — Differences in Forced Vital Capacity (A = boys, B = girls) and FEV₁ (C = boys; D = girls) between three HAZ categories. Significant differences are noted by asterisks. FEV₁, forced expiratory volume at 1 second.

Significant FVC and FEV₁ differences exist among the three HAZ categories at all ages for both boys and girls. Post-hoc analysis indicates that differences between stunted children (HAZ ≤ −2) and children whose HAZ-scores ≥ −1 are statistically significant in all age groups. On the other hand, differences between children in the intermediate category (i.e., HAZ-scores between −2 and −1) and children with HAZ-scores ≥ −1 are often not statistically significant—particularly among girls.

Lung volume predictions

Figure 5A–D shows the differences between observed FVC values and those predicted by GLF and NHANESIII equations. The lines shown represent least squares regressions of the residuals relative to age. FEV₁ residuals are not shown because they show a pattern similar to that shown for FVC. Mean differences between observed FVC and FEV₁ values and values predicted by the two low altitude standards are shown for 6–11-year olds, 12–14-year olds, and 15–20-year olds in Supplementary Table 3. While all three HAZ groups exhibit positive residuals (i.e., FVC values are greater than predicted by both NHANESIII and GLF), differences between observed and predicted values tend to be greater when GLF standards are used than when NHANESIII standards are used.

FIG. 5. — Deviations from Forced Vital Capacity values predicted from GLF equations (A = boys, B = girls) and from NHANESIII equations (C = boys; D = girls). GLF, Global Lung Function Initiative; NHANESIII, Third National Health and Nutrition Examination Survey.

Tibetan boys ages 11 and younger show similar deviations from GLF standards, regardless of HAZ status. Beginning at age 12, however, non-stunted boys (HAZ-scores between −2 and −1 or HAZ-scores ≥ −1) show greater positive deviations from GLF predicted values than boys who are stunted (HAZ-scores ≤ −2). When NHANESIII standards are used, stunted boys show greater positive deviations from predicted values than non-stunted boys up to age 11 and lower positive deviations after age 12. The magnitude of deviations from low altitude standards also tends to be greater among non-stunted, compared to stunted, girls; but differences among the three HAZ categories are much smaller than for boys, and disappear completely after age 18.

Discussion

The FVC and FEV₁ of high altitude populations have frequently been compared to low altitude standards in order to gauge the general increase associated with either genetic adaptation or developmental adjustments to high altitude hypoxia (Frisancho, 1969; Frisancho et al., 1973; Malik and Singh, 1979; Beall, 1984; Greksa et al., 1987, 1988; Havryk et al, 2002; Kiyamu et al., 2012). The results of this study indicate that the inclusion of stunted children in high altitude populations compromises the validity of such comparisons. This is because stunted Tibetan children (i.e., those with HAZ-scores ≤ −2) show generally lower positive deviations from low altitude standards compared to non-stunted children.

The inclusion of stunted Tibetan boys (129/342, 37.7% of the total male sample) reduced the average deviation from low altitude GLF standards by about 24% compared to the average deviation of non-stunted boys only; and reduced the average deviation from low altitude NHANESIII standards by about 30% compared to non-stunted boys only. The inclusion of stunted Tibetan girls (79/231, 34.2% of the total female sample) reduced the average deviation from low altitude GLF and NHANESIII standards by about 22% compared to the average deviation of non-stunted girls.

There are two potential explanations for the differences in observed versus predicted FVC and FEV₁ values between stunted and non-stunted children. One is that the relationship between stature and lung volumes, which is the foundation of low altitude standards, is altered by differences in body proportions associated with stunting. Differences in sitting-height-to-stature ratios are known to be a source of error when applying prediction equations based on one population to others or when comparing differences in lung function between ethnic groups (Yap et al., 2001; Harik-Khan et al., 2004; Pellegrino et al., 2005; Qunajer et al. 2015).

At low altitude, differences in chest circumference are generally discounted as a source of variation in lung volumes (Caldeira Vda et al., 2007). However, there has been no investigation of whether the larger chest-circumference-to-stature ratios observed among stunted children (Malina et al., 1975; Ounsted et al., 1986; Post and Victoria, 2001) might produce additional deviations from predicted values. At high altitude, where populations already exhibit enhanced thorax dimensions (Frisancho et al., 1997; Brutsaert et al., 1999; Wu and Kaiser, 2006), differences in chest-circumference-to-stature ratios associated with stunting could further alter the relationship between stature and lung volumes.

In this sample of high altitude Tibetan children, sitting height shows the same allometric relationship with stature between the ages of 6 and 20 years among all children, regardless of HAZ status. A similar pattern has been observed in growth-advanced versus growth-delayed US children, indicating that differences in maturity are not associated with differences in sitting height at any given stature (Frisancho and Housh, 1988).

Relative to age, however, stunted Tibetan children show greater sitting-height-to-stature ratios compared to non-stunted Tibetan children. Differences are most significant among 6–11-year olds. This is because taller, non-stunted Tibetan children have proportionately shorter sitting heights and longer legs at the same age compared to stunted children. Stunted and non-stunted children also display different relationships between chest circumference and stature or sitting height. Prior to puberty (i.e., ages 11 and younger), chest circumference, like sitting height, does not increase as rapidly as stature, producing larger chest-circumference-to-stature ratios among shorter children at the same age.

At older ages, the increases in chest circumferences relative to stature are greater among stunted compared to non-stunted children. Thus, relative to stature alone, stunted Tibetan adolescents (ages 12 and older) exhibit larger chest circumferences than non-stunted adolescents, regardless of gender. However, when the differences in stature at the same age are taken into consideration, the chest-circumference-to-stature ratios of shorter (stunted) Tibetan adolescent boys and taller (non-stunted) boys show no differences.

On the other hand, the magnitude of chest circumference growth relative to stature is much greater among stunted, compared to non-stunted girls. Thus, at ages 16 and 17 and 18–20 years, girls show similar absolute chest circumferences, despite differences in stature. Consequently, the chest-circumference-to-stature and chest-circumference-to-sitting-height ratios are somewhat larger among stunted than among non-stunted girls. These results provide only ambiguous support for the hypothesis that stunting exaggerates chest-circumference-to-stature or chest-circumference-to-sitting-height ratios among Tibetans at high altitude. Girls tend to fit the model, while boys do not.

The relatively larger sitting-height-to-stature and chest-circumference-to-stature ratios among Tibetan boys in the younger age groups may explain why they have larger residuals when compared to FVC and FEV₁ predicted by NHANESIII equations; and why a similar, although less marked, pattern exists for younger Tibetan girls. However, when GLF predictions are used, differences between observed and predicted FVC and FEV₁ do not differ significantly between stunted and non-stunted children in the younger age groups, despite differences in body proportions.

After age 12, stunted boys show lower positive deviations from low altitude predictions than non-stunted boys, particularly when GLF equations are used. This pattern does not correspond to the similar sitting-height-to-stature ratios among boys ages 12 and older, nor does it correspond to either the greater increases in the chest circumferences of stunted boys relative to stature, or to similar chest-circumference-to-stature ratios among stunted and non-stunted boys relative to age. At ages 10 through 15 years, stunted girls also show lower positive deviations from low altitude predictions compared to non-stunted girls, although differences are not as great as for boys. However, like boys, the lower positive deviations from low altitude predictions noted among stunted girls do not correspond to either the greater increases in chest circumferences relative to stature among stunted compared with non-stunted girls, or to the existence of generally similar sitting-height-to-stature and chest-circumference-to-stature ratios, relative to age.

After age 16 (particularly among 18–20-year olds), stunted and non-stunted girls show similar deviations from low altitude standards, despite the fact that the former exhibit higher sitting-height-to-stature ratios (at ages 16 and 17) and larger chest-circumference-to-stature ratios. These results clearly indicate that differences in body proportions between stunted and non-stunted Tibetan children do not correspond to differences between observed FVC and FEV₁ and those predicted by low altitude standards.

The second potential explanation for differences between observed and predicted values among HAZ categories concerns differences in the rate of maturation. This also is a likely reason for the apparent lack of correspondence between differences in body proportions and differences in observed versus predicted lung volumes. Stunted children are not simply shorter; they also exhibit maturational delays (Bogin, 1999), including a delay in the onset of the adolescent growth spurt in stature. During adolescence, increases in lung volumes are not proportional to increases in height. Among boys in particular, but also to some extent among girls, the onset and acceleration of lung volume growth during adolescence lags behind the onset and acceleration of the adolescent spurt in stature (Sherrill et al., 1989).

A number of factors have been implicated in this delay. One is the slower growth in airway passages relative to alveolar tissue–so-called dysanaptic growth—that occurs during puberty (Smith et al., 2015). Since height and maturation are associated with an increase in the size of the bronchiolar tree, and taller children have greater conducting airway volumes than smaller individuals (Zeman and Bennett, 2006), stunted children can be expected to have smaller airway volumes than non-stunted children, both because they are shorter and because they are likely to exhibit a delay in lung maturation. Additionally, stunted children may show lower increases in volumes during adolescence because of a delay in improvements in muscular strength (Shrader et al., 1988) or a smaller increase in alveolar size (Merkus et al., 1996).

The cross-sectional nature of this study makes it impossible to determine whether or when the adolescent acceleration in stature and/or lung function had occurred for individual children. Nevertheless, it is likely that differences in maturation explain why deviations from predicted lung volumes are most variable among 12–14-year olds. Depending on gender and whether FVC or FEV₁ is being compared to low altitude standards, differences between observed and predicted values for stunted children in this age group are 2 to 6 times lower than for children whose HAZ-scores are ≥ −1.

This discrepancy is likely a consequence of including stunted children who have not yet begun their adolescent growth spurt along with non-stunted children who have. Low altitude standards use age and/or age-squared to model the maturational increase in lung volume at any stature associated with pubertal changes in thorax dimensions and pulmonary dynamics (deGroodt et al. 1988). As a result, low altitude standards predict greater relative FVC and FEV₁ values for children after the onset of puberty than before, even if they have the same stature (Borsboom et al., 1996).

Consequently, low altitude equations will “over-predict” the lung volumes of stunted and maturationally-delayed Tibetan adolescents at high altitude, leading to relatively small deviations between observed and predicted volumes. Taller Tibetans, particularly boys, exhibit a general increase in deviations from low altitude standards after age 12. This could be explained by a lung maturational timing that is more like low altitude adolescents, combined with greater alveolar and/or air passage growth associated with developmental or genetic adaptations to hypoxia.

At low altitude, lung growth for boys lasts throughout adolescence (Neve et al. 2002) and even after height growth is completed (Hibbert et al., 1995). Among growth-delayed boys, the adolescent acceleration in lung growth begins at a later age and shows a lower peak velocity, so that late maturing boys still show considerable annual increments in pulmonary function—even at age 18 (Wang et al., 1993). If stunted Tibetan boys experience a greater delay in lung volume growth relative to stature growth and a slower rate of lung growth because of a delay in maturation, this may explain why they continue to show generally lower volumes for their stature compared to low altitude boys (or Tibetan boys with higher HAZ-scores) through age 20. It is possible that stunted boys could continue to mature past age 20, leading to an increase in the deviation from low altitude standards during adulthood. But this could not be determined using the current data set.

Among girls, lung growth and maturation are more rapid than among boys, and their earlier growth spurt includes both somatic and lung growth (Sherrill et al. 1989). Because of the earlier onset of stature and lung growth, even maturationally-delayed girls complete both lung and stature growth by age 18 (Wang et al., 1993). A more rapid maturation would explain why deviations from low altitude predictions appear to be transitory among stunted Tibetan girls (i.e., are greatest between ages 11 and 14); and a more rapid completion of adolescent growth, even among stunted girls, would explain why deviations between observed and predicted values are similar, regardless of stature among 18–20-year old.

It is also possible that girls may show a greater environmental buffering compared to boys. If this were the case, then the impact of stunting on lung growth might be ameliorated to some extent. However, no research has been conducted regarding gender differences in lung growth in response to undernutriton. So it is difficult to know whether (or how much) such an effect might explain the gender differences noted in this study.

Conclusions

The inclusion of stunted children in this sample of high altitude Tibetans alters the degree to which low altitude predictions can be used to evaluate the effect of hypoxia on FVC and FEV₁ changes during growth. Stunted children, particularly boys after age 12 and girls between ages 10 and 16, exhibit a smaller divergence from low altitude predictions than non-stunted children. This is most likely due to delayed maturation, even though stunting is associated with allometric changes in sitting height relative to stature and to a different pattern of chest circumference relative to stature growth.

As a result, the effect of hypoxia is likely to be underestimated when low altitude standards are used to evaluate the lung growth of high altitude populations that include a large proportion of stunted children. The degree of underestimation will depend upon the proportion of stunted children in a sample, as well the age and gender distribution of stunted versus non-stunted children. Thus, the degree of underestimation caused by the inclusion of stunted children in this group of Tibetan children cannot be generalized to all samples—each will be unique.

While it might seem superior to compare a high altitude group to a low altitude component of the same population, this too would be problematic if there were significant differences in the proportion of stunted children included in the two groups. Perhaps the only solution to such problems is to focus on the lung volumes of high altitude children whose statures are most like the low altitude reference population—preferably children with HAZ-scores ≥ −1. If this strategy is used, then it is probably best to select a lung function standard that is based on the same population as the growth standard.

Since our computation of HAZ-scores was based on the stature of US children determined from the NHANESIII sample, this means that comparing Tibetan children whose HAZ-scores are ≥ −1 with US NHANESIII lung function standards provides a better evaluation of the effects of hypoxia than the use of GLF standards. If HAZ-scores were based on the stature of children from northeast Asia, then it might then be equally appropriate to use the GLF-northeast Asia standards. Mixing stature standards and lung function standards may have contributed to the generally larger deviations that exist when the FVC and FEV₁ values of non-stunted (defined in terms of U.S. standards) Tibetan children are compared to GLF standards. However, the average deviation of all Tibetan children (regardless of stature) from GLF standards is higher than the average deviation from NHANESIII standards. Thus, it also is important to bear in mind that using different standards may produce different results, thereby making inter-study comparisons difficult.

Limitations

In the absence of any independent assessment of puberty status, this analysis presumes that most of the children in the youngest age group in this growth-retarded population were not likely to have begun puberty; that children in the middle age group likely included a mix of children who had begun puberty and those who had not; and that the oldest age group likely included individuals who were post-pubescent. This is most likely to have affected predictions among 12–14-year olds. However, assessment of pubertal status would be necessary to confirm that differences in lung volumes between stunted and non-stunted adolescents are associated with pubertal status (Neve et al., 2002).

Another limitation is the cross-sectional nature of this analysis. Thus, HAZ status at the time of the study cannot be used to imply anything about previous (or future) stature. The individual pattern of relative growth retardation is highly variable, such that children who might not be stunted at one age may become stunted at another, and vice-versa. Consequently, lung volumes in this study may reflect a variety of developmental trajectories.

The gradual reduction in the percent of children who are stunted at older ages is likely a consequence of longer growth that could compensate for earlier growth stunting. Thus, older adolescents who remained growth stunted had probably experienced a life-long pattern of growth retardation. However, it is certainly possible that some older adolescents who were non-stunted may have been stunted at an earlier age. If this is the case, then differences in lung function that might have been caused by stresses encountered earlier in life would not be detectable.

Finally, this study concerns only children and adolescents between the ages of 6 and 20 years. We have not evaluated the effect of stunting among adults.

Supplementary Material

Supplemental data

Supp_Table1.pdf^{(26.2KB, pdf)}

Supplemental data

Supp_Table2.pdf^{(22.8KB, pdf)}

Supplemental data

Supp_Table3.pdf^{(22.9KB, pdf)}

Acknowledgments

We are indebted to Dr. Chen-Ting Chin for her many years of scientific contribution to this long-term field research project. Even at the age of 82, she continued to work with us in the field. She died in December 2003 at the age of 89.

We are indebted to Pieter Zanen MD, PhD, University Medical Centre Utrecht, Division of Heart and Lungs Pulmonary Function Laboratory, Heidelberglaan 100 3584 CX, Utrecht, the Netherlands, for his help in applying the Global Lung function prediction equations to this data set.

Many government and health officials have assisted in bringing this project to completion. We wish to thank the Minister of Health, People's Republic of China, and the Minister of Public Health, Qinghai Province, for their long-term cooperation and support. In particular, Beijing (now Peking) Medical University and the Qinghai Bureau of Public Health provided support and personnel for this research program. Dr. Banma Denzing, former Deputy Governor of Qinghai Province and former president of the Qinghai branch of the Chinese Medical Association, was instrumental in the success of our program.

We also wish to thank the many local community and regional officials in Guinan, Mado, and Maqin who gave their cooperation and support. The research team that participated in the data collection, in addition to the authors is as follows: From Beijing Medical University; L.Y. Shen, M. C. Miao, L.M. Lin, Z. Zhen, X-Q. Liu, H.W. Su and S.L. Ma; From Xining; Rui-Ling Liu, K.F. Yuan, J.A. Chen, Z.Q. Qi, L. Yang, S.L. Xu, J. Zhou and B. Yu; From Guinan; Q. Kang, T.Y. Ma, X.Z.M. Cai, X.L. Gong, M-C Li, W.P. Li, G.Y. Song, S.L. Ma, H.L. Yang, and X.Y. He; From Maqin; S.J Wang, H.X. Feng, H.M. Wang, S.Q. Zhang, W.L. Wu, L.F. Zhu, C.X. Jiang and T.C.X. Fan.

Funding Sources: National Science Foundation, Grant Number BNS-9018805; Wenner Gren Foundation for Anthropological Research; Temple University; National Institutes of Health, Intramural Research Program.

Author Disclosure Statement

The authors declare no conflicting financial interests exist.

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Yap WS, Chan CC, Chan SP, and Wang YT. (2001). Ethnic differences in anthropometry among adult Singaporean Chinese, Malays and Indians, and their effects on lung volumes. Respir Med 95:297–304 [DOI] [PubMed] [Google Scholar]
Zeman KL, and Bennett WD. (2006). Growth of the small airways and alveoli from childhood to the adult lung measured by aerosol-derived airway morphometry. J Appl Physiol 100:965–971 [DOI] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

Supplemental data

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Supplemental data

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Supplemental data

Supp_Table3.pdf^{(22.9KB, pdf)}

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PERMALINK

Stunting and the Prediction of Lung Volumes Among Tibetan Children and Adolescents at High Altitude

Charles A Weitz

Ralph M Garruto

Abstract

Introduction

Materials and Methods