Published Papers: Citations and Abstracts (in chronological order)

Lauer RM, Connor WE, Leaverton PE, Reiter MA, Clarke WR. Coronary heart disease risk factors in school children: the Muscatine Study. J Pediatr 1975;86:697-706.

The frequency of coronary risk factors was documented in 4,829 school children in Muscatine, Iowa, over a 14-month period of time. Serum cholesterol levels were similar for children at all ages; the mean serum cholesterol level was 182 mg/dl (SD lus or minus 29). Twenty four percent had levels larger than or equal to 200 mg/dl, 9% were larger than or equal to 220 mg/dl, 3 % were larger than or equal to 240 mg/dl, and 1% were larger than or equal to 260 mg/dl. Casual levels of serum triglyceride increased with age: the mean level was 71 mg/dl (SD plus or minus 36) at age 6 years and 108 mg/dl (SD plus or minus 45) at age 18 years. Only 15% of the children had serum triglyceride levels of 140 mg/dl or more. Blood pressure increased strikingly with age. No child between 6 and 9 years of age had blood pressures larger than or equal to 140 mm Hg systolic or larger than or equal to 90 mm Hg diastolic. In the age group 14 to 18 years, 8.9% had systolic blood pressures larger than or equal to 140 mm Hg, 12.2% had diastolic blood pressures larger than or equal to 90 mm Hg, and in 4.4% both pressures were at or above these levels. Obesity also increased through the school years. At ages 6 to 9 years, 20% had weights relative to those of the group as a whole of larger than or equal to 110%, and 5% were larger than or equal to 130%; in the 14 to 18 years age group, 25% had relative weights of larger than or equal to 110%, and 8% were larger than or equal to 130%. These data indicate that a considerable number of school-age children have risk factors which in adults are predictive of coronary heart disease.

Rames LK, Clarke WR, Connor WE, Reiter MA, Lauer RM. Normal blood pressure and the evaluation of sustained blood pressure elevation in childhood: the Muscatine Study. Pediatrics. 1978;61:245-51.

This study describes the seated blood pressure distributions of 6,622 predominantly white schoolchildren in Muscatine, Iowa. Subjects with seated pressures equal to or greater than the 95th percentile for age and sex or 140 mm Hg systolic or 90 mm Hg diastolic were examined on repeated occasions. Approximately 13% of subjects were found to have blood pressures at these levels when first examined, but less than 1% were found to have persistent blood pressure elevations. Of 41 subjects found to have persistent blood pressure elevations, 23 were obese with relative weights in excess of 120%. Of the 18 lean subjects, 5 had secondary hypertension and 13 were considered to have essential hypertension. Mass screening of school-age children identifies many children with transient elevation of blood pressure and few with fixed high blood pressures. Children's blood pressures should be assessed during their continuing care where pressures can be measured over a period of time to identify those with fixed blood pressure elevations.

Clarke WR, Schrott HG, Leaverton PE, Connor WE, Lauer RM. Tracking of blood lipids and blood pressures in school age children: the Muscatine Study. Circulation. 1978;58:626-34.

In four cross sectional school screens, the Muscatine Study has sampled 8,909 school children; 820 have been studied repeatedly over a six-year period. Tracking of measurements described by the relationship between repeated observations and the relationship between peer rank orderings over the six-year period has been studied. For height and weight, correlations between observations six years apart were approximately 0.74 and about 60% of children initially in the upper quintile were there again six years later. Six-year correlations were 0.65 for skinfold and 0.61 for cholesterol. Four-year correlation for fasting triglyceride was 0.40. Six-year correlations were 0.30 for casual systolic blood pressure and 0.18 for diastolic blood pressure. Peer rank orderings for both blood pressures were highly variable. Height and weight track well, and thus routine measurement of these variables are useful in identifying children with growth perturbing disorders. Cholesterol and, to a lesser degree, triglycerides also track, and a significant proportion of children with initially high values demonstrated consistently high values throughout the study period. Blood pressures do not track as well; consistently high blood pressures are unusual, thus indicating the need for repeated blood pressure measurements to identify children with persistent elevated levels. The future significance of transient blood pressure elevations has yet to be established.

Schrott HG, Bucher KA, Clarke WR, Lauer RM. The Muscatine hyperlipidemia family study program. Prog Clin Biol Res. 1979;32:619-46.

Abstract pending

Schrott HG, Clarke WR, Wiebe DA, Connor WE, Lauer RM. Increased coronary mortality in relatives of hypercholesterolemic school children: the Muscatine Study. Circulation. 1979;59:320-6.

From 2,874 school children participating in the 1971 and 1973 Muscatine Coronary Risk Factor Survey, we selected three groups of index cases for detailed family study: the HIGH group (n = 56), with cholesterol levels greater than the 95th percentile twice; the MIDDLE group (n = 46), cholesterol levels between the 5th and 95th percentile; and the LOW group (n = 46), cholesterol levels less than the 5th percentile twice. Coronary mortality determined from death certificates was increased in the young relatives (ages 30-59) of the HIGH group index cases, as follows: twofold excess in HIGH male relatives compared with the MIDDLE or LOW group (p less than 0.05); tenfold excess in the HIGH female relatives compared with the MIDDLE and LOW group combined (p less than 0.01). After correction for years at risk, there was an approximately twofold significantly-increased coronary mortality. Stroke mortality was higher, although not significantly, in the older relatives (ages greater than or equal to 60) of the HIGH index cases. Cancer mortality was not significantly different among the relatives of the three groups of index cases. This study indicates that school children's cholesterol levels cluster with those of their family members and that persistent hypercholesterolemia in children identifies families at risk for coronary artery disease.

Schieken RM, Clarke WR, Lauer RM. Left ventricular hypertrophy in children with blood pressures in the upper quintile of the distribution. The Muscatine Study. Hypertension. 1981;3:669-75.

From echocardiography measurements of left heart dimensions, cardiac output was estimated in 264 school children whose systolic blood pressure persisted in the lowest, middle, or highest quintile of the distribution for their age and sex. Children with blood pressure in the upper quintile were taller, heavier, and more obese. Echocardiographically determined left ventricular wall mass, corrected for body size, was significantly greater in these children than those in the lower quintiles of blood pressure. These children displayed a continuum of cardiac output. Those with the highest cardiac output in the upper blood pressure quintile had the greatest left ventricular wall mass.

Bucher KD, Schrott HG, Clarke WR, Lauer RM. The Muscatine Cholesterol Family Study: distribution of cholesterol levels within families of probands with high, low and middle cholesterol levels. J Chronic Dis. 1982;35:385-400.

The Muscatine Cholesterol Family Study includes the relatives of three groups of schoolchildren: those with cholesterol levels above the 95th percentiles in two consecutive school screens, those with cholesterol levels below the 5th percentile twice, and random sample of those with cholesterol levels between the 5th and 95th percentiles twice. This paper examines the cholesterol distribution within and among these families for evidence of major gene effects. Three screening techniques are used: admixture analysis using maximum likelihood, comparison of within-sibship variances among groups, and regression of within-sibships variance on within-sibship mean. The results of the three techniques are consistent and indicate the existence of a major gene in a subset of the families with a proband above the 95th percentile, but not in the other two groups of families. We estimate that 15% of schoolchildren with a cholesterol level above the 95th percentile twice, or 3 per thousand in the general population, have a dominant gene as a cause of the cholesterol elevation.

Schrott HG, Clarke WR, Abrahams P, Wiebe DA, Lauer RM. Coronary artery disease mortality in relatives of hypertriglyceridemic school children: the Muscatine Study. Circulation. 1982;65:300-5.

From 2655 healthy school children participating in the 1973 and 1975 Muscatine Coronary Risk Factor School surveys, two groups of index cases were selected for a detailed family study of coronary mortality: a group with fasting triglyceride levels greater than the ninetieth percentile on both surveys (n = 75) and a group with triglyceride levels less than the tenth percentile on both surveys (n = 47). Coronary mortality in adult (age 30 years or older) first- and second-degree relatives was not different between the two groups. When the families of the high-triglyceride group was further subdivided based on the cholesterol percentile of the index child, greater coronary mortality was observed in the relatives of index cases with high cholesterol (higher than the seventy-fifth percentile). This study suggests that family members of children with elevated triglyceride and low cholesterol levels do not have excess coronary mortality.

Mahoney LT, Clarke WR, Mark AL, Lauer RM. Forearm vascular resistance in the upper and lower quintiles of blood pressure in adolescent boys: The Muscatine Study. Pediatr Res. 1982;16:163-5.

Nineteen 16 year old white boys whose systolic blood pressures were in the upper (r = 9) and lowest (r = 10) quintile of the distribution in two school surveys in 1975 and 1977 were selected. In 1979 forearm blood flow, blood pressure and heart rate were measured at rest, and during peak reactive hyperemia. Minimal forearm vascular resistance during peak reactive hyperemia was used to assess the structural contribution to vascular resistance. At rest the high quintile group again had significantly higher blood pressures than the low quintile group but their forearm vascular resistance was not significantly different. The high quintile group showed significantly higher minimal forearm vascular resistance at peak reactive hyperemia. The latter observation suggests that there is a difference in the structural contribution to forearm vascular resistance in adolescents with blood pressure in the upper versus lower quintile of the distribution.

Lauer RM, Akers RL, Massey J, Clarke WR. Evaluation of cigarette smoking among adolescents: the Muscatine Study. Prev Med. 1982;11:417-28.

In Muscatine, Iowa, the smoking behaviors and related factors were studied in 2,156 school children ages 12 through 18 years. Data were collected through a questionnaire, a “randomized question response,” and by saliva thiocyanate analyses. The proportion reporting smoking on the confidential questionnaire and the anonymous randomized question response were not significantly different. Those reporting the greatest frequency of smoking had the highest levels of saliva thiocyanate. No difference in self-reported smoking was observed in subjects who, prior to completing the questionnaire, were told their saliva would be analyzed for tobacco products and those who were not. These data suggest that children under certain circumstances may honestly and validly complete a questionnaire about their smoking behavior. Of respondents who report both parents as nonsmokers and whose best friends are nonsmokers, 80% have never smoked, and 3% are regular smokers. Of those with both parents and best friends who smoke, only 11% have never smoked and 74% are frequent smokers. Thus the smoking behaviors of parents and peers are important factors relating to children's smoking and nonsmoking decisions.

Schieken RM, Clarke WR, Prineas R, Klein V, Lauer RM. Electrocardiographic measures of left ventricular hypertrophy in children across the distribution of blood pressure: the Muscatine Study. Circulation. 1982;66:428-32.

We sought to test the effectiveness of the ECG as a measure of increased left ventricular wall mass in children with high blood pressure. One hundred eighty-one children, ages 9-18 years, were selected from the lowest, middle and highest quintile of systolic blood pressure from the Muscatine Study, based upon two biennial school screenings. After correction for age, sex, height, weight and skinfold thickness, children with the highest blood pressure had increased echocardiographic left ventricular wall mass (p less than 0.02). Voltage measurements of maximum R and S waves in the standard and precordial leads were measured by computer. We correlated blood pressure and echocardiographic measurements of the interventricular septum, left ventricular posterior wall and left ventricular wall mass to electrocardiographic combinations used to predict left ventricular hypertrophy in both children and adults. The electrocardiographic correlations ranged from -0.01 to + 0.17. Poor correlations were found between electrocardiographic measures and blood pressure, left ventricular wall thickness or left ventricular wall mass. Skinfold thickness and weight had negative correlations, suggesting a damping effect upon measured voltage. We conclude that the echocardiogram is a more sensitive measurement of increased left ventricular mass than the ECG in children with elevated blood pressure.

Schieken RM, Clarke WR, Lauer RM. The cardiovascular responses to exercise in children across the blood pressure distribution. The Muscatine Study. Hypertension. 1983;5:71-8.

Children with elevated systolic blood pressure have a wide range of cardiac output. To better understand the mechanisms regulating resting and exercise blood pressure, we investigated the cardiovascular responses to both dynamic and isometric exercise in 264 children who were selected from the low, middle, and upper quintile of the distribution of blood pressure of an entire school population. We sought to identify patterns of response to exercise that correlated with both resting cardiac output and resting blood pressure. During isometric exercise, systolic pressure adjusted for age and body size increased in all groups. The low group's mean pressure remained significantly lower than the high group's pressure throughout the entire exercise period. Body size adjusted group systolic and diastolic blood pressure level differences exist during dynamic exercise. The product of the systolic blood pressure times the heart rate, in the high blood pressure group, was significantly higher throughout dynamic exercise than in the other two groups. Elevated resting resistance is correlated with elevated resistance during isometric exercise and elevated diastolic blood pressure during dynamic exercise. Cardiac index had a significant negative correlation to age (r = -0.58) at all levels of blood pressure. This observation, in children, lends some support to the concept of the evolution from a hyperkinetic circulation in early childhood to a circulation with lower cardiac output and more elevated systemic vascular resistance at an older age.

Hanis CL, Sing CF, Clarke WR, Schrott HG. Multivariate models for human genetic analysis: aggregation, coaggregation, and tracking of systolic blood pressure and weight. Am J Hum Genet. 1983;35:1196-210.

A multivariate path model parameterizing the sources of familial aggregation and coaggregation of systolic blood pressure and weight, as well as their tracking across time, is applied to longitudinal data collected in Muscatine, Iowa. Genetic, common household, and individual environmental effects, pleiotropy, and a direct regression effect of blood pressure on weight are parameterized. The sample consisted of 998 individuals distributed in 261 families of whom 601 were measured on four successive occasions. The data were divided with times 1 and 2 forming group 1, and times 3 and 4, group 2. Model fitting and estimation was performed using group 1, followed by testing the model and estimates using the data in group 2. Heritability estimates for systolic blood pressure and weight were .15 and .54, respectively. The genetic correlation between these traits was nonsignificant, but there was a significant direct regression effect. The results indicate that 30% of the full-sib correlation for systolic blood pressure is attributable to the aggregation of weight. In terms of tracking, 59% and 60% of the predicted systolic blood pressure and weight correlations, respectively, were attributable to genetic effects. Testing the model from group 1 in group 2 indicates that the qualitative relationships between blood pressure and weight are stable with time.

Lauer RM, Clarke WR, Beaglehole R. Level, trend, and variability of blood pressure during childhood: the Muscatine Study. Circulation. 1984;69:242-9.

On alternate years from 1970 to 1981 blood pressure has been measured in school children living in Muscatine, Iowa. A total of 4313 children beginning at 5 to 14 years of age have been examined on three to six occasions. To compare blood pressures throughout the period of observation, each value was expressed as a percentile rank. For each subject the average percentile rank (level), the trend in rank, and the variability over time were calculated. Values for height, weight, relative weight, and triceps skinfold thickness were expressed in the same fashion. The relationship between average rank of blood pressure and average rank of body size as well as between trend of blood pressure and trend of body size percentiles were significant (p less than .05). These observations indicate the importance of relative rate of growth in the establishment of the rank order of blood pressure. Using the variables of level, trend, and variability, we identified groups of children who appear to be consistently tracking toward future hypertension: 233 (5.4%) children, whose systolic levels were in the upper quintile with either a flat or rising trend and low variability, and 280 (6.0%) children with systolic levels in the lower four quintiles with high trend and low variability. In addition there were 321 (7.4%) children whose mean systolic levels were in the upper quintile with high variability and who thus resemble adults with labile hypertension. There were similar numbers of children with diastolic pressures showing these features.

Lauer RM, Burns TL, Clarke WR. Assessing children's blood pressure--considerations of age and body size: the Muscatine Study. Pediatrics. 1985;75:1081-90.

Blood pressure was assessed in 4,207 children, aged 5 to 18 years, examined in the schools of Muscatine, Iowa during 1981. Overall, 69.9% of the age-sex-specific quintiles and height-sex-specific quintiles of systolic blood pressure were identical. In only 1.0% of children did these quintiles differ by more than one. Children whose blood pressure was in the highest quintile for both age and height were more obese than their peers. Those whose blood pressure was high for age but not for height were proportionately taller and heavier than their age peers. Children whose blood pressure was high for height but not for age were older, shorter, and lighter. Thus, having precocious levels of blood pressure for age during childhood is associated with excessive body weight or precocious height, whereas having high blood pressure for height but not for age is associated with being short for age. The latter suggests that age may be a factor independent of height and weight affecting blood pressure level in childhood. These relationships of body size and age to blood pressure must be considered when evaluating children's blood pressure levels in the clinical setting, and a technique for doing so is presented.

Lauer RM, Mahoney LT, Clarke WR. Tracking of blood pressure during childhood: the Muscatine Study. Clin Exp Hypertens A. 1986;8:515-37.

Four thousand three hundred and thirteen children beginning at five to fourteen years of age have been examined on three to six occasions in Muscatine, Iowa on alternate years. To compare blood pressures throughout the period of observation each value was expressed as a percentile rank. For each subject the average percentile rank (level), the trend in rank and the variability over time were calculated. Values for height, weight, relative weight and triceps skinfold thickness measurements were expressed in the same fashion. The relationship between average rank of blood pressure and average rank of body size as well as between trend of blood pressure and trend of body size percentiles were significant (p less than .05). These observations indicate the importance of relative rate of growth in the establishment of the rank order of blood pressure.

Clarke WR, Schrott HG, Burns TL, Sing CF, Lauer RM. Aggregation of blood pressure in the families of children with labile high systolic blood pressure. The Muscatine Study. Am J Epidemiol. 1986;123:67-80.

The aggregation of systolic blood pressure, diastolic blood pressure, and heart rate is compared among the relatives of three groups of index children: children with low systolic blood pressure (less than the 5th percentile), middle range systolic blood pressure (between the 5th and 95th percentiles), or labile high blood pressure (above the 95th percentile when first sampled but below the 95th percentile when resampled four to six months later). Both systolic and diastolic blood pressures aggregate more strongly in the families of children with labile high systolic blood pressure than in the families of children with middle or low range systolic blood pressure. The degree of aggregation of heart rate does not differ among the three groups. Since blood pressures aggregate so strongly in families of children with labile high systolic blood pressure, study of these children and their families may yield important information about the etiology of hypertension.

Clarke WR, Woolson RF, Lauer RM. Changes in ponderosity and blood pressure in childhood: the Muscatine Study. Am J Epidemiol. 1986;124:195-206.

This paper describes the association between longitudinal changes in blood pressure and changes in measures of ponderosity. Between 1971 and 1981, 2,925 Muscatine, Iowa schoolchildren were measured at least once between ages 6 and 15 years and again between ages 15 and 18. The study shows that change in ponderosity is associated with change in blood pressures; children whose ponderosity decreases relative to their peers usually exhibit a similar drop in their systolic and diastolic blood pressures, while children who gain in ponderosity show a similar gain in their blood pressures. The magnitude of change in blood pressure is related to amount of ponderosity gain or loss and does not depend on initial blood pressure. These data suggest that for obese children weight loss might be an effective method for reducing their blood pressure.

Burns TL, Moll PP, Rost CA, Lauer RM. Mothers remember birthweights of adolescent children: the Muscatine Ponderosity Family Study. Int J Epidemiol. 1987;16:550-5.

The mothers of 127 adolescents living in Muscatine, Iowa were asked at the time of a clinic examination to recall their child's birthweight in pounds and ounces. For comparison, the hospital-recorded birthweight was obtained for each child. On the average, mothers underreported their child's birthweight by 1.3 oz. Sixty of 127 (47%) mother-reported birthweights were the same as those from hospital delivery records; 12% of the mothers overreported the birthweight by at least 5 oz and 17% underreported by at least that amount. The age of the mother and number of biological children were related to the ability to recall the birthweight exactly. The mean age of the children, and thus the average length of the mother's recall, was 16.1 years. Neither the length of recall, nor the mother's education, her current body size, or the current body size of the child were related to recall ability. However, mothers who overreported their child's birthweight were significantly shorter and lighter and their children tended to be taller and heavier, when compared to the mothers who underreported and their children. When the degree of agreement found in our study between reported and recorded birthweight exists, the effect of using reported rather than recorded birthweights in an epidemiological investigation is sufficiently small to allow inferences to be made regarding the relationship between birthweight and body size at mid-adolescence.

Lauer RM, Clarke WR. A longitudinal view of blood pressure during childhood: the Muscatine Study. Stat Med. 1988;7:47-57.

Four thousand three hundred and thirteen children beginning at five to fourteen years of age have been examined on three to six occasions in Muscatine, Iowa, on alternate years. To compare blood pressures throughout the period of observation each value was expressed as a percentile rank. For each subject the average percentile rank (level), the trend in rank and the variability over time were calculated. Values for height, weight, relative weight and triceps skinfold thickness measurements were expressed in the same fashion. There is a relationship between average rank of blood pressure and average rank of body size as well as between trend of blood pressure and trend of body size percentiles. These observations indicate the importance of relative rate of growth in the establishment of the rank order of blood pressure during childhood.

Mahoney LT, Schieken RM, Clarke WR, Lauer RM. Left ventricular mass and exercise responses predict future blood pressure. The Muscatine Study. Hypertension. 1988;12:206-13.

Increased blood pressure and left ventricular mass are associated with increased morbidity and mortality in adults with coronary heart disease. To define the predictors of subsequent childhood blood pressure and left ventricular mass, serial echocardiograms and blood pressure responses during exercise were studied in 274 children aged 6 to 15 years, whose systolic blood pressures were in the high, middle, or low range. Persistence of rank order for left ventricular mass and blood pressure, at rest and during exercise, was maintained over a mean follow-up period of 3.4 years, with correlations ranging from 0.33 to 0.44. Subsequent systolic blood pressure was best predicted from initial resting and maximal exercise systolic blood pressures and left ventricular mass. Subsequent left ventricular mass was best predicted from initial left ventricular mass and maximal exercise diastolic blood pressure, but resting systolic blood pressure did not add to this latter prediction. Since left ventricular mass relates best to exercise blood pressure and not to resting blood pressure, left ventricular mass may provide an integrated view of the effects of blood pressure both at rest and during stress. We speculate that increased left ventricular mass in childhood may be an important predictor of subsequent hypertension and its consequences.

Lauer RM, Lee J, Clarke WR. Factors affecting the relationship between childhood and adult cholesterol levels: the Muscatine Study. Pediatrics. 1988;82:309-18.

A group of 2,446 subjects initially examined at 8 to 18 years of age were reexamined as young adults of 20 to 25 or 26 to 30 years of age. Measurements of cholesterol, height, weight, and triceps skinfold thickness were obtained during childhood. Lipids, lipoprotein fractions, and family history, as well as medication, alcohol, and tobacco use, were determined during the adult examination. Elevated levels of cholesterol during childhood were associated with elevation in adult life. Obesity acquired in adolescence and the young adult years, oral contraceptive use, and cigarette smoking had deleterious effects on adult cholesterol levels and lipoprotein fractions.

Spear SF, Akers RL. Social learning variables and the risk of habitual smoking among adolescents: the Muscatine Study. Am J Prev Med. 1988;4:336-42.

During the past 10 years a good deal of effort has focused on preventing cigarette smoking among adolescents. This effort has often been made without a clear understanding of (1) which groups within the population are at highest risk, (2) which variables are associated with habitual smoking rather than experimentation, and (3) how the influence of those factors differs across levels of the variables that locate the adolescent in his or her social environment. The purpose of this research was to use a social learning model to address those three questions. The data were collected as part of the first wave of a longitudinal research project on adolescent smoking behavior. The results indicated that the ability to integrate smoking into the adolescent's lifestyle, followed by positive attitudes toward smoking and association with peers who smoked, had the greatest influence on the likelihood of habitual smoking. In addition, adolescents who were at the extreme ends of the popularity continuum or were the least integrated into the school environment were at the greatest risk for becoming habitual smokers.

Burns TL, Moll PP, Lauer RM. The relation between ponderosity and coronary risk factors in children and their relatives. The Muscatine Ponderosity Family Study. Am J Epidemiol. 1989;129:973-87.

A family study was conducted in Muscatine, Iowa in 1984-1985 to evaluate the relation between ponderosity in children and coronary risk factor levels in these children and in their family members, and the genetic contribution to familial clustering of levels of ponderosity (body weight relative to height). Four groups of probands were selected from the 1,783 students who participated in three consecutive biennial school surveys. A random group (n = 70), a random sample of students from the entire pool; a lean group (n = 72), students in the lowest quintile of relative weight on all three surveys; a gain group (n = 70), students who gained at least two quintiles of relative weight over the four-year period; and a heavy group (n = 72), students in the highest quintile of relative weight on all three surveys. The parents, siblings, a related aunt or uncle, and a first cousin of these probands were also examined. The data show that levels of high density lipoprotein (HDL) cholesterol, apolipoproteins A-1 and B, and systolic blood pressure in heavy group probands are consistent with increased coronary risk. This same association exists among the relatives with excess ponderosity. Levels of body mass index in the mothers, fathers, and siblings cluster with the levels in the probands, and genetic differences among persons explain 36-52 per cent of the variability in body mass index across the range of ponderosity represented by the probands and their relatives. While the contribution from genes is strong, these data suggest that the contribution from environmental factors is equally as important.

Anderson RA, Burns TL, Lee J, Swenson D, Bristow JL. Restriction fragment length polymorphisms associated with abnormal lipid levels in an adolescent population. Atherosclerosis. 1989;77:227-37.

The association of restriction fragment length polymorphism genetic markers at the apolipoprotein AI-CIII-AIV gene locus with lipid and lipoprotein levels was evaluated in subsets of the 666 Caucasian students from the junior high school (11-14 years old) population of Muscatine, Iowa. Male students whose leukocyte DNA had an uncommon haplotype consisting of the minor allele of a SacI restriction site polymorphism (S2) in combination with the more common allele of an MspI site variation (M1) had significantly lower levels of high density lipoprotein (HDL)-cholesterol (P less than 0.05) when compared to a random sample of males; these levels were stable over a 2-year follow-up. The minor allele of an XmnI restriction site polymorphism (X2) was more frequent in females with triglyceride levels in the upper decile of the age and gender-specific triglyceride distribution than in normotriglyceridemic females (0.10 less than P less than 0.15) and triglyceride levels were higher in random sample females with an X2 allele than in X1 homozygotes (P less than 0.10). These results suggest that alleles of the known apolipoprotein genes (AI, CIII, AIV) at this locus or closely linked gene sequences may have major effects on lipid levels in members of the general population.

Lauer RM, Clarke WR. Childhood risk factors for high adult blood pressure: the Muscatine Study. Pediatrics. 1989;84:633-41.

In adult populations, elevated blood pressure is related to the development of occlusive atherosclerosis, stroke, and renal disease. The significance of blood pressure levels in childhood, unless extremely elevated, has not been related to disease outcomes. In this study, the risk of high blood pressure in young adult life is evaluated based on the observations of blood pressure and other factors made during the school-aged years. Subjects, 2445 in number, were first observed at ages 7 through 18 years and again between 20 and 30 years. During childhood, measurements of blood pressure, height, and weight were made in alternate years. At adult ages, the same measurements were again made and a health questionnaire was administered. According to the data, adult blood pressure is correlated with childhood blood pressure, body size, and change in ponderosity from childhood to adult life. Adult ponderosity is related to childhood ponderosity, and those who are most obese as adults show the greatest increase in weight for height from their childhood years. These observations suggest that strategies to prevent the acquisition of excess ponderosity during adolescence may be useful in preventing adult hypertension.

Lauer RM, Lee J, Clarke WR. Predicting adult cholesterol levels from measurements in childhood and adolescence: the Muscatine Study. Bull N Y Acad Med. 1989;65:1127-42; discussion 1154-60.

2,446 subjects initially examined at ages eight to 18 years were reexamined as young adults at ages 20-25 years or 26-30 years. Measurements of cholesterol, height, weight, and triceps skinfold thickness were obtained during childhood. Lipids, lipoprotein fractions, family history as well as medication, alcohol, and tobacco use were determined during the adult examination. Elevated levels of cholesterol during childhood were associated with elevation in adult life. On average, of children found to have cholesterol levels greater than or equal to the 90th percentile for their age and gender, on a single measurement 43% remained above the 90th percentile, 62% remained above the 75th percentile, and 81% remained above the 50th percentile. Obesity acquired in adolescence and the young adult years, oral contraceptive use, and cigarette smoking had deleterious effects upon adult cholesterol levels and lipoprotein fractions.

Reimers TM, Pomrehn PR, Becker SL, Lauer RM. Risk factors for adolescent cigarette smoking. The Muscatine Study. Am J Dis Child. 1990;144:1265-72.

Smoking among adolescents is a developmental phenomenon with several factors exerting an influence on cigarette use at different times. We examined the longitudinal influences of several behavioral and social variables on the smoking status of 443 students followed from early to late adolescence. Of the factors examined, association with friends who smoke and previous smoking status were consistently associated with an adolescent's future smoking status. Other factors, such as attachment to father or to mother, parental supervision, extracurricular activity, perceived negative and positive effects of smoking, and academic involvement, were all related to late adolescent smoking status. These observations suggest that strategies that influence smoking behavior need to be directed not only to the individual child but also to influences within the child's home and school environment.

Lauer RM, Clarke WR. Use of cholesterol measurements in childhood for the prediction of adult hypercholesterolemia. The Muscatine Study. JAMA. 1990;264:3034-8. Comment in: JAMA. 1990;264:3060-1. JAMA. 1991;265:3003-5. JAMA. 1991;265:3246-9.

This article describes the validity and utility of screening tests for total cholesterol levels in school-age children to predict those who, when adults, will have cholesterol levels that the National Cholesterol Education Program suggests need continuing surveillance and intervention. Two thousand three hundred sixty-seven children aged 8 to 18 years were examined on several occasions and were followed up to ages 20 to 30 years. Of children with cholesterol concentrations exceeding the 75th percentile on two occasions, 75% of girls and 56% of boys would not qualify for intervention as adults by the National Cholesterol Education Program criteria. Of children with cholesterol levels exceeding the 90th percentile on two occasions, 57% of girls and 30% of boys would not qualify for intervention as adults. Because the efficacy, safety, acceptability, and cost of treatment for high cholesterol concentrations in childhood is evolving, the need for universal screening of childhood cholesterol levels must be considered carefully in view of the number of children with high levels of cholesterol who, as adults, do not meet the criteria for intervention suggested by the National Cholesterol Education Program.

Mahoney LT, Lauer RM, Lee J, Clarke WR. Factors affecting tracking of coronary heart disease risk factors in children. The Muscatine Study. Ann N Y Acad Sci. 1991;623:120-32.

The public health implications of reducing or preventing the excess increase in blood pressure and the acquisition of obesity during childhood years are important. Many children with high blood pressure, particularly those who are initially obese or become obese as young adults and those with excess left ventricular mass for body size, become adults with high blood pressure. Although blood pressure and cholesterol have been shown to track during childhood and from childhood into the adult years, the use of repeated determinations along with measures of obesity and information concerning family history of diabetes and coronary heart disease can significantly add to the prediction of future elevated levels.

Moll PP, Burns TL, Lauer RM. The genetic and environmental sources of body mass index variability: the Muscatine Ponderosity Family Study. Am J Hum Genet. 1991;49:1243-55.

The role of genetic and environmental factors in determining the variability in body mass index (BMI; kg/m2) was investigated in 1,302 relatives identified through 284 schoolchildren from Muscatine, IA. BMI levels were first adjusted for variability in age, by gender and by relative type. There was significant familial aggregation of adjusted BMI in the pedigrees, as indicated by inter- and intraclass correlation coefficients significantly different from zero. A mixture of two normal distributions fit the adjusted BMI data better than did a single normal distribution. Genetic and environmental models that could explain both the familial aggregation and the mixture of normal distributions were investigated using complex segregation analysis. There was strong support for a single recessive locus with a major effect that accounted for almost 35% of the adjusted variation in BMI. Polygenic loci accounted for an additional 42% of the variation. Approximately 23% of the adjusted variation was not explained by genetic factors. For spouses living in the same household, their shared environment accounted for 12% of their variation. For siblings living in the same household, their shared environment accounted for 10% of their variation. While shared environments contributed to variation in adjusted BMI, more than 75% of the variation was explained by genetic factors that include a single recessive locus. Approximately 6% of the individuals in the population from which these pedigrees were sampled are predicted to have two copies of the recessive gene, while 37% of the individuals are predicted to have one copy of the gene.

Janz KF, Golden JC, Hansen JR, Mahoney LT. Heart rate monitoring of physical activity in children and adolescents: the Muscatine Study. Pediatrics. 1992;89:256-61.

To assess the usefulness of whole-day heart rate monitoring as a quantitative measure of physical activity in children, the activity of 76 children and adolescents (ages 6 to 17 years), randomly selected from a school population, was measured during a typical summer day using a light-weight, nonrestrictive heart rate telemetry unit. A 12-hour recall and a simple self-rating of usual activity questionnaire were also administered on the same day. An additional 12-hour recall questionnaire was administered on another day. Within 1 month of the heart rate monitoring, the skinfold measures, peak aerobic capacity, and sexual maturation were assessed. Data analysis indicated that activity as measured by telemetry was related to questionnaire recall on the monitored day (r = .50), nonmonitored day (r = .32), and self-rating (r = .35); level of activity as measured by telemetry was related to peak aerobic capacity in girls (r = .36) but not in boys (r = -.06); body fat was related inversely to activity (r = -.32); and prepubescent children were more active than post- and pubescent children (P less than .003). No difference was found in activity level between boys and girls (P greater than .05). This study suggests that for children whole-day heart rate monitoring is an objective, nonobtrusive method for measuring physical activity; and maturation, but not gender, is an influential mediating factor for activity.

Burns TL, Moll PP, Lauer RM. Increased familial cardiovascular mortality in obese schoolchildren: the Muscatine Ponderosity Family Study. Pediatrics. 1992;89:262-8.

Total and cause-specific mortality was investigated in 387 first- and second-degree deceased adult relatives of three groups of children selected from those who participated in three biennial school surveys in Muscatine, Iowa: the lean group (students in the first quintile of relative weight on all three surveys); the random group (a random sample of all eligible students); and the heavy group (students in the fifth quintile of relative weight on all three surveys). A greater proportion of death certificates for heavy group relatives listed a cardiovascular cause of death (60%) compared with lean (48%) and random (43%) group relatives. The relative risk of dying of cardiovascular disease for heavy group vs random group relatives was 1.41 (95% confidence interval 1.01, 1.98). In a subset of heavy group families identified by children with elevated systolic blood pressure, the proportion of death certificates listing a cardiovascular cause was even higher (76%) and the estimate of relative risk vs random group relatives was 2.20 (95% confidence interval 1.43, 3.37). These results indicate that persistent obesity in children, particularly when accompanied by persistent blood pressure elevation, identifies families whose members are at increased risk of dying of cardiovascular disease.

Clarke WR, Lauer RM. Does childhood obesity track into adulthood? Crit Rev Food Sci Nutr. 1993;33:423-30.

Between 1971 and 1981 the Muscatine Coronary Risk Factor Project measured, in six biennial school surveys, 2631 schoolchildren 9 to 18 years of age. Beginning in 1981, these individuals were measured near their 23rd, 28th, and 33rd birthday. This article examines the tracking from childhood into young adult years of the heights, weights, body mass indices (BMI), and triceps skinfold thicknesses (TSF) of these individuals. Depending on age and gender, tracking correlations for height ranged from 0.41 to 0.97; for weight they ranged from 0.51 to 0.88; for BMI they ranged from 0.58 to 0.91; and for TSF they ranged from 0.26 to 0.58. From 49 to 70% of children in the upper quintile of weight were found in the upper quintile of weight as adults, from 48 to 75% of children in the upper quintile of BMI were again in the upper quintile as adults, and from 25 to 56% of children in the upper quintile of TSF were again in the upper quintile as adults. These measures track from childhood into young adult life, and the majority of obese children become obese adults. However, about 31% of children from the upper quintile of BMI became adults with substantially lower levels, while a similar number of lean children become obese adults. Why some obese children become obese adults and others do not remains an unanswered question. The data presented herein indicate that obesity is often acquired during childhood and adolescence when preventive measures could be applied.

Lauer RM, Clarke WR, Mahoney LT, Witt J. Childhood predictors for high adult blood pressure. The Muscatine Study. Pediatr Clin North Am. 1993;40:23-40.

In adult populations, elevated blood pressure is related to the development of stroke, renal disease, and occlusive atherosclerosis. The significance of blood pressure levels in childhood, unless extremely elevated, has not been related to disease outcomes. In a study carried out in Muscatine, Iowa, the risk of high blood pressure in young adult life was evaluated based on the observations of blood pressure and other factors made during the school-aged years. Subjects, 2445 in number, were first observed at ages 7 through 18 years and again between 20 and 30 years. During childhood, measurements of blood pressure, height, and weight were made on alternate years. At adult ages, the same measurements were again made and a health questionnaire was administered. Adult blood pressure was correlated with childhood blood pressure, body size, and change in ponderosity from childhood to adult life. Adult ponderosity was related to childhood ponderosity, and those who were most obese as adults showed the greatest increase in weight from their childhood years. These observations suggest that strategies to prevent the acquisition of excess ponderosity during childhood may be useful in preventing adult hypertension.

Malcolm DD, Burns TL, Mahoney LT, Lauer RM. Factors affecting left ventricular mass in childhood: the Muscatine Study. Pediatrics. 1993;92:703-9.

OBJECTIVE. To examine the contribution of age, body size, and blood pressure to left ventricular mass (LVM) in childhood and develop a population-based reference of normative LVM data. METHODS. Age, sex, height, weight, and auscultatory systolic and diastolic blood pressures were measured and an echocardiogram was performed to estimate LVM in 904 normal children, aged 6 to 16 years, in Muscatine, IA. Pearson product-moment correlation coefficients were determined to describe the degree of linear association between LVM and age, body size, and blood pressure. Age-sex-, weight-sex-, and height-sex-specific Z scores were determined for LVM, age, weight, height, and blood pressure. Sex-specific LVM prediction equations were derived using weighted-least-squares regression analysis. RESULTS. A strong positive linear association of LVM with age, weight, height, Quetelet index, and systolic and diastolic blood pressure was demonstrated. Z scores for eight different LVM quintile patterns revealed that age, height, weight, and blood pressure each exert an independent influence on LVM in children. Sex-specific predicted M-mode LVM and upper limits of the 90% prediction intervals based on age and height are presented. CONCLUSION. Since age, height, weight, and blood pressure may each exert an independent influence on LVM in children, each factor must be considered when interpreting LVM in childhood. While age, sex, and height are unalterable, both weight and blood pressure can be modified. Thus the pathologic contribution of excess weight and blood pressure ought not be masked by statistical adjustments in reference values for LVM. Sex-specific values of LVM and the 90% and 95% prediction intervals of LVM that do not factor out the effects of obesity or blood pressure are presented. These provide the upper-limit reference values of LVM for the evaluation of children in whom increased LVM is suspected.

Muhonen LE, Burns TL, Nelson RP, Lauer RM. Coronary risk factors in adolescents related to their knowledge of familial coronary heart disease and hypercholesterolemia: the Muscatine Study. Pediatrics. 1994;93:444-51.

OBJECTIVE. To determine the utility of a school-based questionnaire, to identify adolescents with adverse coronary risk factor levels. DESIGN. In Muscatine, IA, students (9th through 12th grade) completed a questionnaire providing medical history information about first- and second-degree relatives. Anthropometric measures were obtained and blood pressure, lipid, lipoprotein, and apolipoprotein levels were determined. RESULTS. A history of parental coronary heart disease (CHD) was rare and a history of parental high cholesterol frequently was unknown; however, when known, a history of high cholesterol or early (30 to 55 years of age) or later (> 55 years of age) CHD (myocardial infarction, coronary bypass, or death from a heart attack) in grandfathers enriched the identification of adolescents with adverse coronary risk factors. Parental history of CHD was associated with an increased risk for high body mass index and low apolipoprotein A1 levels in their children. Grandfather history of early or later CHD was associated with an increased risk for low apolipoprotein A1 and high density lipoprotein cholesterol levels and high body mass index in their grandchildren. Students with positive grandfather histories of high cholesterol had higher total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and low density lipoprotein cholesterol to high density lipoprotein cholesterol ratios. Grandmother histories, because most were negative, did not help identify adolescents in this population with adverse coronary risk factors. CONCLUSIONS. A parental history of CHD as well as a grandfather history of high cholesterol or CHD enriches the identification of children with adverse coronary risk factor levels. The positive predictive values associated with using a school-based history obtained from adolescents, many with the aid of their parents, are small and many adolescents do not know their family history. It is essential that pediatricians inquire about parental and especially grandparental medical histories in accordance with the National Cholesterol Education Program guidelines to help identify children at highest familial risk. The importance of determining parental and grandparental histories of CHD or hypercholesterolemia should be emphasized to families who are uncertain of their histories to identify children and adolescents who require a physician's care. It is also important for pediatricians to remind their colleagues who care for patients with premature ischemic heart disease to refer their progeny for pediatric care so that their lipids and lipoproteins may be screened and counseling provided.

Fitzmaurice GM, Laird NM, Lipsitz SR. Analysing incomplete longitudinal binary responses: a likelihood-based approach. Biometrics. 1994 Sep;50(3):601-12.

In this paper, we describe a likelihood-based method for analysing balanced but incomplete longitudinal binary responses that are assumed to be missing at random. Following the approach outlined in Zhao and Prentice (1990, Biometrika 77, 642-648), we focus on "marginal models" in which the marginal expectation of the response variable is related to a set of covariates. The association between binary responses is modelled in terms of conditional log odds-ratios. We describe a set of scoring equations for jointly estimating both the marginal parameters and the conditional association parameters. An outline of the EM algorithm used to obtain the maximum likelihood estimates is presented. This approach yields valid and efficient estimates when the responses are missing at random, but not necessarily missing completely at random. An example, using data from the Muscatine Coronary Risk Factor Study, is presented to illustrate this methodology.

Janz KF, Burns TL, Mahoney LT. Predictors of left ventricular mass and resting blood pressure in children: the Muscatine Study. Med Sci Sports Exerc. 1995 Jun;27(6):818-25.

The objective of this study was to determine predictors of left ventricular mass (LVM) and resting systolic blood pressure (SBP) in preteenage children. Subjects consisted of 124 children (7.9-12 yr) from Muscatine, Iowa. Methods consisted of echocardiographic examinations, random-zero SBP, hormone determination of serum androgens, physician's examination for Tanner stage, anthropometry, maximal bicycle ergometry, hand grip dynamometry, and a physical activity survey. Least square's regression analysis quantified the percentage of explained variability in LVM and resting SBP attributable to the predictor variables. All models were adjusted for body composition. In boys, 72% of the variability in LVM was explained by fat-free body mass (FFM), sum of skinfolds, and peak SBP. In girls, FFM and peak SBP explained 69% of the variability in LVM. Peak SBP was also a significant predictor of resting SBP in boys and girls. Study results indicated that physical fitness and physical activity are not significant predictors of LVM nor resting SBP; however, after adjusting for body composition, peak SBP was an independent predictor of LVM and resting SBP. This result suggests that peak SBP may aid in the prediction of subsequent hypertension and its complications such as left ventricular hypertrophy.

Mahoney LT, Burns TL, Stanford W, Thompson BH, Witt JD, Rost CA, Lauer RM. Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine Study. J Am Coll Cardiol. 1996;27:277-84.

OBJECTIVES. This study was designed to estimate the prevalence of coronary artery calcification in young adult men and women and to examine the association between the presence of coronary artery calcification and coronary risk factors measured in childhood and young adult life. BACKGROUND. Electron beam computed tomography is a sensitive, noninvasive method for detecting coronary artery calcification, a marker of the atherosclerotic process. Coronary artery calcification is associated with coronary risk factors in older adults. METHODS. Subjects (197 men, 187 women) had coronary risk factors measured in childhood (mean age 15 years) and twice during young adult life (mean ages 27 and 33 years). Each underwent an electron beam computed tomographic study at their second young adult examination. RESULTS. The prevalence of coronary artery calcification was 31% in men and 10% in women. Increased body size, increased blood pressure and decreased high density lipoprotein (HDL) cholesterol levels were the coronary risk factors that showed the strongest association with coronary artery calcification. Significant odds ratios for coronary artery calcification, using standardized risk factor measurements at a mean age of 33 years in men and women, respectively, were 6.4 and 13.6 for the highest decile of body mass index, 6.4 and 6.4 for the highest decile of systolic blood pressure and 4.3 and 4.7 for the lowest decile of HDL cholesterol. CONCLUSIONS. Coronary artery calcification is more prevalent in men in this young adult population. Coronary risk factors measured in children and young adults are associated with the early development of coronary artery calcification. Increased body mass index measured during childhood and young adult life and increased blood pressure and decreased HDL cholesterol levels measured during young adult life are associated with the presence of coronary artery calcification in young adults.

Janz KF, Mahoney LT. Three-year follow-up of changes in aerobic fitness during puberty: the Muscatine Study. Res Q Exerc Sport. 1997;68:1-9.

To assess the tracking of aerobic fitness during puberty and its relationship to changes in body composition and indexes of growth, the authors of this study measured body fat, echocardiographic left ventricular mass (LVM), fat-free mass (FFM), height, physical activity, resting blood pressure, sexual maturation, and maximal aerobic fitness (VO2peak) in 123 children (ages 7-12 years). Measures were repeated 3 years later. Tracking was assessed by Spearman rank correlation coefficients between baseline and follow-up data. Predictors of changing aerobic fitness were examined using stepwise regression. Significant tracking of aerobic fitness was observed with correlations ranging from .70-.75. Increased FFM and increased LVM explained 51% of the variability in improved aerobic fitness (ml.min-1) in boys. Increased FFM and increased height explained 26% of the variability in improved aerobic fitness (ml.min-1) in girls. During puberty, children who gain the greatest amount of lean tissue (including cardiac) experience the greatest improvements in aerobic fitness (ml.min-1). Measures of aerobic fitness prior to and during early puberty tend to predict aerobic fitness during puberty.

Lauer RM, Clarke WR, Burns TL. Obesity in childhood: the Muscatine Study. Acta Paed Sin. 1997;38:432-7.

Beginning in 1971 children in grades kindergarten through the 12th grade were examined on alternate years until 1992 in Muscatine, Iowa, in these examinations the following variables were assessed: height, weight, skinfold thickness, lipids, lipoproteins, smoking behaviors, as well other variables. In order to lend relevance to risk factors in childhood a number strategies have been used. These include: 1) Examination of familial aggregation and mortality; 2) Segregation analysis of genetic mechanisms; 3) Relationship of obesity in childhood to other established risk factors; 4) Examination of the relationship of childhood obesity to the development of coronary artery calcification as assessed by electron beam computed tomography. In these studies we have shown that obese children's siblings, mothers, fathers, aunts and uncles have significant greater body mass indices than leaner children. Children who are obese have significantly higher systolic and diastolic blood pressure, higher plasma triglycerides and lower HDL-cholesterol levels. The first and second degree relatives of obese hypertensive children have a higher mortality rate from cardiovascular disease than leaner children's relatives. From complex segregation analyses about 35% of the population of Muscatine appear to carry a gene for obesity and 6% appear homozygous. Over the past decade we have observed that the children in Muscatine, Iowa have become more obese than previously. Our longitudinal observations indicate that obesity acquired in childhood is predictive of adult obesity and is also predictive of the development of coronary artery calcification. Thus obesity in childhood is not only an important risk factor in children but also a growing public health problem for children and adolescents.

Dawson JD. Sample size calculations based on slopes and other summary statistics. Biometrics. 1998;54:323-30.

Sample size calculations based on two-sample comparisons of slopes have been reported by many. This paper extends such discussions to include summary statistics other than slopes, such as post-baseline means, change scores, and final observations. Specifically, sample size formulas for analyses based on a broad class of summary statistics are presented, with modifications proposed to allow for missing data caused by staggered entry and random dropouts. The formulas developed are used to illustrate how required sample size is affected by summary statistic choice, variance parameters, the type of treatment difference of interest, and the manner in which incomplete observations are used in the analysis. An example based on longitudinal data from the Muscatine Study is presented.

Janz KF, Burns TL, Witt JD, Mahoney LT. Longitudinal analysis of scaling VO2 for differences in body size during puberty: the Muscatine Study. Med Sci Sports Exerc. 1998;30:1436-44.

PURPOSE: The purpose of this study was to determine an appropriate method to "normalize" oxygen uptake (VO2) for body size in children and adolescents. METHODS: We examined allometric scaling factors for a cohort of 126 children (mean age at baseline = 10.3 yr) participating in a 5-yr follow-up study. Each year for 5 yr we measured peak VO2, submaximal VO2, body mass, height, body composition, and sexual maturation. We sorted the 5-yr data set by sexual maturation and gender and then used the generalized estimating equation method to estimate regression parameters that described the influence of log transformed body mass on log transformed VO2. All analyses were repeated using log transformed fat-free body mass (FFM) in lieu of log transformed body mass. RESULTS: Models using FFM appeared better at eliminating the effect of body size on VO2. In boys a univariate model with a FFM exponent of 0.91 and in girls a univariate model with a FFM exponent of 0.87 satisfactorily normalized peak VO2. However, we could not identify a common body size exponent for both boys and girls. CONCLUSIONS: Results support the use of allometric scaling of VO2 as a function of FFM for maturing boys and girls but indicate that the effects of maturation on the relationship between VO2 and body size differ between boys and girls.

Wang HM, Jones MP, Burns TL. Regression diagnostics for the class A regressive model with quantitative phenotypes. Genet Epidemiol. 1999;17:174-87.

Regression diagnostic methods are developed and investigated under the Class A regressive model proposed by Bonney [(1984) Am J Med Genet 18:731-749]. We call a family whose phenotypic distribution does not conform to the same genetic model as the majority of the families an etiotic family. The exact case-deletion approach for identifying etiotic families, based on examining the changes in each model parameter estimate by excluding one family at a time, is very time-consuming. We proposed three alternative diagnostic methods: the empirical influence function (EIF), the one-step approximation, and the approximated one-step approach. These methods can be computed efficiently and were incorporated into the existing software package S.A.G.E. A thorough Monte-Carlo investigation of the performance of the diagnostic methods was conducted and generally supports the EIF approach as the recommended alternative. The phenotypic variance is the parameter whose associated regression diagnostic most frequently and correctly identified etiotic families in the models that were examined. An analysis of body mass index data from 402 individuals in 122 Muscatine, Iowa families is used to illustrate the methods. A Class A regressive model with a recessive major locus and equal mother-offspring and father-offspring correlations provided the best-fitting model. The proposed regression diagnostics identified up to 7.4% of the 122 families as etiotic. As a result of this investigation, case-deletion diagnostic assessment is now a practical component in the analysis of quantitative family data.

Davis PH, Dawson JD, Mahoney LT, Lauer RM. Increased carotid intimal-medial thickness and coronary calcification are related in young and middle-aged adults. The Muscatine Study. Circulation. 1999 Aug 24;100(8):838-42.

BACKGROUND: Increased carotid intimal-medial thickness (IMT) and coronary artery calcification (CAC) are used as 2 markers of early atherosclerosis. Our objectives were to assess whether increased IMT and CAC are related and to determine the relationship between cardiovascular risk factors and carotid IMT in young adults. METHODS AND RESULTS: A sample of 182 men and 136 women aged 33 to 42 years living in Muscatine, Iowa, underwent B-mode carotid ultrasound to determine the mean of 12 measurements of maximal carotid IMT. CAC was defined as calcification in the proximal coronary arteries in >/=3 contiguous pixels with a density of >/=130 HU. The mean IMT was 0.788 mm (SD 0.127) for men and 0.720 mm (SD 0.105) for women. CAC was present in 27% of men and 14% of women and was significantly associated with IMT in men (P<0.025) and women (P<0.005). With multivariate analysis, after adjustment for age, significant risk factors for carotid IMT were LDL cholesterol (P<0.001) and pack-years of smoking (P<0.05) in men and LDL cholesterol (P<0.001) and systolic blood pressure (P<0.01) in women. These risk factors remained significant after CAC was included in the multivariate model. CONCLUSIONS: There is an association between increased carotid IMT and CAC and between cardiovascular risk factors and increased IMT in young adults. Carotid IMT may provide information in addition to CAC that can be used to identify young adults with premature atherosclerosis.

Janz KF, Dawson JD, Mahoney LT. Predicting heart growth during puberty: The Muscatine Study. Pediatrics. 2000;105:E63. OBJECTIVES:

During childhood, heart growth is closely associated with somatic growth including increases in body weight, fat-free body mass (FFM), and height. However, with age, greater variability in heart size in relationship to body size is observed, presumably attributable to the increased effect of cardiac workload. At this time, little is known as to what functional attributes (eg, aerobic fitness) contribute to cardiac workload and the relative contribution of these attributes to heart growth during childhood and adolescence. In this article, we report cross-sectional and longitudinal relationships among aerobic fitness, body size, blood pressure (BP), and left ventricular mass (LVM) through puberty including the predictors of heart growth during puberty and the tracking of LVM from pre-puberty to late and post-puberty. Describing the predictors of heart size and heart growth and establishing the likelihood that a large heart, relative to peers, may (or may not) remain a large heart should aid pediatricians in discerning between normal developmental increases in LVM and increases in LVM suggestive of excessive heart growth (left ventricular hypertrophy). METHODOLOGY: Using a repeated-measures design, we assessed aerobic fitness, FFM, fatness, weight, height, sexual maturation, resting BP, peak exercise BP, and LVM in 125 healthy children (mean baseline age: 10.5 years) for a period of 5 years. All subjects were either in prepuberty or early puberty at the beginning of the study. At follow-up, 110 subjects attempted all research procedures (87% of the initial cohort). Using anthropometry and bioelectrical impedance, we measured FFM, fatness, weight, and height quarterly (once every 3 months) for a total of 20 examinations. Resting BP and LVM (2-dimensional echocardiography) were also assessed quarterly. Aerobic fitness, peak exercise BP, and sexual maturation (staging of secondary sex characteristics and, for boys, serum testosterone) were measured annually (5 examinations). The same field staff conducted all examinations. Statistical methods included Spearman rank correlation coefficients (r(s)) calculated to estimate how well the year 5 LVM was predicted by LVM at earlier years. We also categorized the LVM data into tertiles and reported the percentage who remained in the extreme tertiles in year 5, given they began in that tertile in year 1. Gender-specific stepwise multivariate analysis was used to evaluate predictors of follow-up LVM and predictors of changes in LVM. The latter model examined whether the variability in the changes in LVM, as quantified by subject-specific slopes, could be explained by changes in predictor variables, also quantified by subject-specific slopes. RESULTS: At baseline and at follow-up, boys tended to be taller, leaner, more aerobically fit, and had greater LVM than girls. Rate of change for these variables was also greater in boys than girls. For example, LVM increased 62% in boys and 48% in girls. At year 5, subjects had advanced at least 1 stage in genital or breast development and over 80% of the subjects were in late- or post-puberty. Significant and strong tracking of heart size (r(s) =.65-.87) was observed. The likelihood that a subject would be in an extreme tertile for heart size at follow-up was approximately doubled if he or she started there at baseline. In boys, baseline FFM explained 54% of the variability in follow-up LVM. Change in aerobic fitness and change in FFM explained 55% of the variability in change in LVM. In girls, baseline aerobic fitness and fatness explained 45% of the variability in follow-up LVM. Because FFM did not enter in this model, we constructed an alternative model in which baseline aerobic fitness adjusted for FFM was entered. Using this approach, 43% of the variability in follow-up LVM was explained by baseline FFM, fatness, and adjusted aerobic fitness. Change in FFM explained 58% of the variability in change in LVM. Using this approach, 43% of the variability in follow-up LVM was explained by baseline FFM, fatness, and adjusted aerobic fitness. Change in FFM explained 58% of the variability in change in LVM. For both boys and girls, all statistically significant variables entered as positive regression coefficients. Conclusions. Our tracking results suggest predictability in LVM, most likely attributable to normal growth and regulated by the genetic and hormonal influences that affect FFM as well as LVM. Our multiple regression results indicate that during adolescence FFM is an important determinant of heart size and heart growth for both boys and girls but changes in aerobic fitness, presumably attributable to improvements in cardiac function, also affect heart growth in boys. This latter finding indicates that the known age-related decrease in the ability of body size to fully predict heart size begins sooner in males than females. It also suggests that changes in cardiac functioning as well as morphologic increases in lean tissue cause the “athletic heart syndrome.”

Janz KF, Dawson JD, Mahoney LT. Tracking physical fitness and physical activity from childhood to adolescence: the Muscatine Study. Med Sci Sports Exerc. 2000;32:1250-7.

PURPOSE: Physical fitness and physical activity tracking data enhance our understanding as to when children settle into their long-term exercise and fitness patterns and, therefore. provide insight as to when programs focusing on preventing sedentary adults behaviors should be initiated. METHODS: In this paper, the tracking of physical fitness and physical activity was examined in a 5-yr population-based study of children and adolescents in Muscatine, IA. Study subjects (N = 126) were pre- or early-pubescent at baseline (mean age boys 10.8 yr and girls 10.3 yr). Physical fitness was measured using direct determination of oxygen uptake and maximal voluntary isometric contraction while physical activity was assessed via questionnaire. RESULTS: Boys classified as sedentary based on initial measurements of TV viewing and video game playing were 2.2 times more likely than their peers to also be classified as sedentary at follow-up. Tracking of most physical fitness and physical activity variables was moderate to high, indicating some predictability of early measurements for later values. Sedentary behavior tracked better in boys, whereas vigorous activity tended to track better in girls. CONCLUSION: These observations suggest that preventive efforts focused on maintaining physical fitness and physical activity through puberty will have favorable health benefits in later years.

Mahoney LT, Burns TL, Stanford W, Thompson BH, Witt JD, Rost CA, Lauer RM. Usefulness of the Framingham risk score and body mass index to predict early coronary artery calcium in young adults (Muscatine Study). Am J Cardiol. 2001;88:509-15.

The value of a coronary artery disease prediction algorithm, the Framingham risk score (score), for detecting coronary artery calcium (CAC) was examined in 385 men and 472 women, aged 29 to 43 years. Scores were compared in subjects with and without CAC and were also used to predict presence of CAC. Receiver-operating characteristic curves were computed to compare different prediction models. The score model was compared with age only, natural logarithm of body mass index (lnBMI) only, and score plus lnBMI models. CAC was detected in 30% of men and 16% of women. The mean score was significantly higher in men and women with CAC. For every 2-point increase in the score, the odds of CAC increased by 30% in women and 20% in men. Significant associations between CAC status and risk factors were observed for age in women, and high- density lipoprotein cholesterol and blood pressure in men and women. The area under the receiver-operating characteristic curve for the score was 0.67 and 0.57 for women and men, respectively. When lnBMI was added to the score model, the area increased to 0.76 in women (lnBMI p <0.0001, score p <0.005). For men, the area increased from 0.57 to 0.67, and the score was no longer significant (p >0.60) in the model with lnBMI (p <0.0001). Score predicts CAC in asymptomatic young adults. Inclusion of lnBMI in the score model adds significantly to the prediction of CAC in women and men. The lnBMI model has a greater predictive value than the score in this young population.

Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study. Circulation. 2001;104:2815-9.

BACKGROUND: Higher carotid intimal-medial thickness (IMT) is associated with cardiovascular risk factors and is predictive of coronary artery disease and stroke in older adults. Carotid IMT was measured in young and middle-aged adults to determine its relationship with risk factors measured (1) in childhood, (2) currently, and (3) as a "load" from childhood to adulthood. METHODS AND RESULTS: Carotid ultrasound studies were performed in 346 men and 379 women aged 33 to 42 years who were representative of a cohort followed since childhood and who live in Muscatine, Iowa. The mean of the measurements of maximal carotid IMT at 12 locations was determined for each subject. A medical questionnaire was completed, and measurements of anthropometric characteristics and risk factors were obtained. The mean maximum carotid IMT was 0.79+/-0.12 mm for men and 0.72+/-0.10 mm for women. On the basis of multivariable analysis, the significant current predictors of IMT were age and LDL cholesterol in both sexes and diastolic blood pressure in women. Total cholesterol was a significant childhood predictor in both sexes, while childhood body mass index was significant only in women. For men, LDL cholesterol, HDL cholesterol, and diastolic blood pressure were predictive of carotid IMT in a risk factor load model, whereas in women, LDL cholesterol, body mass index, and triglycerides were predictive. CONCLUSIONS: Higher carotid IMT in young and middle-aged adults is associated with childhood and current cardiovascular risk factors, as well as risk factor load.

Janz KF, Dawson JD, Mahoney LT. Increases in physical fitness during childhood improve cardiovascular health during adolescence: the Muscatine Study. Int J Sports Med. 2002;23 Suppl 1:S15-21.

Longitudinal studies from childhood through adolescence have the potential of defining maturational changes in cardiovascular risk factors and may provide insight into the prediction of future cardiovascular disease. We assessed aerobic fitness, muscular strength, vigorous and sedentary activity, maturation, blood pressure, lipids, and body composition in 125 healthy children for a period of five years (mean baseline age, 10.5 years). All subjects were in pre- or early-puberty at baseline. After adjusting for age and gender and considering the confounding effects of growth and maturation, we examined whether changes in fitness and activity during the first four years of our study could predict cardiovascular health outcomes at year-five of our study. Change in muscular strength explained 4 % of the variability in year-five systolic blood pressure. Change in aerobic fitness explained 11 % of year-five total cholesterol to high density lipoprotein ratio and 5 % of year-five low density lipoprotein cholesterol. Changes in aerobic fitness and muscular strength explained 15 % of the variability in year-five adiposity and 15 % of the variability in year-five abdominal adiposity. Childhood health promotion programs that specifically target increases in physical fitness may help to reduce the increasing prevalence of adolescent obesity.

Stanford W, Burns TL, Thompson BH, Witt JD, Lauer RM, Mahoney LT. Influence of body size and section level on calcium phantom measurements at coronary artery calcium CT scanning. Radiology. 2004;230:198-205.

PURPOSE: To determine whether differences in body mass index (BMI) and image section levels representing the proximal through the distal sections of the heart are associated with attenuation differences in images of calcium phantoms scanned during computed tomographic (CT) imaging of study subjects. MATERIALS AND METHODS: Mean attenuation values for three calcium phantoms (each with a different calcium hydroxyapatite concentration), as measured at each of four different image section levels, were obtained for 691 participants in the Muscatine CT Vascular Calcium Study. The subjects were grouped according to sex-specific BMI quartiles, and the degree of attenuation in each phantom was investigated as a function of image section level and BMI quartile. Spearman rank order correlation coefficients and one-, two-, and three-factor repeated-measures analysis of variance were used to examine the association between section level and BMI and the mean phantom attenuations. RESULTS: Attenuation was, for the most part, significantly associated with both section level (P <.005) and BMI quartile (P <.0025-.05). The degree of attenuation tended to decrease in images obtained at the more distal cardiac levels and to increase with increasing BMI quartile. CONCLUSION: Differences in attenuation related to BMI and image section level appear to have a significant effect on current calcium scoring methods.

Iovannisci DM, Lammer EJ, Steiner L, Cheng S, Mahoney LT, Davis PH, Lauer RM, Burns TL. Association between a leukotriene C4 synthase gene promoter polymorphism and coronary artery calcium in young women: the Muscatine Study. Arterioscler Thromb Vasc Biol. 2007;27:394-9.

OBJECTIVE: A majority of the recognized risk factors for atherosclerosis and the development of cardiovascular disease have been derived from the study of older populations who have already manifested clinical symptoms. If risk factors can be identified earlier in life, such as genetic variation, preventive measures may be taken before overt symptoms of pathology have manifested, and when treatments may be most effective. METHODS AND RESULTS: In an effort to identify individuals at increased risk for cardiovascular disease, we genotyped 732 members of the Muscatine Study Longitudinal Adult Cohort for candidate genetic markers associated with several pathogenetic processes. We identified age-adjusted increased risks for coronary artery calcium (OR 4.29; 95% CI 1.78, 10.31) and increased mean carotid artery intimal-medial thickness associated with the (-444)A>C promoter polymorphism of Leukotriene C4 Synthase (LTC4S) in women. There were no similar associations in men. CONCLUSIONS: LTC4S plays a key role in the process of inflammation as the rate limiting enzyme in the conversion of arachidonic acid to cysteinyl-leukotrienes, important mediators of inflammatory responses. The (-444)C variant upregulates LTC4S mRNA expression, increasing the synthesis of proinflammatory leukotrienes. Our results support genetic variation modifying inflammatory pathways as an important mechanism in the development of atherosclerosis.

Mendoza MC, Burns TL, Jones MP. Case-deletion diagnostics for maximum likelihood multipoint quantitative trait locus linkage analysis. Hum Hered. 2009;67:276-86.

OBJECTIVES: Case-deletion diagnostic methods are tools that allow identification of influential observations that may affect parameter estimates and model fitting conclusions. The goal of this paper was to develop two case-deletion diagnostics, the exact case deletion (ECD) and the empirical influence function (EIF), for detecting outliers that can affect results of sib-pair maximum likelihood quantitative trait locus (QTL) linkage analysis. METHODS:Subroutines to compute the ECD and EIF were incorporated into the maximum likelihood QTL variance estimation components of the linkage analysis program MAPMAKER/SIBS. Performance of the diagnostics was compared in simulation studies that evaluated the proportion of outliers correctly identified (sensitivity), and the proportion of non-outliers correctly identified (specificity). RESULTS: Simulations involving nuclear family data sets with one outlier showed EIF sensitivities approximated ECD sensitivities well for outlier-affected parameters. Sensitivities were high, indicating the outlier was identified a high proportion of the time. Simulations also showed the enormous computational time advantage of the EIF. Diagnostics applied to body mass index in nuclear families detected observations influential on the lod score and model parameter estimates. CONCLUSIONS: The EIF is a practical diagnostic tool that has the advantages of high sensitivity and quick computation.

Dawson JD, Sonka M, Blecha MB, Lin W, Davis PH. Risk factors associated with aortic and carotid intima-media thickness in adolescents and young adults: the Muscatine Offspring Study. J Am Coll Cardiol. 2009;53:2273-9. Comment in: J Am Coll Cardiol. 2009;53:2280-2.

OBJECTIVES: This study sought to determine whether cardiovascular risk factors are associated with aortic intima-media thickness (aIMT) and carotid intima-media thickness (cIMT) in adolescents and young adults. BACKGROUND: Atherosclerotic lesions begin developing in youth, first in the distal abdominal aorta and later in the carotid arteries. Knowledge of how risk factors relate to aIMT and cIMT may help in the design of early interventions to prevent cardiovascular disease. METHODS: Participants were 635 members of the Muscatine Offspring cohort. The mean aIMT and cIMT were measured using an automated reading program. RESULTS: The mean (SD) values of aIMT and cIMT were 0.63 (0.14) and 0.49 (0.04) mm, respectively. In adolescents (age 11 to 17 years), aIMT was associated with triglycerides, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist/hip ratio, after adjusting for age, sex, and height. In young adults (age 18 to 34 years), aIMT was associated with those same 5 risk factors, plus high-density lipoprotein cholesterol and pulse pressure. In adolescents, cIMT was associated with SBP, pulse pressure, heart rate, BMI, and waist/hip ratio. In young adults, cIMT was associated with total cholesterol, low-density lipoprotein cholesterol, triglycerides, SBP, DBP, BMI, waist/hip ratio, and glycosylated hemoglobin. In both age groups, aIMT and cIMT were significantly correlated with the Pathobiological Determinants of Atherosclerosis in Youth coronary artery risk score. CONCLUSIONS: Both aIMT and cIMT are associated with cardiovascular risk factors. Using aIMT in adolescents gives information beyond that obtained from cIMT alone. Measurement of aIMT and cIMT may help identify those at risk for premature cardiovascular disease.

Burns TL, Letuchy EM, Paulos R, Witt J. Childhood predictors of the metabolic syndrome in middle-aged adults: The Muscatine Study. J Pediatr. 2009;155:S5.e17-26.

Objective: To investigate the association between components of the metabolic syndrome (MetS) measured during childhood/adolescence, and adult MetS. Study Design: This investigation focused on members of the Muscatine Study Longitudinal Adult Cohort. Predictor variables were risk factor measurements obtained between 1970 and 1981 when cohort members participated in school survey examinations. Risk factor measurements obtained between 1982 and 2008 when cohort members participated in follow-up examinations as young and middle-aged adults were used for MetS classification. Results: 33.0% (29.7% of 474 women; 37.0% of 384 men) of cohort members were classified as having the MetS. The initial MetS classification occurred at ages ranging from 23 to 52 years, with a mean age of 37.2 years (SD = 7.4). Cohort members with the MetS had significantly higher body mass index, systolic blood pressure, and triglycerides at the time they participated in the school survey examinations (P < .0001). Estimated probabilities of remaining MetS free at age 35 for those whose school survey body mass index and triglyceride measurements were both <50th vs ³ 75th percentiles were strikingly different (0.94 vs 0.42). Conclusions: BMI is the strongest childhood predictor of adult MetS. Early identification of at-risk children may reduce the burden of atherosclerotic cardiovascular disease.

Schubert CM, Sun SS, Burns TL, Morrison JA, Huang T-K. Predictive ability of childhood metabolic components for adult metabolic syndrome and type 2 diabetes. J Pediatr. 2009;155:S6.e1-7.

Objective: To estimate sensitivity, specificity, and positive and negative predictive values of components of the metabolic syndrome (MetS) during childhood for MetS and type 2 diabetes (T2D) in adulthood. Study Design: Data from 3 major studies – the Fels Longitudinal Study, the Muscatine Study, and the Princeton Follow-up Study – were combined to examine how thresholds of metabolic components during childhood determine adult MetS and T2D. Available metabolic components examined in the 1789 subjects included high-density lipoprotein, triglyceride levels, glucose, and percentiles for body mass index, waist circumference, triglycerides, and systolic and diastolic blood pressures. Sensitivity, specificity, and positive and negative predictive values for a refined set of component threshold values were examined individually and in combination. Results: Sensitivity and positive predictive values remained low for adult MetS and T2D for individual components. However, specificity and negative predictive values were fairly high for MetS and exceptionally so for T2D. In combination, having 1 or more of the components showed the highest sensitivity over any individual component and high negative predictive value. Overall, specificity and negative predictive values remained high whether considering individual or combined components for T2D. Conclusions: Sensitivity and positive predictive values on the basis of childhood measures remained relatively low, but specificity and negative predictive values were consistently higher, especially for T2D. This indicates that these components, when examined during childhood, may provide a useful screening approach to identifying children not at risk so that further attention can be focused on those who may be in need of future intervention.

Davis PH, Dawson JD, Blecha MB, Mastbergen RK, Sonka M. Measurement of aortic intimal-medial thickness in adolescents and young adults. Ultrasound Med Biol. 2010;36:560-5.

Atherosclerosis begins in childhood in the distal abdominal aorta and later involves the carotid arteries. Noninvasive screening to detect these lesions may allow early intervention. Ultrasound images of the distal 10 mm of the aorta were obtained after an 8-h fast and were analyzed by an automated program to determine the mean far wall intimal-medial thickness (IMT). The results were compared with the mean carotid IMT obtained concurrently. The mean age of the 313 males and 322 females imaged was 20.4 years (SD 5.6) and 61 participants had a second study to assess reproducibility. The mean aortic IMT was 0.63 mm (SD 0.14) for males and 0.61 mm (SD 0.13) for females while the mean carotid IMT was 0.50 (SD 0.04) mm and 0.49 (SD 0.04) mm, respectively. Images were analyzed in 95% of participants. Intra-subject reproducibility for the mean aortic IMT had a coefficient of variation of 18% with a mean absolute difference of 0.12 mm (SD 0.10). For carotid IMT, the results were 3% and 0.02 mm (SD 0.01), respectively. Aortic IMT can be measured in normal adolescents and young adults with low rates of missing data and reasonable reproducibility. Aortic IMT increased with age at a greater rate than carotid IMT.

Juonala M, Magnussen CG, Venn A, Dwyer T, Burns TL, Davis PH, Chen W, Srinivasan SR, Daniels SR, Kähönen M, Laitinen T, Taittonen L, Berenson GS, Viikari JS, Raitakari OT. Influence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium. Circulation. 2010;122:2514-20.

BACKGROUND: Atherosclerosis has its roots in childhood. Therefore, defining the age when childhood risk exposure begins to relate to adult atherosclerosis may have implications for pediatric cardiovascular disease prevention and provide insights about the early determinants of atherosclerosis development. The aim of this study was to investigate the influence of age on the associations between childhood risk factors and carotid artery intima-media thickness, a marker of subclinical atherosclerosis. METHODS AND RESULTS: We used data for 4380 members of 4 prospective cohorts-Cardiovascular Risk in Young Finns Study (Finland), Childhood Determinants of Adult Health study (Australia), Bogalusa Heart Study (United States), and Muscatine Study (United States)-that have collected cardiovascular risk factor data from childhood (age 3 to 18 years) and performed intima-media thickness measurements in adulthood (age 20 to 45 years). The number of childhood risk factors (high [highest quintile] total cholesterol, triglycerides, blood pressure, and body mass index) was predictive of elevated intima-media thickness (highest decile) on the basis of risk factors measured at age 9 years (odds ratio [95% confidence interval] 1.37 [1.16 to 1.61], P=0.0003), 12 years (1.48 [1.28 to 1.72], P<0.0001), 15 years (1.56 [1.36 to 1.78], P<0.0001), and 18 years (1.57 [1.31 to 1.87], P<0.0001). The associations with risk factors measured at age 3 years (1.17 [0.80 to 1.71], P=0.42) and 6 years (1.20 [0.96 to 1.51], P=0.13) were weaker and nonsignificant. CONCLUSIONS: Our analyses from 4 longitudinal cohorts showed that the strength of the associations between childhood risk factors and carotid intima-media thickness is dependent on childhood age. On the basis of these data, risk factor measurements obtained at or after 9 years of age are predictive of subclinical atherosclerosis in adulthood. Comment in: Circulation. 2010;122:2493-4.

Juonala M, Magnussen CG, Berenson GS, Venn A, Burns TL, Sabin MA, Srinivasan SR, Daniels SR, Davis PH, Chen W, Sun C, Cheung M, Viikari JS, Dwyer T, Raitakari OT. Childhood adiposity, adult adiposity, and cardiovascular risk factors. N Engl J Med. 2011;365:1876-85.

BACKGROUND: Obesity in childhood is associated with increased cardiovascular risk. It is uncertain whether this risk is attenuated in persons who are overweight or obese as children but not obese as adults. METHODS: We analyzed data from four prospective cohort studies that measured childhood and adult body-mass index (BMI, the weight in kilograms divided by the square of the height in meters). The mean length of follow-up was 23 years. To define high adiposity status, international age-specific and sex-specific BMI cutoff points for overweight and obesity were used for children, and a BMI cutoff point of 30 was used for adults. RESULTS: Data were available for 6328 subjects. Subjects with consistently high adiposity status from childhood to adulthood, as compared with persons who had a normal BMI as children and were nonobese as adults, had an increased risk of type 2 diabetes (relative risk, 5.4; 95% confidence interval [CI], 3.4 to 8.5), hypertension (relative risk, 2.7; 95% CI, 2.2 to 3.3), elevated low-density lipoprotein cholesterol levels (relative risk, 1.8; 95% CI, 1.4 to 2.3), reduced high-density lipoprotein cholesterol levels (relative risk, 2.1; 95% CI, 1.8 to 2.5), elevated triglyceride levels (relative risk, 3.0; 95% CI, 2.4 to 3.8), and carotid-artery atherosclerosis (increased intima-media thickness of the carotid artery) (relative risk, 1.7; 95% CI, 1.4 to 2.2) (P = 0.002 for all comparisons). Persons who were overweight or obese during childhood but were nonobese as adults had risks of the outcomes that were similar to those of persons who had a normal BMI consistently from childhood to adulthood (P>0.20 for all comparisons). CONCLUSIONS: Overweight or obese children who were obese as adults had increased risks of type 2 diabetes, hypertension, dyslipidemia, and carotid-artery atherosclerosis. The risks of these outcomes among overweight or obese children who became nonobese by adulthood were similar to those among persons who were never obese. (Funded by the Academy of Finland and others.). Comment in: N Engl J Med. 2011;365:1927-9 and Nat Rev Endocrinol. 2011;8:67.

Dwyer T, Sun C, Magnussen CG, Raitakari OT, Schork NJ, Venn A, Burns TL, Juonala M, Steinberger J, Sinaiko AR, Prineas RJ, Davis PH, Woo JG, Morrison JA, Daniels SR, Chen W, Srinivasan SR, Viikari JS, Berenson GS. Cohort Profile: The International Childhood Cardiovascular Cohort (i3C) Consortium. Int J Epidemiol. 2012 Mar 20. [Epub ahead of print]

This is a consortium of large children's cohorts that contain measurements of major cardiovascular disease (CVD) risk factors in childhood and had the ability to follow those cohorts into adulthood. The purpose of this consortium is to enable the pooling of data to increase power, most importantly for the follow-up of CVD events in adulthood. Within the consortium, we hope to be able to obtain data on the independent effects of childhood and early adult levels of CVD risk factors on subsequent CVD occurrence.

Patel SS, Mahoney LT, Burns TL. Is a Shorter Atrioventricular Septal Length an Intermediate Phenotype in the Spectrum of Nonsyndromic Atrioventricular Septal Defects? J Am Soc Echocardiogr. 2012 Apr 25. [Epub ahead of print]

BACKGROUND: Atrioventricular septal defects (AVSDs) account for 7% of all congenital cardiovascular malformations. The atrioventricular septum (AVS) is the portion of the septal tissue that separates the right atrium from the left ventricle; deficiency of the AVS contributes to the AVSD phenotype. A study of case and control families was performed to identify whether an intermediate phenotype consisting of a shortened AVS existed in relatives of children with AVSDs. METHODS: AVS length (AVSL) was measured on the echocardiograms of clinically unaffected parents and siblings from families that were identified through children with nonsyndromic AVSDs and in families with no histories of congenital heart disease. RESULTS: No significant differences were seen between case and control family members in terms of gender, age, weight, and height. AVSLs were significantly shorter in case parents compared with control parents. Similar findings were noted within the sibling groups. There was significant evidence for two-component distributions in the case parent, case sibling, and control sibling groups after standardizing AVSL for age and body surface area. Heritability of AVSL standardized for age and body surface area was 0.82 and 0.71 in nonsyndromic case and control families, respectively. CONCLUSIONS: Evidence for two-component distributions from the analysis of AVSL standardized for age and body surface area for case parents and case siblings suggests the presence of an intermediate phenotype for nonsyndromic AVSD. The high heritability in the control families suggests that there may be polygenic involvement in the determination of AVSL. Broadening the definition of AVSD to include those with shortened AVSL may increase the power of genetic association and mapping studies to identify susceptibility genes for AVSD.