The role of age on dose-limiting toxicities in phase I dose-escalation trials.

PURPOSE: Elderly oncology patients are not enrolled in early-phase trials in proportion to the numbers of geriatric patients with cancer. There may be concern that elderly patients will not tolerate investigational agents as well as younger patients, resulting in a disproportionate number of dose-limiting toxicities (DLT). Recent single-institution studies provide conflicting data on the relationship between age and DLT. EXPERIMENTAL DESIGN: We retrospectively reviewed data about patients treated on single-agent, dose-escalation, phase I clinical trials sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Patients' dose levels were described as a percentage of maximum tolerated dose, the highest dose level at which <33% of patients had a DLT, or recommended phase II dose (RP2D). Mixed-effect logistic regression models were used to analyze relationships between the probability of a DLT and age and other explanatory variables. RESULTS: Increasing dose, increasing age, and worsening performance status (PS) were significantly related to an increased probability of a DLT in this model (P < 0.05). There was no association between dose level administered and age (P = 0.57). CONCLUSIONS: This analysis of phase I dose-escalation trials, involving more than 500 patients older than 70 years of age, is the largest reported. As age and dose level increased and PS worsened, the probability of a DLT increased. Although increasing age was associated with occurrence of DLT, this risk remained within accepted thresholds of risk for phase I trials. There was no evidence of age bias on enrollment of patients on low or high dose levels.

Surveillance of infectious complications associated with central venous access devices in children with haemophilia.

PURPOSE: To analyse the risk factors for infection associated with central venous access device (CVAD) use in children with haemophilia. METHODS: Risk factors for CVAD infection among patients with congenital haemophilia who had had a CVAD implanted at a single institution were evaluated utilizing the following variables: age at CVAD placement, age at end of study, number of days with a CVAD, percentage of lifetime with a CVAD, and history of inhibitor. RESULTS: Fifty-nine patients had a total of 97,936 (median 1768 days per patient) CVAD days in the study period. The median age at CVAD placement was 2.7 years (range 0-14.0). Twenty-six (44%) patients reported CVAD infections during the study period from January 1993 to October 2000. Twenty-four patients had their CVAD replaced, 17 (71%) of whom reported having infections and seven (29%) of whom had a history of inhibitor. The strongest predictor for having any infections was inhibitor status (P=0.16), although none of the risk factors had statistically significant effects. Among the 26 patients reporting infections, 42% had more than one CVAD-related infection. Seven patients had multiple infections involving the same organism. The mean rate of infection was 0.45 per 1000 catheter days, with a 95% confidence interval of 0.33-0.60. Those with a history of inhibitor had an infection rate of 0.66 compared with 0.38 per 1000 catheter days (P=0.09) for those without a history of inhibitor. Patients who were older (greater than the median age of 2.7) at CVAD placement had a lower rate of infection (0.29 vs. 0.65, P<0.01) compared with those < or =2.7 years. Adjustment for inhibitor status had little impact on these results. For the group as a whole, the median time to first infection was 1977 days from CVAD placement. Patients who were older at CVAD placement or study exit had lower relative hazards of infection (P=0.05 and P=0.09 respectively), while those who had inhibitors had a higher but not statistically significant relative hazard of 1.88 (P=0.13). CONCLUSIONS: These data reveal that while considerable numbers of patients develop CVAD-related infection, the interval between catheter placement and infection can be quite long. In addition, the earlier in life a CVAD is placed, the higher the risk of infectious complications, as evidenced by the tendency towards a higher infection rate. Measures to prevent CVAD-related infection might be focused on very young patients who appear to be at higher risk.

Prediction equations for handgrip strength in healthy Indian male and female subjects encompassing a wide age range.

PRIMARY OBJECTIVE: Handgrip strength is a simple index of skeletal muscle function and a functional index of nutritional status. A major lacuna in the use of handgrip strength is the limited availability of normative data. The main objective of this paper was to develop prediction equations for handgrip strength in Indians covering a wide age range. METHODS: Handgrip strength and basic anthropometric parameters were measured in 1024 healthy Indian subjects of both genders (613 males, 411 females) between the ages of 5 and 67 years. The sample was randomly divided into two sets; one set (n = 677) was used to develop the prediction equations for handgrip strength and the other (n = 347) was used to validate the equations. Each data set was further divided into two subsets (adults > 18 years, sub-adults

Defining the impact of hemophilia: the Academic Achievement in Children with Hemophilia Study.

OBJECTIVES: We characterized a population-based cohort of school-aged children with severe hemophilia with respect to type of treatment, on-demand versus prophylaxis, and frequency of bleeding episodes in the year before enrollment. We also investigated the association between hemophilia-related morbidity, measured by number of bleeding episodes in the year before enrollment, and academic performance after adjustment for other factors known to have an effect on achievement. Finally, we explored the mechanisms for the association between bleeding episodes and academic achievement. STUDY DESIGN: This study was a multicenter investigation of boys 6 to 12 years old with severe factor VIII deficiency (clotting factor level <2%) receiving care in US hemophilia treatment centers. Children with a history of inhibitor, severe developmental disorder, significant psychiatric disorder, or insufficient fluency in English were excluded from the study. On-demand treatment was defined as administration of clotting factor on the occurrence of a bleeding episode. Prophylactic therapy was defined as a course of regular infusions for >2 months with a goal of preventing bleeding episodes. Academic achievement was measured by the Wechsler Individual Achievement Test. Quality of life was measured by the Child Health Questionnaire. Of particular interest was the Physical Summary (PhS) measure of the Child Health Questionnaire. The type of information captured by the PhS includes limitations in physical activity, limitations in the kind or amount of schoolwork or social activities the child engaged in, and presence of pain or discomfort. RESULTS: One hundred thirty-one children were enrolled, a median center recruitment rate of 77%. The mean age of the participants was 9.6 years, and approximately half of the participants had completed less than the fourth grade at the time of enrollment. Sixty-two percent of the children were on prophylaxis at enrollment, and 9% had previously been on prophylaxis but were currently on on-demand therapy. Two groups were defined: ever treated with prophylaxis and never treated with prophylaxis. For those ever treated, treatment duration ranged from 2.7 months to 7.7 years, with one half of the children treated with prophylaxis for >40% of their lifetimes; 29% had always been on on-demand therapy. Children in both treatment groups were similar with respect to age, clotting factor level, parents' education, and IQ. The median number of bleeding episodes experienced in the year before enrollment for the cohort as a whole was 12. The median number of bleeding episodes in children on prophylaxis at enrollment was significantly lower than in children on on-demand therapy (6 vs 25.5). The mean achievement scores were within the average range of academic performance: reading, 100.4; mathematics, 101.6; language, 108.1; writing, 95.4; and total achievement, 102.5. When children were categorized as above or below the study group median by number of bleeding episodes, those who had a low number of bleeding episodes (< or =11) had better total achievement (104.4 vs 100.6) and mathematics (103.6 vs 99.6) than children in the higher bleeding episode category (> or =12) after adjusting for child's IQ and parents' education. Treatment with prophylaxis per se was not associated with better test scores, but children who had been treated on a regimen of long-term prophylaxis (>40% of lifetime) and reported < or =11 bleeding episodes in the year before enrollment had significantly higher scores in total achievement (104.9 vs 100.6), mathematics (105.2 vs 99.6), and reading (104.0 vs 98.6) than all other children reporting > or =12 bleeding episodes in the same time period. Increased school absenteeism and hemophilia-related limitations in physical functioning among children with greater frequency of bleeding episodes were proposed as the mechanisms for lower scores. The number of bleeding episodes was positively correlated with school absenteeism (Spearman correlation = 0.23), and children with more school absences had lower scores in mathematics, reading, and total achievement, even after adjusting for the child's IQ and parents' education. Children with fewer bleeding episodes also had better PhS scores than children in the high bleeding episode category (48.4 vs 41.3). The mean PhS for children in the low bleeding episode group (48.4) was similar to that of the general US population (50), but the mean PhS for children in the higher bleeding episode group was almost a full standard deviation lower than the mean for the general US population. PhS scores were positively related to reading and total achievement scores after adjusting for IQ and parents' education. Of interest and concern was a group of children who were reportedly being treated with prophylaxis during the year before enrollment (N = 18) but whose bleeding events were not optimally suppressed. These children were 3 times as likely (33.3% vs 11.1%) to be receiving < or =2 infusions per week as children on prophylaxis who reported < or =11 bleeding episodes during the same period. A review of the sites of bleeding reported for the 18 children revealed that 12 (66.6%) experienced > or =25% of their bleeding episodes in the same joint. CONCLUSIONS: Each child should have the opportunity to achieve his or her potential. Control of a chronic disorder must include this important goal as well as the more commonly identified medical outcomes. This study has identified an important association between the number of bleeding episodes experienced and academic achievement in a cohort of school-aged children with severe hemophilia. The data support the assertion that therapeutic care programs in this population must not be evaluated only in terms of financial cost to achieve adequate musculoskeletal outcomes. Also significant are the individual and societal benefits of increased academic accomplishments if adequate suppression of hemorrhagic events can be attained. The number of bleeding episodes experienced, regardless of treatment regimen, should be followed to optimize the child's academic outcome.

Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex.

The true prevalence of pulmonary lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex (TSC) is unknown. The prevalence of LAM, radiological features, and lung function in patients with TSC was measured. The presence of LAM, as defined by the presence of cysts by high-resolution chest computed tomography (HRCT) scan, was determined in patients with TSC without prior pulmonary disease (Group 1). To determine the significance of early detection, severity of disease in screened patients (Group 1) was compared with that in patients with TSC with a prior diagnosis of LAM (Group 2). Forty-eight patients with TSC and no prior history of LAM were screened. Of the 38 females, 13 (34%) had LAM; LAM was absent in males. Lung function was preserved in patients with TSC who were found to have LAM by screening. In patients previously known to have LAM, FEV(1) and DL(CO) correlated inversely with severity of disease as assessed by CT scan. The prevalence of LAM in women with TSC was 34%, approximately 10-fold that previously reported, consistent with a large hitherto unrecognized subclinical population of patients at risk for pulmonary complications.

Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC).

OBJECTIVE: Diets reduced in fat and cholesterol are recommended for children over 2 years of age, yet long-term safety and efficacy are unknown. This study tests the long-term efficacy and safety of a cholesterol-lowering dietary intervention in children. METHODS: Six hundred sixty-three children 8 to 10 years of age with elevated low-density lipoprotein cholesterol (LDL-C) were randomized to a dietary intervention or usual care group, with a mean of 7.4 years' follow-up. The dietary behavioral intervention promoted adherence to a diet with 28% of energy from total fat, <8% from saturated fat, up to 9% from polyunsaturated fat, and <75 mg/1000 kcal cholesterol per day. Serum LDL-C, height, and serum ferritin were primary efficacy and safety outcomes. RESULTS: Reductions in dietary total fat, saturated fat, and cholesterol were greater in the intervention than in the usual care group throughout the intervention period. At 1 year, 3 years, and at the last visit, the intervention compared with the usual care group had 4.8 mg/dL (.13 mmol/L), 3.3 mg/dL (.09 mmol/L), and 2.0 mg/dL (.05 mmol/L) lower LDL-C, respectively. There were no differences at any data collection point in height or serum ferritin or any differences in an adverse direction in red blood cell folate, serum retinol and zinc, sexual maturation, or body mass index. CONCLUSION: Dietary fat modification can be achieved and safely sustained in actively growing children with elevated LDL-C, and elevated LDL-C levels can be improved significantly up to 3 years. Changes in the usual care group's diet suggest that pediatric practices and societal and environmental forces are having positive public health effects on dietary behavior during adolescence.

Imputation strategies for missing data in a school-based multi-centre study: the Pathways study.

Pathways is a multi-centre school-based trial sponsored by the National Heart, Lung, and Blood Institute testing the efficacy of an obesity prevention intervention in American Indian children. During the study's protocol development, we prepared an analysis plan that accounted for missing data. In this paper, we present a case study of the process we used to decide upon the final analysis plan. The primary endpoint of the Pathways study is a comparison of per cent body fat between treatment and usual care groups at the end of a three-year intervention. Other studies on children and Native Americans have had moderate to large amounts of missing data. As a result we were concerned that missing data in Pathways would affect the type I error rate and power of the test of our primary endpoint. We present results from our evaluation of three alternative procedures in this paper. The first is a multiple imputation procedure in which we replace missing values with resampled values from the observed data. The second is based on the Wilcoxon rank sum test; missing data in the intervention group receive the worst ranks. In the third, we use a multiple imputation procedure and replace missing values with predicted values from a regression equation with the coefficients estimated from observed follow-up data and baseline values. We found that the multiple imputation procedure that replaces missing values with predicted values had the best properties of the procedures we considered. The results from our simulation study showed that, for missing data patterns that are relevant to the Pathways study, this procedure has high power and maintains the type I error rate. Published in 2001 by John Wiley & Sons, Ltd.

Testing for treatment and interaction effects in semi-parametric analysis of covariance.

Semi-parametric regression models assume that the effects of covariates on the mean response are additive. We propose a test of additivity when there is one continuous covariate and a group indicator. At p fixed points, the differences of the within-group kernel estimates of the means are calculated, and the likelihood ratio test that the p differences have a constant mean is formed. The kernel bandwidth and the location of the p fixed points are chosen to give the test good power. Performance of the proposed test is compared with parametric and non-parametric tests of additivity. Published in 2001 by John Wiley & Sons, Ltd.

Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: the Dietary Intervention Study in Children.

BACKGROUND: Few studies have shown the efficacy and safety of lower-fat diets in children. OBJECTIVE: Our objective was to assess the efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol to decrease LDL-cholesterol concentrations in children. DESIGN: A 6-center, randomized controlled clinical trial was carried out in 663 children aged 8-10 y with LDL-cholesterol concentrations greater than the 80th and less than the 98th percentiles for age and sex. The children were randomly assigned to either an intervention group or a usual care group. Behavioral intervention promoted adherence to a diet providing 28% of energy from total fat, <8% from saturated fat,

Incidence, predictive factors, and prognostic significance of supraventricular tachyarrhythmias in congestive heart failure.

BACKGROUND: The incidence, predictive factors, morbidity, and mortality associated with the development of supraventricular tachyarrhythmias (SVTs) in patients with congestive heart failure (CHF) are poorly defined. METHODS: In the Digitalis Investigation Group trial, patients with CHF who were in sinus rhythm were randomly assigned to digoxin (n = 3,889) or placebo (n = 3,899) and followed up for a mean of 37 months. Baseline factors that predicted the occurrence of SVT and the effects of SVT on total mortality, stroke, and hospitalization for worsening CHF were determined. RESULTS: Eight hundred sixty-six patients (11.1%) had SVT during the study period. Older age (odds ratio [OR], 1.029 for each year increase in age; p = 0.0001), male sex (OR, 1.270; p = 0.0075), increasing duration of CHF (OR, 1.003 for each month increase in duration of CHF; p = 0.0021), and a cardiothoracic ratio of > 0.50 (OR, 1.403; p = 0.0001) predicted an increased risk of experiencing SVT. Left ventricular ejection fraction, New York Heart Association functional class, and treatment with digoxin vs placebo were not related to the occurrence of SVT. After adjustment for other risk factors, development of SVT predicted a greater risk of subsequent total mortality (risk ratio [RR] = 2.451; p = 0.0001), stroke (RR = 2.352; p = 0.0001), and hospitalization for worsening CHF (RR = 3. 004; p = 0.0001). CONCLUSION: In CHF patients in sinus rhythm, older age, male sex, longer duration of CHF, and increased cardiothoracic ratio predict an increased risk for experiencing SVT. Development of SVT is a strong independent predictor of mortality, stroke, and hospitalization for CHF in this population. Prevention of SVT may prolong survival and reduce morbidity in CHF patients.

Estimation of body fat from anthropometry and bioelectrical impedance in Native American children.

OBJECTIVE: Obesity, as measured by body mass index, is highly prevalent in Native American children, yet there are no valid equations to estimate total body fatness for this population. This study was designed to develop equations to estimate percentage body fat from anthropometry and bioelectrical impedance as a critical part of Pathways, a multi-site study of primary prevention of obesity in Native American children. DESIGN: Percentage fat was estimated from deuterium oxide dilution in 98 Native American children (Pima/Maricopa, Tohono O'odham and White Mountain Apache tribes) between 8 and 11 y of age. The mean fat content (38.4%+/-8. 1%) was calculated assuming the water content of the fat-free body was 76%. Initial independent variables were height, weight, waist circumference, six skinfolds and whole-body resistance and reactance from bioelectrical impedance (BIA). RESULTS: Using all-possible-subsets regressions with the Mallows C (p) criterion, and with age and sex included in each regression model, waist circumference, calf and biceps skinfolds contributed least to the multiple regression analysis. The combination of weight, two skinfolds (any two out of the four best: triceps, suprailiac, subscapular and abdomen) and bioelectrical impedance variables provided excellent predictability. Equations without BIA variables yielded r2 almost as high as those with BIA variables. The recommended equation predicts percentage fat with a root mean square error=3.2% fat and an adjusted r2=0.840. CONCLUSION: The combination of anthropometry and BIA variables can be used to estimate total body fat in field studies of Native American children. The derived equation yields considerably higher percentage fat values than other skinfold equations in children.

Treatment of acute myocardial infarction: does the type of hospital make a difference? PPAMI Study Group.

There is sparse data on the treatment practices being followed for acute myocardial infarction at various hospitals that differ in their financial infrastructure, availability of facilities and attachment to a medical college. In this prospective observational study, we evaluated the treatment practices for acute myocardial infarction, its appropriateness based on ACC/AHA guidelines and possible influence by type of hospital and certain patient characteristics. Thrombolysis, beta-blockers and angiotensin-converting enzyme-I inhibitors were used in 674 (63%), 506 (47%) and 413 (38%) respectively of 1072 patients. However, when evaluated according to ACC/AHA guidelines, appropriate use was noted in 83 percent, 78 percent and 99.3 percent, respectively. Thrombolysis was inappropriately denied to 14.7 percent patients whereas in 2.4 percent it was used contrary to recommendations. The most common reason for ineligibility for thrombolysis was late arrival. Beta-blockers were denied to 25.1 percent patients. Decision on use of angiotensin-converting enzyme-I was appropriate in most patients. Aspirin was used in 1027 (95.8%) patients. Government hospitals were least likely to thrombolyse a patient as compared to private, industrial and voluntary hospitals; however, this difference was not seen with the use of beta-blockers and angiotensin-converting enzyme-I. Hospitals attached to medical colleges follow guidelines for use of thrombolysis and beta-blockers more closely than non-teaching hospitals. To conclude, evaluation of appropriateness of a therapeutic modality is of greater clinical significance than mere absolute use. Benefits of thrombolytic therapy can be extended by minimising pre-hospital delay; and there is scope for improved utility of beta-blockers which are cost-effective. In addition, the hospital type also has an impact on the treatment practice being followed for acute myocardial infarction.

Body composition assessment in American Indian children.

Although the high prevalence of obesity in American Indian children was documented in several surveys that used body mass index (BMI, in kg/m2) as the measure, there is limited information on more direct measurements of body adiposity in this population. The present study evaluated body composition in 81 boys (aged 11.2+/-0.6 y) and 75 girls (aged 11.0+/-0.4 y) attending public schools in 6 American Indian communities: White Mountain Apache, Pima, and Tohono O'Odham in Arizona; Oglala Lakota and Sicangu Lakota in South Dakota; and Navajo in New Mexico and Arizona. These communities were participating in the feasibility phase of Pathways, a multicenter intervention for the primary prevention of obesity. Body composition was estimated by using a combination of skinfold thickness and bioelectrical impedance measurements, with a prediction equation validated previously in this same population. The mean BMI was 20.4+/-4.2 for boys and 21.1+/-5.0 for girls. The sum of the triceps plus subscapular skinfold thicknesses averaged 28.6+/-7.0 mm in boys and 34.0+/-8.0 mm in girls. Mean percentage body fat was 35.6+/-6.9 in boys and 38.8+/-8.5 in girls. The results from this study confirmed the high prevalence of excess body fatness in school-age American Indian children and permitted the development of procedures, training, and quality control for measurement of the main outcome variable in the full-scale Pathways study.

Design and statistical analysis for the Pathways study.

We report the design, rationale, and statistical procedures used in Pathways, a randomized, school-based intervention for the primary prevention of obesity in American Indian children. The intervention, which is now being implemented in 7 American Indian communities around the country, includes a health-promotion curriculum, a physical education program, a school meal program, and a family involvement component. Forty-one schools serving American Indian children were randomly assigned to be either intervention or control groups. The intervention will begin in the third grade and continue through the end of the fifth grade. Efficacy of intervention will be assessed by differences in mean percentage body fat, calculated by a prediction equation, between intervention and control schools at the end of the fifth grade. Power computations indicate that the study has power to detect a mean difference of 2.8% in body fat. Data analysis will use intention-to-treat concepts and the mixed linear model. The study will be completed in 2000.

Physical activity assessment in American Indian schoolchildren in the Pathways study.

The objective of the Pathways physical activity feasibility study was to develop methods for comparing type and amount of activity between intervention and control schools participating in a school-based obesity prevention program. Two methods proved feasible: 1) a specially designed 24-h physical activity recall questionnaire for assessing the frequency and type of activities and 2) use of a triaxial accelerometer for assessing amount of activity. Results from pilot studies supporting the use of these methods are described. Analyses of activity during different segments of the day showed that children were most active after school. The activities reported most frequently (e.g., basketball and mixed walking and running) were also the ones found to be most popular in the study population on the basis of formative assessment surveys. Both the physical activity recall questionnaire and the triaxial accelerometer methods will be used to assess the effects of the full-scale intervention on physical activity.

Behavioral and pharmacologic interventions: the Raynaud's Treatment Study.

The Raynaud's Treatment Study (RTS) exemplified clinical trials with treatments that differ qualitatively both in their modes and in their methods of delivery. The RTS compared finger-temperature biofeedback to slow-release nifedipine, a calcium channel blocker, in patients with primary Raynaud's disease. Factors influencing the study design were the nature of the interventions and control measures of the protocol, the possibility of perceived differences by the patients between the treatments once the final protocol was developed, and concern on the part of the investigators over the fact that the primary endpoint was self-reported. This paper presents the final statistical model: a double parallel design with both a placebo group and a nonspecific behavioral control group.

Repeated probit regression when covariates are measured with error.

This paper develops a model for repeated binary regression when a covariate is measured with error. The model allows for estimating the effect of the true value of the covariate on a repeated binary response. The choice of a probit link for the effect of the error-free covariate, coupled with normal measurement error for the error-free covariate, results in a probit model after integrating over the measurement error distribution. We propose a two-stage estimation procedure where, in the first stage, a linear mixed model is used to fit the repeated covariate. In the second stage, a model for the correlated binary responses conditional on the linear mixed model estimates is fit to the repeated binary data using generalized estimating equations. The approach is demonstrated using nutrient safety data from the Diet Intervention of School Age Children (DISC) study.

Effects of diet and sexual maturation on low-density lipoprotein cholesterol during puberty: the Dietary Intervention Study in Children (DISC).

BACKGROUND: The Dietary Intervention Study in Children (DISC) is a multicenter, randomized, controlled clinical trial designed to examine the efficacy and safety of a dietary intervention to reduce serum LDL cholesterol (LDL-C) in children with elevated LDL-C. METHODS AND RESULTS: The effects of dietary intake of fat and cholesterol and of sexual maturation and body mass index (BMI) on LDL-C were examined in a 3-year longitudinal study of 663 boys and girls (age 8 to 10 years at baseline) with elevated LDL-C levels. Multiple linear regression was used to predict LDL-C at 3 years. For boys, LDL-C decreased by 0.018 mmol/L for each 10 mg/4.2 MJ decrease in dietary cholesterol (P<.05). For girls, no single nutrient was significant in the model, but a treatment group effect was evident (P<.05). In both sexes, BMI at 3 years and LDL-C at baseline were significant and positive predictors of LDL-C levels. In boys, the average LDL-C level was 0.603 mmol/L lower at Tanner stage 4+ than at Tanner stage 1 (P<.01). In girls, the average LDL-C level was 0.274 mmol/L lower at Tanner stage 4+ than at Tanner stage 1 (P<.05). CONCLUSIONS: In pubertal children, sexual maturation, BMI, dietary intervention (in girls), and dietary cholesterol (in boys) were significant in determining LDL-C. Sexual maturation was the factor associated with the greatest difference in LDL-C. Clinicians screening for dyslipidemia or following dyslipidemic children should be aware of the powerful effects of pubertal change on measurements of lipoproteins.

Safety of a fat-reduced diet: the Dietary Intervention Study in Children (DISC).

OBJECTIVE: To assess the relationship between energy intake from fat and anthropometric, biochemical, and dietary measures of nutritional adequacy and safety. DESIGN: Three-year longitudinal study of children participating in a randomized controlled trial; intervention and usual care group data pooled to assess effects of self-reported fat intake; longitudinal regression analyses of measurements at baseline, year 1, and year 3. PARTICIPANTS: Six hundred sixty-three children (362 boys and 301 girls), 8 to 10 years of age at baseline, with elevated low-density lipoprotein cholesterol, who are participants of the Dietary Intervention Study in Children. MEASURES: Energy intake from fat assessed from three 24-hour recalls at each time point was the independent variable. Outcomes were anthropometric measures (height, weight, body mass index, and sum of skinfolds), nutritional biochemical determinations (serum ferritin, zinc, retinol, albumin, beta-carotene, and vitamin E, red blood cell folate, and hemoglobin), and dietary micronutrients (vitamins A, C, E, thiamin, riboflavin, niacin, vitamins B-6, B-12, folate, calcium, iron, zinc, magnesium, and phosphorus). RESULTS: Lower fat intake was not related to anthropometric measures or serum zinc, retinol, albumin, beta-carotene, or vitamin E. Lower fat intake was related to: 1) higher levels of red blood cell folate and hemoglobin, with a trend toward higher serum ferritin; 2) higher intakes of folate, vitamin C, and vitamin A, with a trend toward higher iron intake; 3) lower intakes of calcium, zinc, magnesium, phosphorus, vitamin B-12, thiamin, niacin, and riboflavin; 4) increased risk of consuming less than two-thirds of the Recommended Dietary Allowances for calcium in girls at baseline, and zinc and vitamin E in boys and girls at all visits. CONCLUSIONS: Lower fat intakes during puberty are nutritionally adequate for growth and for maintenance of normal levels of nutritional biochemical measures, and are associated with beneficial effects on blood folate and hemoglobin. Although lower fat diets were related to lower self-reported intakes of several nutrients, no adverse effects were observed on blood biochemical measures of nutritional status. Current public health recommendations for moderately lower fat intakes in children during puberty may be followed safely.

Nutrient intake and blood pressure in the Dietary Intervention Study in Children.

Delineating the role that diet plays in blood pressure levels in children is important for guiding dietary recommendations for the prevention of hypertension. The purpose of this study was to investigate relationships between dietary nutrients and blood pressure in children. Data were analyzed from 662 participants in the Dietary Intervention Study in Children who had elevated low-density lipoprotein cholesterol and were aged 8 to 11 years at baseline. Three 24-hour dietary recalls, systolic pressure, diastolic pressure, height, and weight were obtained at baseline, 1 year, and 3 years. Nutrients analyzed were the micronutrients calcium, magnesium, and potassium; the macronutrients protein, carbohydrates, total fat, saturated fat, polyunsaturated fat, and monounsaturated fat; dietary cholesterol; and total dietary fiber. Baseline and 3-year longitudinal relationships were examined through multivariate models on diastolic and systolic pressures separately, controlling for height, weight, sex, and total caloric intake. The following associations were found in longitudinal analyses: analyzing each nutrient separately, for systolic pressure, inverse associations with calcium (P < .05); magnesium, potassium, and protein (all P < .01); and fiber (P < .05), and direct associations with total fat and monounsaturated fat (both P < .05); for diastolic pressure, inverse associations with calcium (P < .01); magnesium and potassium (both P < .05), protein (P < .01); and carbohydrates and fiber (both P < .05), and direct associations with polyunsaturated fat (P < .01) and monounsaturated fat (P < .05). Analyzing all nutrients simultaneously, for systolic pressure, direct association with total fat (P < .01); for diastolic pressure, inverse associations with calcium (P < .01) and fiber (P < .05), and direct association with total and monounsaturated fats (both P < .05). Results from this sample of children with elevated low-density lipoprotein cholesterol indicate that dietary calcium, fiber, and fat may be important determinants of blood pressure level in children.