Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young.

AIMS/HYPOTHESIS: Larger childhood body size and rapid growth have been associated with increased type 1 diabetes risk. We analysed height, weight, BMI and velocities of growth in height, weight and BMI, for association with development of islet autoimmunity (IA) and type 1 diabetes. METHODS: Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased type 1 diabetes risk, based on HLA-DR, -DQ genotype or family history, for the development of IA and type 1 diabetes. IA was defined as the presence of autoantibodies to insulin, GAD or protein tyrosine phosphatase islet antigen 2 twice in succession, or autoantibody-positive on one visit and diabetic at the next consecutive visit within 1 year. Type 1 diabetes was diagnosed by a physician. Height and weight were collected starting at age 2 years. Of 1,714 DAISY children <11.5 years of age, 143 developed IA and 21 progressed to type 1 diabetes. We conducted Cox proportional hazards analysis to explore growth velocities and size measures for association with IA and type 1 diabetes development. RESULTS: Greater height growth velocity was associated with IA development (HR 1.63, 95% CI 1.31-2.05) and type 1 diabetes development (HR 3.34, 95% CI 1.73-6.42) for a 1 SD difference in velocity. CONCLUSIONS/INTERPRETATION: Our study suggests that greater height growth velocity may be involved in the progression from genetic susceptibility to autoimmunity and then to type 1 diabetes in pre-pubertal children.

Comparison of a live attenuated and an inactivated varicella vaccine to boost the varicella-specific immune response in seropositive people 55 years of age and older.

Healthy, varicella-zoster virus (VZV)-seropositive subjects, aged 55-89 years (mean age 66 years), received either 4000 PFU of live, attenuated VZV vaccine (n=85) or an equal volume of this vaccine that was heat-inactivated (n=82). Both vaccines significantly boosted VZV antibody (enzyme immunoassay) and gamma-interferon production by peripheral blood mononuclear cells stimulated by VZV antigen. These responses returned to baseline by 12 months. Circulating mononuclear cells that proliferated in response to VZV antigen were significantly more numerous (responder cell frequency assay) after either vaccine, and persisted with a half-life of 17. 5-21.3 months. There were no differences in immune response to either vaccine in this older age cohort.

Relating the classical covariance adjustment techniques of multivariate growth curve models to modern univariate mixed effects models.

The relationship between the modern univariate mixed model for analyzing longitudinal data, popularized by Laird and Ware (1982, Biometrics 38, 963-974), and its predecessor, the classical multivariate growth curve model, summarized by Grizzle and Allen (1969, Biometrics 25, 357-381), has never been clearly established. Here, the link between the two methodologies is derived, and balanced polynomial and cosinor examples cited in the literature are analyzed with both approaches. Relating the two models demonstrates that classical covariance adjustment for higher-order terms is analogous to including them as random effects in the mixed model. The polynomial example clearly illustrates the relationship between the methodologies and shows their equivalence when all matrices are properly defined. The cosinor example demonstrates how results from each method may differ when the total variance-covariance matrix is positive definite, but that the between-subjects component of that matrix is not so constrained by the growth curve approach. Additionally, advocates of each approach tend to consider different covariance structures. Modern mixed model analysts consider only those terms in a model's expectation (or linear combinations), and preferably the most parsimonious subset, as candidates for random effects. Classical growth curve analysts automatically consider all terms in a model's expectation as random effects and then investigate whether "covariance adjusting" for higher-order terms improves the model. We apply mixed model techniques to cosinor analyses of a large, unbalanced data set to demonstrate the relevance of classical covariance structures that were previously conceived for use only with completely balanced data.

Use of a live attenuated varicella vaccine to boost varicella-specific immune responses in seropositive people 55 years of age and older: duration of booster effect.

Varicella-zoster virus (VZV)-specific T cell immunity was measured in 130 persons > or = 55 years of age 6 years after they received a live attenuated VZV vaccine. Circulating T cells, which proliferated in vitro in response to VZV antigen, were enumerated (VZV responder cell frequency assay). Six years after the booster vaccination, the VZV-responding cell frequency (1/61,000 circulating cells) was still significantly (P < .05) improved over the baseline measurements (1/70,000) and appears to have diminished the expected decline in frequency as these vaccinees aged (to 1/86,000). Ten herpes-zoster--like clinical events were recorded. Although the frequency of these events, approximately 1/100 patient-years, is within the expected range of such events for this age cohort, the number of lesions was small, there was very little pain, and there was no postherpetic neuralgia. These results support the development of a vaccine to prevent or attenuate herpes zoster.

Substance-dependent, conduct-disordered adolescent males: severity of diagnosis predicts 2-year outcome.

Most delinquent youths have conduct disorder (CD), often with comorbid substance use disorder (SUD), attention-deficit/hyperactivity disorder (ADHD) and depression. Some youths' conduct problems later abate, while those of others persist into adult antisocial personality disorder. Earlier CD onset and ADHD reportedly predict persisting antisocial problems, but predictors of persisting SUD are poorly understood. Males aged 13-19 years (n = 89), most referred by criminal justice and social service agencies, received residential treatment for comorbid CD and SUD. They had diagnostic assessments for SUD at intake and for CD, ADHD, and depression (as well as drug-use assessments) at intake and 6, 12 and 24 months later. At intake nearly all had DSM-III-R substance dependence (usually on alcohol and marijuana) and CD with considerable violence and criminality. The 2-year follow-ups revealed improvements in criminality, CD, depression and ADHD, but substance use remained largely unchanged. Various aspects of conduct, crime and substance outcomes at 2 years were predicted by intake measures of intensity of substance involvement, and by CD severity and onset age, but not by severity of either ADHD or depression, nor by treatment duration. Earlier CD onset, more severe CD and more drug dependence predicted worse outcomes, supporting the validity of these diagnoses in adolescents.

Predicting the duration of dependence on parenteral nutrition after neonatal intestinal resection.

OBJECTIVE: To determine whether there are clinical or physical factors that could be used to predict the duration of dependence on parenteral nutrition (PN) in infants who have undergone resection of small intestine in the neonatal period. STUDY DESIGN: Medical records of 44 patients who had small intestinal resection as neonates from 1985 to 1996 and who were dependent on PN for at least 3 months were reviewed. Statistical evaluation of patient variables and their impact on duration of dependence on PN were determined by using the Cox Proportional Hazard model. RESULTS: Twenty-seven patients became independent of PN before the age of 36 months. Seven patients between 40 and 129 months of age are permanently dependent on PN. Outcome could not be determined in 10 patients, four of whom died of hepatic failure while still receiving PN and six of whom are still receiving PN but are younger than 36 months of age. Small bowel length after initial surgery and the percent of daily energy intake received by the enteral route at 12 weeks' adjusted age were significantly related to the duration of dependence on PN. Gestational age, presence of the ileocecal valve, and development of cholestasis were not significantly related. With the use of the Cox Proportional Hazards survival model, a formula was generated to allow estimation of the duration of dependence on PN. CONCLUSIONS: The duration of dependence on PN can be predicted at an early age in neonatal short bowel syndrome by using two patient variables: the length of residual small bowel after initial surgery and the percent of daily energy intake tolerated through the enteral route.

Using a nonlinear mixed model to evaluate three models of human stature.

The modern mixed model approach is used to evaluate three current nonlinear models of development of human stature. By combining both fixed and random effects in the same model, the mixed approach incorporates variability between subjects in the estimation of the mean parameter values. This allows us to provide a single statistical test for the differences between each pair of statistical models. Asymptotic growth models from Preece and Baines (1978), Jolicoeur et al. (1988, 1991,1992), and Kanefuji and Shohoji (1990) were applied to height data collected from 28 males and 25 females. The NLINMIX Macro from SAS was used to evaluate the fit of each model allowing for two random components in addition to the fixed mean parameter values. In every case, the addition of random parameters improved the fit of each growth model. Models were evaluated by the calculation of the Akaike Information Criterion, differences in -2 log likelihood, and determination of the residual variance. For males, the Jolicoeur et al. model was superior, while for females, the Kanefuji and Shohoji model provided the best fit. This new approach is more parsimonious than previous techniques by allowing for individual variation in the estimation of model parameters in a population average model of growth.

Fieller's theorem, Scheffé simultaneous confidence intervals, and ratios of parameters of linear and nonlinear mixed-effects models.

The issue of joint confidence region and simultaneous confidence interval estimation for ratios of the parameters of a nonlinear mixed-effects model is addressed using a Fieller's theorem approach. The method presented is similarly applicable to linear mixed-effects models. In addition, previous work on linear fixed-effects models is demonstrated to be a special case of the present method. The methodology is applied to the ratios of slopes in a study of gestational maturation of placental glucose transfer capacity in sheep.

Separate and joint effects of arginine and glucose on ovine fetal insulin secretion.

To determine separate and joint effects of increases (delta) in fetal plasma concentrations of arginine (Af) and glucose (Gf) on fetal insulin (If) secretion (delta If), 15 late-gestation fetal sheep were given 5-min arginine bolus infusions (40, 86, 144, 201, and 402 mumol/kg estimated fetal wt) at 90 min of 120 min steady-state glucose clamps (basal Gf, basal + 0.6 mM Gf, and basal + 1.1 mM Gr), producing absolute and percent increases above basal Af of 25.8 +/- 1.3 microM (+33%), 50.9 +/- 6.3 microM (+66%), 83.8 +/- 7.1 microM (+108%), 122.1 +/- 9.4 microM (+156%), and 302.2 +/- 28.2 microM (+386%), respectively. Acute hyperglycemia alone produced an increase above basal If of 9 +/- I microU/ml (+80%) and 19 +/- 2 microU/ml (+170%) after basal + 0.6 mM Gf and basal + 1.1 mM Gf, respectively. Increasing values of delta Af showed separate but lesser effects on delta If, which were significant only at very high values of Af (> 100% above mean normal Af) unless marked hyperglycemia (1.5- to 2-fold normal) was also present, demonstrating joint effects of delta Af and delta Gf on delta If according to a best-fit inverse polynomial response surface. We conclude that physiological increases in Af at normal glucose concentrations are not a potent-stimulus to insulin secretion in fetal sheep.

A generalized Michaelis-Menten response surface.

We describe an application of recently developed generalized Michaelis-Menten response surface and non-linear mixed model methodologies to model glucose utilization in foetal sheep. More specifically, we model the response surface of glucose utilization rate in the foetal sheep as a function of glucose and insulin concentrations using a three-dimensional analogue of the Michaelis-Menten pharmacokinetic model. To account for multiple measurements per sheep, we apply the non-linear mixed effects model proposed by Lindstrom and Bates using the EM algorithm computational scheme presented by Hirst et al.

Ultrasonographic assessment of fetal growth: comparison between human and ovine fetus.

OBJECTIVE: Our purpose was to evaluate the rate of ovine fetal growth for several body parameters by serial ultrasonographic measurements and to compare them with analogous data in the human fetus. STUDY DESIGN: Forty-three ewes with singleton gestations were studied. Four parameters were measured: biparietal diameter, abdominal circumference, femur length, and tibia length. Ultrasonographic examinations were performed weekly from 50 to 138 days of gestation (term 147 days). Quadratic regression analysis was used to describe each data set. RESULTS: The biparietal diameter showed a significant deceleration of its growth rate. The abdominal circumference showed a linear growth pattern. Both femur and tibia revealed a significant acceleration of the growth rate. CONCLUSION: The ovine fetal growth pattern is different from that observed in the human fetus, in which all four parameters show deceleration of the growth rate in late gestation. In comparison to the ovine, the human fetus reaches similar abdominal circumference and femur length values at term, but in a gestational period that is twice as long. In sharp contrast to abdominal circumference and femur length growth, the biparietal diameter has a similar growth rate in both species. Thus the human fetus has a slower rate of somatic growth and its greater biparietal diameter at term results from the longer gestational period.

Early ultrasonographic detection of fetal growth retardation in an ovine model of placental insufficiency.

OBJECTIVE: Our aims were as follows: (1) to determine whether fetal growth retardation can be detected noninvasively with ultrasonography in ewes and (2) to establish the time interval between exposure of ewes to environmental stress that causes growth retardation (heat stress) and detection of growth lag for specific fetal body measurements. STUDY DESIGN: Four ewes were exposed to heat stress for 80 days starting at 35 days' gestation. (The duration of pregnancy in sheep is 147 days). Serial ultrasonographic measurements of fetal biparietal diameter, abdominal circumference, and femur and tibia lengths were obtained beginning at 50 days' gestation. Growth curves were calculated for each parameter and compared with growth curves obtained from 43 normal fetuses. RESULTS: Biparietal diameter measurements deviated significantly from normal starting at 90 days' gestation (p < 0.05). Abdominal circumference diverged at 70 days' gestation (p < 0.05), and both femur and tibia length diverged at 80 days (p < 0.05). The regression lines showed significant differences for all the parameters in both slope (p < 0.01) and intercept (p < 0.01). CONCLUSIONS: Fetal growth retardation can be detected noninvasively by ultrasonography after approximately 5 weeks of exposure to heat stress. Fetal growth continues throughout gestation but at a slower rate than normal and according to a pattern similar to that observed in asymmetrically growth-retarded human fetuses. Early detection of stunted fetal growth in an animal model is important for testing intervention strategies in the treatment of fetal growth retardation.

Effects of sound intensity on a midlatency evoked response to repeated auditory stimuli in schizophrenic and normal subjects.

Inhibitory gating of response to repeated stimuli is demonstrated by several event-related potentials, including the auditory P50 wave. The present study examined the effects of variation in sound intensity on this phenomenon in schizophrenics and normal subjects. Paired clicks, 500 ms apart, were presented 50 dB above threshold to 10 normal subjects and 10 schizophrenics. The normal subjects demonstrated significantly more decrement of response to the second stimulus than did the schizophrenics. When the sounds were noticeably louder(70 dB above threshold), no such difference was observed. Rather, both groups had similarly diminished gating of response. A significant difference between schizophrenics and normal subjects was also observed when the sounds were 30 dB above threshold, but the difference was smaller than that at 50 dB. At any stimulus intensity, concomitant eye movements led to loss of gating of P50 in the normal subjects.

Inference for the association between coefficients in a multivariate growth curve model.

This paper generalizes the work of Blomqvist (1977, Journal of the American Statistical Association 72, 746-749) on inference for the relationship between the individual-specific slope and the individual-specific intercept in a linear growth curve model. The paper deals with longitudinal data involving one or more response variables and irregular follow-up times, with each response variable postulated to follow a linear growth curve model. The problem considered is inference concerning the association between one growth curve coefficient and another--for example, the slope and intercept for a selected response variable, or the two slopes for two different response variables--after adjusting for all remaining coefficients among all of the response variables. An inferential approach based on the method of moments and an inferential approach based on maximum likelihood are described, and the asymptotic properties of these procedures are presented. Extensions of the methodology to allow polynomial growth curves and baseline covariates are outlined. The methodology is illustrated with a practical example arising from a clinical trial in lung disease.

Immune responses of elderly persons 4 years after receiving a live attenuated varicella vaccine.

Annually, for 4 years after a live attenuated varicella-zoster virus (VZV) vaccine was administered to 202 elderly (55 to > 87 years old) VZV-immune persons, the immune response of vaccinees was evaluated. Anti-VZV antibody levels were enhanced by vaccination for just 1 year. However, VZV-specific proliferating T cells in peripheral blood were increased in frequency from 1 in 68,000 to 1 in 40,000 at 1 year; VZV-responding T cells were still 1 in 51,000 4 years after vaccination. The calculated half-life of this enhanced immunity was 54 months. Age had little effect on response to the vaccine, but larger doses were associated with longer duration of enhanced immunity. Immunity in approximately 10%-15% of vaccinees, independent of dose, failed to increase with the vaccine. This might complicate the use of this vaccine for prevention or attenuation of herpes zoster in the elderly.

Studying the relationship between change and initial value in longitudinal studies.

Blomqvist's problem of studying the relationship between change and initial value in a linear growth curve setting is reformulated from a random effects model perspective. First, a maximum likelihood estimate of the between-individual covariance matrix for a simple linear regression model with stochastic parameters is obtained via an EM algorithm as discussed by Laird and Ware. Second, the regression coefficient of the individual-specific slopes on the individual-specific intercepts is estimated as a ratio of elements of the between-individual covariance matrix as discussed by Zucker et al. Then a Fieller's type confidence interval for this ratio is proposed. Discussion is facilitated by recognizing the Laird-Ware model as a special case of a more general model discussed by Hocking.

Clinical application of responder cell frequency estimates with four years of follow up.

Limiting dilution cultures have been used to estimate the frequency of T cells which respond to antigen stimulation in vitro, but nothing is known of the reproducibility of this assay when applied to human blood. We developed a simplified form of limiting dilution culture in which blood mononuclear cells were diluted in round bottom 96-well plates and cultured for 10 days. The assay was used to estimate the frequency of blood mononuclear cells proliferating in response to varicella-zoster virus antigen. 250 subjects aged 25-87 years were studied: 95 of these subjects had annual measurements repeated over a 4 year period. The coefficients of variation for intra-assay replicates was 5%, and for inter-assay comparisons was 17.6% and 26% for tests at a 1 or 3 month interval respectively. For subjects studied at 1 year intervals the coefficient of variation was 42% with the total variability equally distributed between the variation between subjects and the variation within subjects. These data provide the first quantitative data to validate limiting dilution cultures for the long term in vitro measurement of human T cell responses.

Zinc supplementation in very-low-birth-weight infants.

Inadequate zinc intake may lead to poor growth and developmental outcome in very-low-birth-weight (VLBW; < 1,500 g) infants. Fifty-two infants (mean birth weight, 1,117 +/- 287 g; mean gestational age, 29 +/- 2.9 weeks) were randomly allocated to two groups. SUPP infants received a regular term formula plus zinc supplements (4.4 mg/L; final content, 11 mg/L); PLAC infants received the same formula plus placebo (final content, 6.7 mg/L). Infants started their formula at 1,853 +/- 109 g and consumed the formula for 6 months. All subjects were evaluated at 3, 6, 9, and 12 +/- 0.75 months corrected-for-gestational-age. At each evaluation, weight, length, and head circumference were measured, a Griffiths developmental assessment was performed, and a blood sample was taken. Higher plasma zinc levels (p < 0.05) were found in the SUPP group at 1 and 3 months, and improved linear growth velocity was found in the SUPP group over the study period for the whole group as well as for girls alone. Maximum motor development scores were higher (p = 0.018) in the SUPP (98 +/- 10) than the PLAC (90 +/- 8) group, indicating that increased zinc intake in early infancy may be beneficial to VLBW infants.

Eighteen-month course of two patients with grafts of fetal dopamine neurons for severe Parkinson's disease.

Two patients with advanced Parkinson's disease were followed for 6 months before, and 18 months after, receiving stereotaxic grafts of fetal mesencephalic tissue from aborted human fetuses. Parameters studied included a series of standardized tests of movement, response to levodopa, electrophysiological recording of the motor readiness potential, and positron emission tomography (PET) with ligands based upon levodopa and upon the dopamine reuptake inhibitor nomifensine. The patients each received stereotaxic implantation of ventral mesencephalic tissue containing midbrain dopamine neurons from aborted human fetuses of 8 to 10 weeks gestational age into the caudate and putamen of one hemisphere. Throughout their 18-month course, the patients were treated with cyclosporine, azathioprine, and glucocorticoids to minimize the risk of graft rejection. There were no significant complications from the procedure, but there was also no major change in their assessment of impairment on the Hoehn and Yahr scale. However, significant changes were observed in clinical, electrophysiological, and PET measures. Changes in these parameters, apparent at 6 months postoperatively, were described in detail in a previous report. The purpose of this present report is to provide follow-up data from the subsequent year with an emphasis on longitudinal evaluation methodology. Standardized clinical testing showed a small but long-term improvement in the first of the two patients. Following the operation, she was able to walk in "off" periods, which she had not been able to do preoperatively. This improvement was accompanied by increased walking speed and reduction in the time necessary to perform a series of pronation and supination movements using both hands. Although these improvements have continued throughout the postoperative period, they have not alleviated her basic neurological impairment. The second patient showed similar improvement during the first 6 months; she then reverted to her preoperative status at the end of the 18-month follow-up period. The electrophysiological recordings were consistent with the clinical findings. Both patients had significant changes in the motor readiness (bereitschafts) potential amplitude, which was greatest 5 to 7 months postoperation. The amplitude of the potential declined subsequently for both patients, but remained significantly elevated over the preoperative baseline for patient 1. The analysis of the PET scans was somewhat compromised by technical problems in the preoperative scans. However, they are also consistent with the clinical data. In comparisons of the operated and the unoperated sides, fluoro-dopa showed increased uptake in the caudate nucleus of patient 1 at 6 months and at 13 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Immune response of elderly individuals to a live attenuated varicella vaccine.

The Oka strain live attenuated varicella-zoster virus (VZV) vaccine was administered subcutaneously to 202 VZV-immune individuals who were 55 to greater than 87 years old. The dose administered varied from 1100 to 12,000 pfu. One cohort received 3000 pfu with a 3000 pfu booster 3 months later. The vaccine was well tolerated. VZV-specific immunologic responses were evaluated over a 24-month period. The mean anti-VZV antibody level was significantly increased for 12 months after vaccination. Interferon-gamma production in vitro by peripheral blood mononuclear cells (PBMC) of vaccinees was also increased for 6 months after vaccination. Most significantly, VZV-specific proliferating T cells in PBMC of vaccinees were increased in frequency from 1 in 68,000 to 1 in 40,000. This vaccine-enhanced frequency of VZV-responding T cells is similar to the frequency observed in 35- to 40-year-old adults. Dose and age of the vaccinees did not significantly influence the magnitude of the mean cell-mediated immune response. The data indicate that VZV immunity in the elderly can be boosted by active immunization. If the increased incidence of herpes zoster that accompanies aging results from the natural waning of immunity, active immunization may prevent or attenuate zoster in the elderly.