The prognostic significance of the skeletal manifestations of acute lymphoblastic leukemia of childhood.

The variety and distribution of skeletal pathology in children with acute lymphoblastic leukemia is rarely seen in other disease states. Skeletal radiographic changes associated with and/or suggestive of acute leukemia include diffuse osteopenia, metaphyseal bands, periosteal new bone formation, geographic lytic lesions, sclerosis, mixed sclerosis/lysis, and permeative destruction. This retrospective analysis of 83 children with acute lymphoblastic leukemia suggests that children without radiographic skeletal abnormalities have an "aggressive" form of leukemia. Children with one to four lesions have an "indolent" form of leukemia that is of short duration. Children with five or more lesions have an indolent form of leukemia that is of longer duration. The longer duration of symptoms before diagnosis reduces the survival rate to that of the aggressive form of leukemia. It is therefore imperative that physicians who treat children recognize the orthopaedic/radiographic manifestations of acute leukemia (the most common pediatric malignancy) to facilitate diagnosis, and, thereby, improve survival.

Genetic contributions to quantitative lipoprotein traits associated with coronary artery disease: analysis of a large pedigree from the Bogalusa Heart Study.

A pedigree of a large family with high prevalence of heart disease is subjected to association and sib-pair linkage analysis to investigate the role of 5 candidate genes in the regulation of lipoprotein metabolism and the development of coronary artery disease. At the 5% nominal significance level, the apolipoprotein B locus (APOB) was found to be linked to high-density lipoprotein cholesterol level (HDL-C), low-density lipoprotein cholesterol level (LDL-C), the ratio HDL-C/LDL-C, and apolipoprotein AI level times this ratio (apoAI x LDL-C/HDL-C). APOB (PvuII) was strongly associated with apolipoprotein B levels (apoB) (P = 0.006) and the VNTR region of the APOB locus showed highly significant association between allele 7 and low triglyceride levels (P = 0.004). No significant linkage results were found with cholesterol ester transfer protein (CETP). At the 1% nominal significance level, CETP [TaqI(B)] showed significant association with LDL-C, apoB, and HDL-C/LDL-C. There was significant linkage of lipoprotein lipase (LPL) with very-low-density lipoprotein cholesterol and the ratio apoAI/HDL-C, and strong association results between LPL (HindIII) and triglyceride levels (P = 0.005). At the 5% nominal significance level, haptoglobin (HPA) was associated with HDL-C, HDL-C/LDL-C, apoAI/HDL-C and apoAI x LDL-C/HDL-C. The apolipoprotein AI locus did not show any significant linkages or associations. The study thus indicated that genetic variation of APOB, LPL, CETP, and lecithin cholesterol acyl transferase (which is linked to HPA and CETP) may play an important role in the regulation of lipoprotein metabolism and could contribute to the risk of coronary artery disease.

Confidence limits based on the first occurrence of an event.

Confidence limits for population prevalence based on the first occurrence of an item in a medical database, or for incidence based on time to first occurrence, should be based on the geometric or exponential distributions, respectively. These intervals are presented and compared with the corresponding intervals based on the binomial and Poisson distributions. The lower confidence limits are shown to be the same, but the upper limits are smaller, hence leading to shorter intervals. Applications of these intervals are also presented.

Fitting growth curve models to longitudinal data with missing observations.

We discuss the analysis of growth curve data with missing or incomplete information. The approach is to fit subject-specific models and then to carry out an analysis in terms of the estimated parameters. This achieves reduction of data and eliminates the need for special considerations for subjects with missing data. Although there is no perfect substitute for complete data, our approach provides a way to handle missing data using a straightforward application of well-known statistical methodology.

The Elston-Stewart algorithm for continuous genotypes and environmental factors.

The Elston-Stewart algorithm for a normally distributed trait under a polygenic model is explained in detail and extended to allow for other continuous environmental variables. This formulation is especially useful for large pedigrees, as it avoids the need to invert matrices. Whereas it may not be feasible by this method to estimate all the various components of previously suggested models for polygenic inheritance, it can allow for a reasonably flexible pedigree correlational structure under which valid tests can be performed for fixed effects that may affect the phenotype.

Effect of regression to the mean in the presence of within-subject variability.

Regression to the mean arises often in statistical applications where the units chosen for study relate to some observed characteristic in the extreme of its distribution. Gardner and Heady attribute the effect of regression to the mean to measurement errors. They assume the model Yi = U + ei, where U is a fixed within-subject component and ei is the random measurement error. They suggest several replicate measurements to reduce the regression effect under the assumption that the measurement errors ei are independent within subjects. While measurement errors play an important role in regression to the mean, one should not overlook within-subject variation. In this paper, we consider a model to estimate the regression effect in the presence of correlated within-subject effects as well as independent measurement errors.

Effects of reduced renal function and dietary protein on muscle protein synthesis.

We describe a rat model of renal failure that separates catabolic and anabolic states from each other. Muscle protein synthesis was compared during the anabolic period between sham (S) operated and renal failure (RF) rats that were fed different levels of dietary protein. Male rats weighing between 60 and 80 g first had a partial left nephrectomy and then were given a tryptophan deficient diet from four to six days to induce weight loss. On the second day of the diet either a renal decapsulation (S rats) or a simple right nephrectomy (RF rats) was done to enhance the catabolic response in both and to induce renal failure in the RF rats. Following the period of feeding the deficient diet, both groups were fed a nutritionally complete 14, 17, 20 or 30% protein diet for three to five days. This induced a brisk anabolic response as measured by weight gain. Differences in body weight between the S and RF rats after three to five days on the repletion diet generally was less than 10%. The rats then were fasted overnight, fed a standard meal and muscle protein synthesis (Sm%) was measured two hours post-feeding. Sm% was estimated from the incorporation of 3H phenylalanine (PHE) into muscle 10 minutes following the i.v. injection of 3HPHE (25 muCi/100 g body wt) with carrier PHE to flood all the precursor amino acid pools. Weight loss in the catabolic phase was greater and the net weight gain for the two phases was less in the RF group. Overall, renal failure resulted in a significant reduction in Sm% (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Age of onset, age at examination, and other covariates in the analysis of family data.

Information on age of onset can easily be incorporated into regressive logistic models by assuming that age of onset follows a logistic distribution. This is analogous to previously proposed models based on the normal distribution. The two distributions, and hence the two types of models, are very similar. In each case the generalized modules power transformation can be used as a basis for more flexibly modeling the age of onset distribution.

Testing the association between polymorphic markers and quantitative traits in pedigrees.

A statistical model that uses an iterative maximum likelihood estimation procedure is proposed for measuring and testing the association between polymorphic genetic markers and quantitative traits in human pedigrees, after adjusting for covariates such as age and sex. The model allows the quantitative trait to have a familial correlation structure among the individuals in the sample and to follow one of a broad class of skewed or kurtotic underlying distributions. The use of the model is illustrated, and the results are compared to those using models that assume normality without any transformation and do not incorporate familial correlations.

Association between polymorphic blood markers and risk factors for cardiovascular disease in a large pedigree.

A large pedigree with high prevalence of heart disease is investigated to analyse the association between polymorphic blood markers and quantitative risk factors for cardiovascular disease. The analysis incorporates a familial correlation structure among the individuals in the pedigree and a generalized power transformation to induce approximate residual normality of the risk factors. A total of 380 marker/risk factor combinations are analysed, and at the normal 1% significance level, positive associations are found between the A antigen of the ABO locus and both serum total cholesterol and low-density lipoprotein cholesterol, and negative associations are found between the B antigen of the ABO locus and serum total cholesterol, and between the B allele of acid phosphatase (AP) locus and systolic blood pressure.