Ball flight kinematics, release variability and in-season performance in elite baseball pitching.

The purpose of this study was to quantify ball flight kinematics (ball speed, spin rate, spin axis orientation, seam orientation) and release location variability in the four most common pitch types in baseball and relate them to in-season pitching performance. Nine NCAA Division I pitchers threw four pitching variations (fastball, changeup, curveball, and slider) while a radar gun measured ball speed and a 600-Hz video camera recorded the ball trajectory. Marks on the ball were digitized to measure ball flight kinematics and release location. Ball speed was highest in the fastball, though spin rate was similar in the fastball and breaking pitches. Two distinct spin axis orientations were noted: one characterizing the fastball and changeup, and another, the curveball and slider. The horizontal release location was significantly more variable than the vertical release location. In-season pitching success was not correlated to any of the measured variables. These findings are instructive for inferring appropriate hand mechanics and spin types in each of the four pitches. Coaches should also be aware that ball flight kinematics might not directly relate to pitching success at the collegiate level. Therefore, talent identification and pitching evaluations should encompass other (e.g., cognitive, psychological, and physiological) factors.

Haplotype-based search for SNPs associated with differential type 1 diabetes risk among chromosomes carrying a specific HLA DRB1-DQA1-DQB1 haplotype.

AIM: The aim of this study was to test chromosomes carrying the same DRB1-DQA1-DQB1 haplotype for single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) that might mark subgroups of the haplotype with different risks for type 1 diabetes (T1D). METHODS: Chromosomes from T1D children, their parents and non-diabetic siblings in families of the Type 1 Diabetes Genetics Consortium (T1DGC) were analysed by two haplotype-based methods: (i) logistic regression analysis restricted to phased chromosomes carrying the same DRB1-DQA1-DQB1 haplotype but differentiated by the two alleles at MHC SNPs, which were individually tested for association with T1D and (ii) homozygous parent transmission disequilibrium test (TDT) for biased transmission of a SNP allele to diabetic children from parents who are heterozygous at the SNP but homozygous for the specific DRB1-DQA1-DQB1 haplotype being evaluated. RESULTS: A number of SNPs gave nominally significant (p < 0.05) evidence of marking two subsets of the 301-501-201 haplotype that might differ with respect to their diabetogenic potency. However, none of the SNPs achieved experiment-wide significance and hence may be false-positive associations. CONCLUSIONS: We discuss limitations and possible deficiencies of our study suggesting further work that might yield more robust SNP associations marking two subgroups of a DRB1-DQA1-DQB1 haplotype with different T1D risks.

Large scale association analysis of novel genetic loci for coronary artery disease.

BACKGROUND: Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. METHODS AND RESULTS: We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11,550 cases and 11,205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81 x 10(-21)). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44 x 10(-7)), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02 x 10(-3)), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34 x 10(-4)). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P=0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86 x 10(-5)) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. CONCLUSIONS: The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.

Anorexia nervosa. A review.

Anorexia nervosa is an illness characterized by significant weight loss, amenorrhea, distorted body image and a relentless pursuit of thinness. The disorder affects primarily young women between the ages of 13 and 20, and is more commonly seen in westernized countries. Although the incidence is relatively rare, affecting approximately 0.5 to 1.0% of younger women in the United States, medical complications can be severe, and long-term mortality rates may approach 20%. Recent studies indicate that subclinical eating disorders occur in at least 5% of women and up to 1/3 of females among special populations such as athletes and insulin-dependent diabetics. The etiology of eating disorders is not known, but there are psychosocial and biological influences. Malnutrition associated with anorexia nervosa can affect nearly every organ system in the body, with cardiac complications responsible for 50% of the deaths in anorexia nervosa. More recent brain studies suggest that grey matter volume deficits may persist after refeeding. Subclinical anorexia nervosa in athletes is associated with premature fractures and long-term osteopenia. Early complications, such as retinopathy, are increasingly seen in female diabetics who have disordered eating patterns. Well-designed empirical trials of treatment with psychotherapy and psychopharmacology are very limited. There is some evidence that family therapy may be more effective than individual therapy in younger anorectics who have been ill less than 3 years. The most promising finding in medication treatment suggests that fluoxetine may help prevent relapse in the weight restored anorectic.

Further support for the association of CCR5 allelic variants with asthma susceptibility.

English and German nuclear families containing multiple asthmatic children and asthmatic parents were analysed to retest a recently reported association between resistance to asthma and the delta32 allele of chemokine receptor 5 (CCR5). Analysis of the families by the transmission-disequilibrium test (TDT) revealed a non-significant trend in the English families that provided marginal confirmation of the association (P < 0.125), but no similar trend was observed in the German families. Case-control comparison of delta32 allele and genotype frequencies in asthmatic vs. non-asthmatic parents revealed a significantly lower frequency of delta32 in asthmatic English parents (P < 0.009) and a similar but non-significant trend in German parents (P < 0.265). Taken together, the pattern of results provides confirmation for the previously observed delta32-asthma association and indicates that susceptibility to asthma may be influenced by CCR5 or another gene in chromosomal region 3p21.

Failure to confirm NOTCH4 association with schizophrenia in a large population-based sample from Scotland.

The NOTCH4 gene was recently reported to be associated with schizophrenia based on TDT analysis of 80 British trios. The strongest evidence for association derived from two microsatellites. We genotyped both loci in a large sample of unrelated Scottish schizophrenics and controls, but failed to replicate the reported association, finding instead that each putative schizophrenia-associated allele had a somewhat lower frequency in schizophrenics than in controls.

General equations for Pt, Ps, and the power of the TDT and the affected-sib-pair test.

Several equations are highlighted here, whose algebraic symmetries and generality make them very useful for understanding and comparing the properties of the transmission disequilibrium test (TDT) and affected sib-pair test. Methods using the equations are also presented that yield precise estimates of sample sizes needed for genome scans or for testing a single candidate gene, and these power methods are shown to compare favorably with alternative approaches recently described by Knapp (1999) and by Tu and Whittemore (1999). Simple relationships are also noted that summarize the relative sample sizes required for equivalent power to detect association by the TDT or case-control designs. As single-nucleotide polymorphism (SNP) maps revolutionize the search for disease-causing genes, the equations should prove useful for planning and evaluating studies of linkage and association across a broad range of possible disease models and relationships between markers and linked disease loci.

Hidden linkage: a comparison of the affected sib pair (ASP) test and transmission/disequilibrium test (TDT).

I compare the transmission/disequilibrium test (TDT) and affected sib pair (ASP) test under a general algebraic model describing a bi-allelic disease locus. Assuming linkage to a bi-allelic marker, I derive two binomial probabilities, one for parental allele 'transmission' (Pt) which determines the magnitude of the TDT chi 2 statistic (chi 2tdt), and a second for identity-by-descent (ibd) marker allele 'sharing' (Ps) which determines the magnitude of the ASP test statistic (chi 2asp). I also consider the ASP test applied to a completely polymorphic marker and demonstrate that the probability of ASP marker allele sharing (Ps) is identical to Ps observed for a bi-allelic marker in equilibrium with the disease locus. I present a general framework for determining the power of the TDT and ASP test based on expressions for Pt, Ps and the proportion (H/F) of ascertained parents who are informative at the marker. Two previous analytic investigations of TDT power based on the work of Ott (1989), and Risch & Merikangas (1996) are shown to be special cases of this general framework. In addition, I show the relationship between the framework I present and a third analytic investigation of TDT power for multi-allelic markers based on the work of Sham & Curtis (1995).

Insulin gene 5' flanking polymorphism. Length of class 1 alleles in number of repeat units.

The 5' flanking polymorphism (5'FP) is a minisatellite, variable number of tandem repeat (VNTR) locus adjacent to the 5' end of the insulin gene (INS). Alleles of the 5'FP are highly variable in length but fall into three discrete size classes. The shortest, or class 1, alleles are associated with insulin-dependent diabetes mellitus (IDDM). Here we present a polymerase chain reaction (PCR)-based technique for subtyping 5'FP class 1 alleles by determining their exact lengths in number of repeat units (RUs). The technique resolves small length differences not detectable by Southern blot and produces a frequency distribution of class 1 allele lengths, which serve as subtypes of the crude class 1 category. We have applied the technique to 132 Caucasian families with IDDM offspring and have found that the lengths of 5'FP class 1 alleles form a quasi-continuous distribution with three distinct modes. We also found precise correlation between class 1 allele length and the allele present on the same chromosome at HUMTH01, a second VNTR locus in the INS region. Specifically, each of the four common alleles of HUMTH01 exhibited near-total association with a narrow size range belonging to one of the three components of the class 1 distribution. We discuss these results in relation to the population history of the 5'FP and INS region haplotypes and in relation to IDDM susceptibility in the INS region.

The TDT reveals linkage and linkage disequilibrium in a rare disease.

We used the TDT as the basis for our analysis of data from Problem 1 of GAW9. Among the 360 marker loci on six chromosomes, we searched for any that might show both linkage and allelic association with the disease. We applied the TDT to each allele at every marker locus and found strong evidence for linkage in two regions: one on chromosome 1, another on chromosome 5.

Linkage disequilibrium in the insulin gene region: size variation at the 5' flanking polymorphism and bimodality among "class I" alleles.

The 5' flanking polymorphism (5'FP), a hypervariable region at the 5' end of the insulin gene, has "class 1" alleles (650-900 bp long) that are in positive linkage disequilibrium with insulin-dependent diabetes mellitus (IDDM). We report that precise sizing of the 5'FP yields a bimodal frequency distribution of class 1 allele lengths. Class 1 alleles belonging to the lower component (650-750 bp) of the bimodal distribution were somewhat more highly associated with IDDM than were alleles from the upper component (760-900 bp), but the difference was not statistically significant. We also examined 5'FP length variation in relation to allelic variation at nearby polymorphisms. At biallelic RFLPs on both sides of the 5'FP, we found that one allele exhibits near-total association with the upper component of the 5'FP class 1 distribution. Such associations represent a little-known but potentially widespread form of linkage disequilibrium. In this type of disequilibrium, a flanking allele has near-complete association with a single mode of VNTR alleles whose lengths represent consecutive numbers of tandem repeats (CNTR). Such extreme disequilibrium between a CNTR mode and flanking alleles may originate and persist because length mutations at some VNTR loci usually add or delete only one or two repeat units.

Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).

A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the "class 1" alleles of the region of tandem-repeat DNA (5' flanking polymorphism [5'FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5'FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not.

What price quality? Assuring the quality of case-managed in-home care.

Case managed community-based long-term care has now become an established component of the service delivery system in the United States. As case management has developed, it has gone through an evolutionary process. In the initial phase of case management, considerable attention was placed on gaining access to resources by the case manager. This article addresses issues of assuring the quality of case-managed care. It focuses on the current concerns and potential problems associated with evaluating the effectiveness of services arranged by case managers, and describes a model, developed in Ohio, to ensure the quality of care. In addition, it discusses the continued challenges for and costs of quality assurance and notes the difficulty of obtaining empirical data in the effort to assure quality.

Dysregulation of the Hypothalamus-Pituitary-Adrenal Axis in Male and Female, Genetically Obese (ob/ob) Mice.

The autosomal, recessive obesity of ob/ob mice is associated with hypercorticosteronemia and amelioration of most symptoms of obesity following adrenalectomy. Increased adrenocorticotropic hormone (ACTH) secretion has been hypothesized on the basis of several reports of higher pituitary ACTH content in ob/ob mice compared to lean littermates. However, the only measurement of ACTH blood concentration found lower levels in ob/ob mice than in leans suggesting that hypercorticosteronemia might result solely from an enhanced adrenal response to ACTH and also suggesting that the ob/ob's elevated pituitary ACTH content might be due to decreased ACTH secretion rather than increased ACTH synthesis. In our study, basal serum ACTH levels were higher in ob/ob males and females compared to sex-matched lean littermates. Anterior pituitary ACTH synthesis was also elevated as indicated by increased content of ACTH and proopiomelanocortin mRNA in obese mice of both sexes; however hypothalamic corticotropin-releasing factor content was not different in lean and obese mice. Basal serum ACTH and corticosterone (CS) levels showed normal circadian rhythm in both phenotypes and sexes, but the circadian increase in CS level was much greater in obese mice than in leans despite equal serum ACTH increases in the two phenotypes. Ether stress at both peak and trough of the circadian rhythm also stimulated much larger serum CS increases in obese mice even though ACTH increases were again equal in the two phenotypes. Taken together, these results strongly indicate that ob/ob mice have increased synthesis and secretion of pituitary ACTH despite the presence of chronically elevated serum CS. This hyperactivity of the hypothalamo-pituitary-adrenal axis appears to be most pronounced in ob/ob females since pituitary ACTH content was equal in obese males and females despite much higher circulating CS levels in the females. Furthermore, the results also indicate an enhanced response to ACTH by the adrenal cortex of the obese mouse. Thus, ob/ob mice exhibit abnormal hypothalamo-pituitary-adrenal axis function with hyperactivity occurring at the level of pituitary ACTH synthesis/secretion as well as at the level of adrenocortical response to ACTH.