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PubMed2002

Efficiency of haplotype frequency estimation when nuclear family information is included.

In genetic studies the haplotype structure of the regarded population is expected to carry important information. Experimental methods to derive haplotypes, however, are expensive and none of them has yet become standard methodology. On the other hand, maximum likelihood haplotype estimation from unphased individual genotypes may incur inaccuracies. We therefore investigated the relative efficiency of haplotype frequency estimation when nuclear family information is included compared to estimation from experimentally derived haplotypes. Efficiency was measured in terms of variance ratios of the estimates. The variances were derived from the binomial distribution for experimentally derived haplotypes, and from the Fisher information matrix corresponding to the general likelihood function of the haplotype frequency parameters, including family information. We subsequently compared these variance ratios to the variance ratios for the case of estimation from individual genotypes. We found that the information gained from a single child compensates missing phase information to a high degree, resulting in estimates almost as reliable as those derived from observed haplotypes. Thus, if children have already been genotyped for other reasons, it is highly recommendable to include them into the estimation. If child information is not already present, it depends on the number of loci and the haplotype diversity if it is useful to genotype a single child just to reduce phase ambiguity. In general, if the number of loci is less than or equal to three or if the number of haplotypes with a frequency >5% is less than or equal to four, haplotype estimation from individuals is quite good already and the improvement gained from a single child can not compensate the genotyping effort for it. On the other hand, under scenarios with many loci and high haplotype diversity, haplotype frequency estimation from trios can be more efficient than haplotype frequency estimation from individuals also on a per genotype base.

Data Interpretation, Statistical↗
PubMedDate not supplied

The G/A nucleotide change at cDNA position 2494 in the E-cadherin gene (CDH1): analysis in Italian patients.

Current studies are investigating new E-cadherin gene (CDH1) mutations that may be responsible for diffuse gastric cancer susceptibility. Recently, a novel CDH1 germline variant presenting a G/A nucleotide change at cDNA position 2494 has been found in Japanese patients with familial diffuse gastric cancer. The consequent amino acid variation (Val/Met) may alter the binding activity to beta-catenin and the adhesive function of the E-cadherin protein. We have investigated its frequency in Italian cases of sporadic diffuse gastric cancer a well as in healthy controls. Peripheral blood samples were collected from consecutive patients with sporadic, diffuse gastric cancer and from healthy controls in the District of Urbino, Marche Region, Central Italy. After DNA extraction, standard techniques for molecular analyses were used to investigate the 2494 G/A germline nucleotide change in CDH1 cDNA. None of the 48 patients and 48 controls showed the G/A 2494 nucleotide change. Assuming a binomial distribution of the mutation among individuals and the absence of mutations in the 48 patients, the 95% upper bound for the underlying mutation frequency was 7.4%. The novel CDH1 nucleotide change is uncommon in Italian patients with sporadic diffuse gastric cancer. Given these results, further analyses in large population-based studies are not advisable.

Adult↗
PubMed2005

Optimization of prostatic biopsy: a prospective randomized trial comparing the sextant biopsy with a 10-core biopsy. Impact of prostatic region of sampling.

OBJECTIVE: New prostatic biopsy protocols suggest to increase the core numbers to enhance detection. Additional cores are usually sampled from the lateral part of the p-zone. We direct the sextant biopsy to the most lateral part of the p-zone, therefore we investigated if there is a gain by adding 4 median biopsy cores. MATERIAL AND METHODS: The prospective randomized trial (n = 200) compared our modified sextant biopsy to a 10-core strategy with 2 additional median cores on both sides. Directed biopsies to suspicious areas were allowed in both groups. Morbidity was assessed by a self-administered questionnaire. RESULTS: PC detection was 32% for 6 cores and 40% for 10 cores. Four patients were detected only by median biopsies. Using the binomial distribution table the gain of 4% is statistically significant. There was no statistical difference in morbidity, but a trend towards a higher rate of side effects in the 10-core group. CONCLUSIONS: The gain in prostate cancer detection rate by additional median biopsies is low, but statistically significant. There is no difference in morbidity and patient acceptance is high, therefore we favor the 10-core biopsy in our patients.

Biopsy↗
PubMed1988

The importance of sample size in the interpretation of the renal biopsy.

The number of abnormal glomeruli present in a renal biopsy can be viewed as a binomial distribution. Recognition of this fact permits a quantitative assessment of the effect of biopsy sample size in renal biopsy interpretation. If the percent of glomerular involvement in a biopsy is used to determine the severity of a focal glomerular lesion, a small biopsy sample size will lead to considerable misclassification of disease severity. In addition, a small biopsy sample size will make the exclusion of focal disease difficult.

Biopsy↗
PubMed1987

Long-term control of Chagas disease in Venezuela: effects on serologic findings, electrocardiographic abnormalities, and clinical outcome.

To evaluate the long-term effects (20 years) of a Chagas control program (CCP) in Venezuela, a prospective serologic evaluation was carried out from 1981 to 1984 on 5771 inhabitants (8%) of Roscio county. This region was selected as a representative area where the national CCP was implemented effectively. Comparison with a serologic survey performed in the same region before the CCP disclosed a reduction in seropositive subjects from 47.8% to 17.1% (p less than .001), most marked amongst children and teenagers from 29.9% to 1.9%, suggesting that transmission of the disease had diminished. Similar seropositivity changes after the CCP were observed nationwide. Because decreased superinfection would also be expected to occur, we tried to ascertain whether the clinical outcome of seropositive individuals living in Roscio county had improved. The mean age of seropositive subjects between both surveys increased significantly from 34.9 +/- 17.3 to 46.7 +/- 15.1 years (p less than .001). Additionally, we examined clinically and obtained electrocardiograms from 775 seropositive subjects. They were classified as asymptomatic (group A, n = 614) or as symptomatic, having mild-to-moderate heart symptoms (group B, n = 99) or having advanced congestive heart failure (group C, n = 62). Their electrocardiograms were compared with those of 923 seronegative subjects collected simultaneously and with published data obtained before the CCP. Comparison of the age-related rates of electrocardiographic abnormalities of seropositive individuals before and after the CCP showed that they did not differ significantly by linear regression analysis, by the Kruskal-Wallis test, or by the normal approximation to the binomial distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2001

Have randomized controlled trials of neuroprotective drugs been underpowered? An illustration of three statistical principles.

BACKGROUND AND PURPOSE: The results of phase III trials of neuroprotective drugs for acute ischemic stroke have been disappointing. We examine the question of whether these trials may have been underpowered. METHODS: Computer simulations were based on the binomial distribution. RESULTS: We illustrate that even small overestimates of the efficacy of an intervention can lead to a serious reduction in statistical power, that the use of data from phase II studies tends to lead to such overestimation, and that a minimum clinically important difference derived with cost-effectiveness modeling techniques is considerably smaller than might be suggested by intuition. CONCLUSIONS: We recommend placing more emphasis on minimum clinically important differences when planning stroke trials, with these differences being derived from an assessment of the public health impact obtained in conjunction with the use of epidemiological and cost-effectiveness models. Even small benefits, when averaged over a sufficiently large number of cases, will, in total, accrue to a large positive impact on the public health.

Brain Ischemia↗
PubMed1975

The prevalence of mycoplasmal complement-fixing antibodies in sarcoidosis.

Complement-fixing antibody titers to Mycoplasama pnuemoniae were measured in the sera of 31 patients with sarcoidosis and 31 control subjects matched by age, sex, and race. Data indicated a binomial distribution and a geometric mean titer of 1:32 in patients with sarcoidosis. In contrast, the control data were skewed,with a geometric mean titer of less than 1:8. Possible explanations include generalized increase in antibody formation, unusual susceptibility to infection with M.pneumoniae, and sarcoidosis as one consquence of infection with M.pneumoniae.

Antibodies↗
PubMed1985

Use of an X-linked human neutrophil marker to estimate timing of lyonization and size of the dividing stem cell pool.

In families with X-linked chronic granulomatous disease (CGD), heterozygous females have two stable populations of polymorphonuclear leukocytes (PMN) in their blood; one normal, the other, deficient in oxygen metabolism. The two types of PMN can be distinguished by the ability or lack of ability to reduce nitroblue tetrazolium dye. The variation in the percent normal PMN among 11 CGD heterozygotes was shown to follow a binomial distribution based on eight independent trials and a chance of success of 50%. This is consistent with the occurrence of X-chromosome inactivation (lyonization) when eight embryonic founder cells for the hematopoietic system are present. Serial determinations of the percent normal PMN in individual heterozygotes showed very limited variability (standard deviations ranged from 2.0% to 5.2%) most of which could be ascribed to experimental error. An estimate of the remaining variation (residual variance) was introduced into a well-known formula to calculate the appropriate number of pluripotent stem cells necessary to support hematopoiesis and a figure exceeding 400 was obtained. Thus, the data indicate that in humans there is a highly polyclonal system of hematopoiesis.

Clone Cells↗
PubMed1987

A field test of Motto's risk estimator for suicide.

The authors undertook a field test of Motto and colleagues' Risk Estimator for Suicide by selecting a subset (N = 593) of psychiatric patients with major or chronic affective disorder that corresponded to Motto's sample. They rated each subject on Motto's scale, using standardized data collected at hospital admission. Fourteen patients (2.4%) in their sample and 136 (4.9%) in Motto's sample died by suicide within 2 years. The authors tested the null hypothesis of a uniform suicide risk across all 10 deciles of risk scores by comparing observed and expected frequencies of suicide using the variance test for homogeneity of the binomial distribution. Their findings raise questions about Motto's risk scale but do not definitively invalidate it.

Adolescent↗
PubMed1983

Estimates of the gain in power utilizing transformations of DMFS scores.

More than 100,000 clinical caries trials were simulated utilizing the negative binomial distribution on a UNIVAC 1100 computer. In each trial, the raw data and logarithmic transformed data were analyzed using a standard t test analysis. The results were summarized as estimates of the power functions for each case. In almost all cases, the transformed data gave greater power than did the untransformed data. In several common situations, the differences were dramatic.

Computers↗
PubMed1999

A method for measuring interrater agreement on checklists.

A method for measuring interrater agreement on checklists is presented. This technique does not assign individual scores to raters, but computes a single agreement score from the concordance of their check mark configurations. An overall coefficient of agreement, called phi, is derived. The agreement coefficient that is expected by chance and the statistical significance of phi are determined by statistical simulation. Despite the dichotomous nature of the checklist agreement (raters either agree or disagree on items), we show that the binomial distribution does not provide a means for testing the statistical significance of phi. A medical education study is used to illustrate the phi methodology.

Education, Medical, Undergraduate↗
PubMed2006

Sample sizes for identifying the key types of container occupied by dengue-vector pupae: the use of entropy in analyses of compositional data.

A method has been developed for estimating the sample sizes needed to identify categories that comprise a large proportion of a compositional data-set. The method is to be used in the design of surveys of mosquito pupae, for identifying the key container types from which the majority of adult dengue vectors emerge. Although a finite-population correction was devised for estimating the mean of a negative binomial distribution, other complications of parametric approaches make them unlikely to yield methods simple enough to be practically applicable. The Shannon-Wiener index was therefore investigated as a more useful alternative, at the cost of theoretical generalizability, in an approach based on re-sampling methods in conjunction with the use of entropy. This index can be used to summarize the degree to which pupae are either concentrated in a few container types, or dispersed among many. An empirical relationship between the index and the repeatability of surveys of differing sample sizes was observed. A step-wise rule, based on the entropy of the cumulative data, was devised for determining the sample size, in terms of the number of houses positive for pupae, at which a pupal survey might reasonably be stopped.

Aedes↗
PubMed2006

Sample-size requirements for developing strategies, based on the pupal/demographic survey, for the targeted control of dengue.

Several methods to determine the sample size required for a reliable and practical assessment of the number of Aedes aegypti pupae in a community in Puerto Rico have been explored. Because the pupae were highly aggregated, the data were fitted to a negative binomial distribution. Classical statistical-inference methods for sample-size determination demanded the sampling of >3,000 premises for a reliable estimation of the mean number of pupae/person (with a 15% error). This number was reduced to 1,000-1,200 premises after applying a finite-population correction. Database sub-sampling simulations, with increasing sample sizes, showed that the variability in the mean relative abundance of container types and in the mean number of pupae/container substantially decreased after sampling 186 and 310 premises, respectively. Sequential sampling was applied to test the hypotheses that the number of female pupae/person was at least 0.19 (considered the dengue epidemic threshold) or no greater than 0.10 (arbitrarily set as the safe level). After sampling only 25 premises in the first survey and 125 in the second, it was determined that the densities of female pupae were above the epidemic threshold. Thus, sequential sampling provided substantial reductions in the sample size required to determine if vector control was needed. Validation of the Ae. aegypti thresholds required for dengue transmission could confer viability and efficiency to dengue-vector surveillance and control programmes.

Aedes↗
PubMed2005

Evaluation of the similarity of gene expression data estimated with SAGE and Affymetrix GeneChips.

BACKGROUND: Serial Analysis of Gene Expression (SAGE) and microarrays have found a widespread application, but much ambiguity exists regarding the evaluation of these technologies. Cross-platform utilization of gene expression data from the SAGE and microarray technology could reduce the need for duplicate experiments and facilitate a more extensive exchange of data within the research community. This requires a measure for the correspondence of the different gene expression platforms. To date, a number of cross-platform evaluations (including a few studies using SAGE and Affymetrix GeneChips) have been conducted showing a variable, but overall low, concordance. This study evaluates these overall measures and introduces the between-ratio difference as a concordance measure pergene. RESULTS: In this study, gene expression measurements of Unigene clusters represented by both Affymetrix GeneChips HG-U133A and SAGE were compared using two independent RNA samples. After matching of the data sets the final comparison contains a small data set of 1094 unique Unigene clusters, which is unbiased with respect to expression level. Different overall correlation approaches, like Up/Down classification, contingency tables and correlation coefficients were used to compare both platforms. In addition, we introduce a novel approach to compare two platforms based on the calculation of differences between expression ratios observed in each platform for each individual transcript. This approach results in a concordance measure per gene (with statistical probability value), as opposed to the commonly used overall concordance measures between platforms. CONCLUSION: We can conclude that intra-platform correlations are generally good, but that overall agreement between the two platforms is modest. This might be due to the binomially distributed sampling variation in SAGE tag counts, SAGE annotation errors and the intensity variation between probe sets of a single gene in Affymetrix GeneChips. We cannot identify or advice which platform performs better since both have their (dis)-advantages. Therefore it is strongly recommended to perform follow-up studies of interesting genes using additional techniques. The newly introduced between-ratio difference is a filtering-independent measure for between-platform concordance. Moreover, the between-ratio difference per gene can be used to detect transcripts with similar regulation on both platforms.

Cell Line, Tumor↗
PubMed2005

On the number of founding germ cells in humans.

BACKGROUND: The number of founding germ cells (FGCs) in mammals is of fundamental significance to the fidelity of gene transmission between generations, but estimates from various methods vary widely. In this paper we obtain a new estimate for the value in humans by using a mathematical model of germ cell development that depends on available oocyte counts for adult women. RESULTS: The germline-development model derives from the assumption that oogonial proliferation in the embryonic stage starts with a founding cells at t = 0 and that the subsequent proliferation can be defined as a simple stochastic birth process. It follows that the population size X(t) at the end of germline expansion (around the 5th month of pregnancy in humans; t = 0.42 years) is a random variable with a negative binomial distribution. A formula based on the expectation and variance of this random variable yields a moment-based estimate of a that is insensitive to the progressive reduction in oocyte numbers due to their utilization and apoptosis at later stages of life. In addition, we describe an algorithm for computing the maximum likelihood estimation of the FGC population size (a), as well as the rates of oogonial division and loss to apoptosis. Utilizing both of these approaches to evaluate available oocyte-counting data, we have obtained an estimate of a = 2 - 3 for Homo sapiens. CONCLUSION: The estimated number of founding germ cells in humans corresponds well with values previously derived from chimerical or mosaic mouse data. These findings suggest that the large variation in oocyte numbers between individual women is consistent with a smaller founding germ cell population size than has been estimated by cytological analyses.

Algorithms↗
PubMed2004

Bayesian estimation of vaccine efficacy.

Protective vaccine efficacy, VEs, is measured as one minus the incidence rate ratio (IRR) or the relative risk (RR) in the vaccinated group compared with the unvaccinated group. In this paper, we systematically present Bayesian estimation of protective vaccine efficacy based on the Poisson and binomial distributions. We also propose a new tool, the vaccine efficacy acceptability curve, to represent the uncertainty for the estimate of the vaccine efficacy graphically. It is very useful, especially when there is no universal agreement on the acceptable vaccine efficacy. The vaccine efficacy acceptability curve is defined as the posterior probability that the measure of vaccine efficacy VEs > or = k for each acceptable value k. When a vaccine is highly efficacious, the number of vaccinated susceptibles being infected is likely to be very small or even zero. Then the assumptions of normality and log-normality of IRR or RR usually do not hold well. Although frequentist exact methods provide good estimates of the confidence interval, they are overly conservative and are computationally difficult to extend to estimate the vaccine efficacy acceptability curve. In this paper, our focus is on Bayesian estimation of protective vaccine efficacy, its highest probability density credible set, and the vaccine efficacy acceptability curve through Markov chain Monte Carlo (MCMC) methods. We illustrate the methods using the data from two pertussis vaccine studies and the H. influenza Type B preventive trial.

Bayes Theorem↗
PubMed2006

Abdominal aortic aneurysm is a specific antigen-driven T cell disease.

To determine whether monoclonal/oligoclonal T cells are present in abdominal aortic aneurysm (AAA) lesions, we amplified beta-chain T cell receptor (TCR) transcripts from these lesions by the nonpalindromic adaptor (NPA)-polymerase chain reaction (PCR)/V-beta-specific PCR followed by cloning and sequencing. Sequence analysis revealed the presence of substantial proportions of identical beta-chain TCR transcripts in AAA lesions in 9 of 10 patients examined, strongly suggesting the presence of oligoclonal populations of alphabeta TCR+ T cells. We have also shown the presence of oligoclonal populations of gammadelta TCR+ T cells in AAA lesions. Sequence analysis after appropriate PCR amplification and cloning revealed the presence of substantial proportions of identical VgammaI and VgammaII TCR transcripts in 15 of 15 patients examined, and of Vdelta1 and Vdelta2 TCR transcripts in 12 of 12 patients. These clonal expansions were very strong. All these clonal expansions were statistically significant by the binomial distribution. In other studies, we determined that mononuclear cells infiltrating AAA lesions express early- (CD69), intermediate- (CD25, CD38), and late- (CD45RO, HLA class II) activation antigens. These findings suggest that active ongoing inflammation is present in the aortic wall of patients with AAA. These results demonstrate that oligoclonal alphabeta TCR+ and gammadelta TCR+T cells are present in AAA lesions. These oligoclonal T cells have been clonally expanded in vivo in response to yet unidentified antigens. Although the antigenic specificity of these T cells remains to be determined, these T cells may play a significant role in the initiation and/or the propagation of the AAA. It appears that AAA is a specific antigen-driven T cell disease.

Antigens↗
PubMed1989

Characterization and charge distribution of the asparagine-linked oligosaccharides on secreted mouse thyrotropin and free alpha-subunits.

Mouse hemipituitaries in vitro secrete TSH, composed of an alpha-beta heterodimer, as well as excess (free) alpha-subunits. By dual metabolic labeling with [35S]sulfate and [3H]mannose, we have characterized oligosaccharides from secreted TSH alpha, TSH beta, and free alpha-subunits released from the apoprotein by enzymatic deglycosylation. Oligosaccharides from each subunit displayed a distinct anion exchange HPLC profile due to a specific pattern of sialylation and sulfation. Six species were obtained from TSH alpha (with two glycosylation sites), including neutral oligosaccharides as well as those with one or two negative charges. For TSH beta (with one glycosylation site) at least eight oligosaccharide species were noted, representing nearly every permutation of sialylation and sulfation; approximately 30% contained three or more negative charges. Analysis of [3H]mannose-labeled oligosaccharides on Concanavalin-A-agarose showed 85% binding for those from TSH alpha, 70% for free alpha, and 50% for those from TSH beta. These data demonstrate that oligosaccharides from secreted TSH beta were more sialylated and sulfated, consistent with a more complex branching pattern, than those from TSH alpha. Oligosaccharides from free alpha-subunit were more sialylated than those from TSH alpha, and the net negative charge was intermediate between those of TSH alpha and TSH beta. Although great microheterogeneity is present even at the single glycosylation site on the beta-subunit of secreted TSH, a pattern of sialylation and sulfation could be discerned. If one assigns probabilities of sialylation [p(N)] and sulfation [p(S)] based on the observed distribution within monoacidic (charge -1) species, the proportion of diacidic (charge -2) oligosaccharides could be predicted for each subunit by [p(N)]2, 2[p(N)] [p(S)], [p(S)]2, corresponding to species containing two sialic acid, one sialic acid and one sulfate, and two sulfate residues, respectively. This suggests that the probability of sialylation or sulfation at a second site on these oligosaccharides is similar to that at the first and that anionic oligosaccharides in secreted TSH and free alpha are distributed binomially with regard to sialic acid and sulfate residues.

Animals↗