Biomedical subjects

E Feingold

Publications and source records attributed to E Feingold.

At least 19 recordsLinked to original sources

PubMed2006

Genetic association of ubiquilin with Alzheimer's disease and related quantitative measures.

The gene coding for ubiquilin 1 (UBQLN1) is located near a linkage peak on chromosome 9q22.2 and it also impacts the function of presenilin proteins involved in early-onset Alzheimer's disease (AD). Recently, genetic variation in UBQLN1 has been shown to affect the risk of AD in two independent family-based samples. The purpose of this study was to confirm the reported association in a large case-control sample and to also examine the association of UBQLN1 SNPs with quantitative measures of AD progression, namely age-at-onset (AAO), disease duration and Mini-Mental State Examination (MMSE) score. We examined the associations of three SNPs in the UBQLN1 gene (intron 6/A>C, intron 8/T>C and intron 9/A>G) in up to 978 LOAD cases and 808 controls. All SNPs were in significant linkage disequilibrium (P<0.0001). While modest significant associations were observed in the single-site regression analysis, 3-site haplotype analysis revealed significant associations (P<0.0001 for overall haplotype analysis). One common haplotype (H4) defined by intron 6/A-intron 8/C-intron 9/G alleles was associated with AD risk and one less common haplotype (H5) defined by intron 6/C-intron 8/C-intron 9/A alleles was associated with protection. The adjusted odds ratios with potentially one and two copies of risk haplotype H4 were 1.5 (95% CI: 0.99-2.26; P=0.054) and 3.66 (95% CI: 1.43-9.39; P=0.007), respectively, and odds ratio for haplotype H5 carriers was 0.31 (95% CI: 0.10-0.95; P=0.0398). In addition to disease risk, the homozygosity of the risk haplotype was also associated with older AAO, longer disease duration and lower MMSE score. In summary, our data from a large case-control cohort indicate that genetic variation in the UBQLN1 gene has a modest effect on risk, AAO and disease duration of AD. Our haplotype data suggest the presence of additional putative functional variants either in the UBQLN1 gene or nearby genes and provide strong justification for additional work in this region on chromosome 9.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Relationship of recombination patterns and maternal age among non-disjoined chromosomes 21.

Advancing maternal age has long been identified as the primary risk factor for human chromosome trisomy. More recently, altered patterns of meiotic recombination have been found to be associated with non-disjunction. We have used trisomy 21 as a model for human non-disjunction that occurs during the formation of oocytes to understand the role of maternal age and recombination. Patterns of recombination that increase the risk for non-disjunction of chromosome 21 include absence of any exchange, an exchange near the centromere or a single, telomeric exchange. Our recent work has shown that different susceptibility patterns are associated with the origin of the meiotic error and maternal age. For MI (meiosis I) errors, the proportion of oocytes with susceptible recombination patterns is highest among young mothers and decreases significantly in the oldest age group. In fact, the pattern of exchanges among the oldest age group mimics the pattern observed among normally disjoining chromosomes 21. These results suggest that oocytes of younger women, with functional meiotic apparatus and/or robust ovarian environment, are able to properly resolve all but the most susceptible exchange patterns. As women age, however, meiotic mechanisms erode, making it difficult to resolve even stable exchange events. Interestingly, our preliminary recombination results on MII errors reveal the opposite relationship with maternal age: susceptible pericentromeric exchanges occur most often in the older age group compared with the younger age group. If confirmed, we will have further evidence for multiple risk factors for non-disjunction that act at different times in the meiotic process.

Chromosomes, Human, Pair 21↗

PubMed2003

Evaluation of human leukocyte N-formylpeptide receptor (FPR1) SNPs in aggressive periodontitis patients.

Polymorphonuclear neutrophils (PMNs) are attracted to sites of infection by N-formylpeptide (fMLP) chemoattractants. The high-affinity fMLP receptor (FPR1) of phagocytic cells interacts with bacterial fMLP and mediates chemotaxis, degranulation, and superoxide production. These cellular functions are disrupted in PMN from aggressive periodontitis (AP) patients. Two FPR1 gene single nucleotide polymorphisms (SNPs), c.329T>C and c.378C>G, have been associated with a localized form of AP in African-American patients. To evaluate the generality of these SNPs in AP patients, we sequenced a 363 bp interval of the FPR1 gene in an ethnically diverse group of patients (n=111) and controls (n=115). Neither c.329T>C nor c.378C>G were detected in the 452 alleles sequenced. Six SNPs were identified including two located in the FPR1 second extracellular loop that were significantly associated with the AP phenotype in African-American patients (p.R190W, P=0.0033; and p.N192K, P=0.0018). These two SNPs show three predominant haplotypes, each associated with a different disease risk in African-Americans. These data do not support the hypothesis that the FPR1 SNPs c.329T>C and c.378C>G play an etiologic role in aggressive periodontitis, but do suggest that SNPs in the second extracellular loop may be etiologically important.

Black or African American↗

PubMed2001

A survey of affected-sibship statistics for nonparametric linkage analysis.

We have compared the power of a large number of allele-sharing statistics for "nonparametric" linkage analysis with affected sibships. Our rationale was that there is an extensive literature comparing statistics for sibling pairs but that there has not been much guidance on how to choose statistics for studies that include sibships of various sizes. We concentrated on statistics that can be described as assigning scores to each identity-by-descent-sharing configuration that a pedigree might take on (Whittemore and Halpern 1994). We considered sibships of sizes two through five, 27 different genetic models, and varying recombination fractions between the marker and the trait locus. We tried to identify statistics whose power was robust over a wide variety of models. We found that the statistic that is probably used most often in such studies-S(all)-performs quite well, although it is not necessarily the best. We also found several other statistics (such as the R criterion, S(robdom), and the Sobel-and-Lange statistic C) that perform well in most situations, a few (such as S(-#geno) and the Feingold-and-Siegmund version of S(pairs)) that have high power only in very special situations, and a few (such as S(-#geno), the N criterion, and the Sobel-and-Lange statistic B) that seem to have low power for the majority of the trait models. For the most part, the same statistics performed well for all sibship sizes. We also used our results to give some suggestions regarding how to weight sibships of different sizes, in forming an overall statistic.

Alleles↗

PubMed2001

Local high-capacity adenovirus-mediated mCTLA4Ig and mCD40Ig expression prolongs recombinant gene expression in skeletal muscle.

Multiple forms of muscular dystrophy are due to the absence of cytoskeletal muscle proteins that normally protect the integrity of muscle cells. The lack of any adequate treatments for these devastating diseases propels research toward the development of strategies for gene delivery to skeletal muscle. High-capacity adenoviral vectors (HC-AdV) devoid of all viral coding sequences have been developed to avoid expression of viral proteins by the gene therapy vector. However, the capsid proteins that are an essential component of the input viral vector and any residual helper virus in the vector preparation could induce an immune response. Furthermore, the therapeutic protein provided by a gene transfer vector presents the potential to induce an immune response in a patient who does not express a normal cellular protein due to genetic mutation. Therefore, we hypothesize that some immune suppression will be required with therapeutic gene delivery designed for the treatment of patients with inherited muscle diseases. In this study, we constructed and rescued three HC-AdVs expressing murine CTLA4Ig, murine CD40Ig, or both. The backbone vector without a gene insert was rescued as a negative control vector. The production of relevant proteins from each vector was determined in vitro. In vivo function of each of the immunosuppressant vectors was assayed by co-injection with an enhanced green fluorescent protein (EGFP)-expressing first-generation adenoviral vector (AdEGFP) into the tibialis anterior muscle of C57BL/10 mice. Higher levels of muscle EGFP expression were observed in animals receiving an immunosuppressant vector. Furthermore, the production of total anti-AdV and anti-EGFP antibodies was reduced in mice treated with each of the three immunosuppressant vectors. A second intramuscular administration of AdEGFP alone 4 weeks after the initial co-injection was successful in all immunosuppressant vector-treated groups, but not in the negative control vector-treated group. All groups had a high antibody response to adenoviral proteins after the second injection of AdEGFP alone, indicating that the initial co-injection did not tolerize against vector capsid antigens.

Abatacept↗

PubMed2001

Methods for linkage analysis of quantitative trait loci in humans.

This paper reviews linkage analysis methods for detecting loci associated with quantitative traits in humans. All such methods are based on the underlying principle that family members who have similar trait values should have higher than expected levels of sharing of genetic material (identity by descent) near the genes that influence those traits. A number of different statistical methods for testing that association between shared trait values and shared identity by descent have been developed over the past 30 or more years. These different types of tests are reviewed here, with emphasis on their theory and derivations. Robustness and power are also discussed.

Bayes Theorem↗

PubMed2001

An automated results notification system for PACS.

The purpose of this study was to determine if the interval between an examination being ordered by an Emergency Department physician and his or her review of the report and images could be shortened by notifying the physician that the results were available. This hypothesis was based on work done previously in the Medical Intensive Care Unit that showed that physicians would wait to review results for a time considerably longer than the time required for the radiologist to review the images and provide a preliminary report. The software developments operate properly and show that even simple integration of multiple information systems (PACS, RIS, speech recognition) can provide useful features. Early results indicate that the Emergency Department (ED) physicians prefer the notification system over the previous (travel to check on images and reports) methods. The hypothesized time reductions did occur, although it is not clear that the notification system accounted for all of them. A system for automated notification of radiology results availability has been shown to be possible and practical. To do this automated interaction of 3 systems with a low-level or no electronic integration was required. Although not fully successful for this study, early physician response has been positive, and requests to expand this service hospitalwide now are common.

Emergency Service, Hospital↗

PubMed2001

Estimating the frequency distribution of crossovers during meiosis from recombination data.

Estimation of tetrad crossover frequency distributions from genetic recombination data is a classic problem dating back to Weinstein (1936, Genetics 21, 155-199). But a number of important issues, such as how to specify the maximum number of crossovers, how to construct confidence intervals for crossover probabilities, and how to obtain correct p-values for hypothesis tests, have never been adequately addressed. In this article, we obtain some properties of the maximum likelihood estimate (MLE) for crossover probabilities that imply guidelines for choosing the maximum number of crossovers. We give these results for both normal meiosis and meiosis with nondisjunction. We also develop an accelerated EM algorithm to find the MLE more efficiently. We propose bootstrap-based methods to find confidence intervals and p-values and conduct simulation studies to check the validity of the bootstrap approach.

Algorithms↗

PubMed2001

Molecular anatomy of an intracranial aneurysm: coordinated expression of genes involved in wound healing and tissue remodeling.

BACKGROUND AND PURPOSE: Approximately 6% of human beings harbor an unruptured intracranial aneurysm. Each year in the United States, >30 000 people suffer a ruptured intracranial aneurysm, resulting in subarachnoid hemorrhage. Despite the high incidence and catastrophic consequences of a ruptured intracranial aneurysm and the fact that there is considerable evidence that predisposition to intracranial aneurysm has a strong genetic component, very little is understood with regard to the pathology and pathogenesis of this disease. METHODS: To begin characterizing the molecular pathology of intracranial aneurysm, we used a global gene expression analysis approach (SAGE-Lite) in combination with a novel data-mining approach to perform a high-resolution transcript analysis of a single intracranial aneurysm, obtained from a 3-year-old girl. RESULTS: SAGE-Lite provides a detailed molecular snapshot of a single intracranial aneurysm. These data suggest that, at least in this specific case, aneurysmal dilation results in a highly dynamic cellular environment in which extensive wound healing and tissue/extracellular matrix remodeling are taking place. Specifically, we observed significant overexpression of genes encoding extracellular matrix components (eg, COL3A1, COL1A1, COL1A2, COL6A1, COL6A2, elastin) and genes involved in extracellular matrix turnover (TIMP-3, OSF-2), cell adhesion and antiadhesion (SPARC, hevin), cytokinesis (PNUTL2), and cell migration (tetraspanin-5). CONCLUSIONS: Although these are preliminary data, representing analysis of only one individual, we present a unique first insight into the molecular basis of aneurysmal disease and define numerous candidate markers for future biochemical, physiological, and genetic studies of intracranial aneurysm. Products of these genes will be the focus of future studies in wider sample sets.

Calcium-Binding Proteins↗

PubMed2000

Composite statistics for QTL mapping with moderately discordant sibling pairs.

Extreme discordant sibling-pair (EDSP) designs have been shown in theory to be very powerful for mapping quantitative-trait loci (QTLs) in humans. However, their practical applicability has been somewhat limited by the need to phenotype very large populations to find enough pairs that are extremely discordant. In this paper, we demonstrate that there is also substantial power in pairs that are only moderately discordant, and that designs using moderately discordant pairs can yield a more practical balance between phenotyping and genotyping efforts. The power we demonstrate for moderately discordant pairs stems from a new statistical result. Statistical analysis in discordant-pair studies is generally done by testing for reduced identity by descent (IBD) sharing in the pairs. By contrast, the most commonly-used statistical methods for more standard QTL mapping are Haseman-Elston regression and variance-components analysis. Both of these use statistics that are functions of the trait values given IBD information for the pedigree. We show that IBD sharing statistics and "trait value given IBD" statistics contribute complementary rather than redundant information, and thus that statistics of the two types can be combined to form more powerful tests of linkage. We propose a simple composite statistic, and test it with simulation studies. The simulation results show that our composite statistic increases power only minimally for extremely discordant pairs. However, it boosts the power of moderately discordant pairs substantially and makes them a very practical alternative. Our composite statistic is straightforward to calculate with existing software; we give a practical example of its use by applying it to a Genetic Analysis Workshop (GAW) data set.

Chromosome Mapping↗

PubMed2000

Genome-wide variation in recombination in female meiosis: a risk factor for non-disjunction of chromosome 21.

Altered recombination patterns along non-disjoined chromosomes is the first molecular correlate identified for non-disjunction in humans. To understand better the factors related to this correlate, we have asked to what extent is recombination altered in an egg with a disomic chromosome: are patterns limited to the non-disjoined chromosome or do they extend to the entire cell? More specifically, we asked whether there is reduced recombination in the total genome of an egg with a non-disjoined chromosome 21 and no detectable recombination. We chose this subclass of non-disjoined chromosomes to enrich potentially for extremes in recombination. We found a statistically significant cell-wide reduction in the mean recombination rate in these eggs with non-disjoined chromosomes 21; no specific chromosomes were driving this effect. Most importantly, we found that this reduction was consistent with normal variation in recombination observed among eggs. Thus, given that recombination is a multifactorial trait, these data suggest that when the number of genome-wide recombination events is less than some threshold, specific chromosomes may be at an increased risk for non-disjunction. Further studies are required to confirm these results, to determine the importance of genetic and environmental factors that regulate recombination and to determine their impact on non-disjunction.

Adult↗

PubMed2000

Comparison of allele-sharing statistics for general pedigrees.

The popularity of "non-parametric" linkage analysis using moderate and large sized pedigrees has increased in the last few years. Only a few of the existing allele-sharing statistics are applicable to general pedigrees, and even fewer are in common use. Little research has been done to compare the power of these statistics. We present some preliminary investigations into the power of the most popular general-pedigree allele-sharing statistics. We show that there are indeed non-trivial differences among the statistics, and that further studies are warranted. In particular, pedigree structure and the degree of recessiveness of the trait appear to be critical factors in determining which statistics are most powerful.

Alleles↗

PubMed2000

Radiology workflow and patient volume: effect of picture archiving and communication systems on technologists and radiologists.

This study was performed to evaluate the changes in workflow and efficiency in various clinical settings in the radiology department after the introduction of a picture archiving and communication system (PACS). Time and motion data were collected when conventional image management was used, and again after the introduction of a PACS. Changes in the elapsed time from examination request until the image dispatch to the radiologist, and from dispatch until report dictation, were evaluated. The relationship between patient volume and throughput was evaluated. The time from examination request until dispatch was significantly longer after the introduction of PACS for examinations taken on patients from the emergency department (ED) (pre-PACS, 20 minutes; post-PACS, 25 minutes; P < .0001), and for examinations taken on patients in the medical intensive care unit (MICU) (pre-PACS, 34 minutes; post-PACS, 42 minutes; P < .0001). The interval from image dispatch until report dictation shortened significantly after the introduction of PACS in the ED (pre-PACS, 38 minutes; post-PACS, 23 minutes; P < .0001) and in the outpatient department (OPD) (pre-PACS, 38 minutes; post-PACS, 20 minutes; P < .0001). Simple least squares regression showed a significant relationship between daily patient volume and the daily median time until report dictation (F = 43.42, P < .001). PACS slowed technologists by prolonging the quality-control procedure. Radiologist workflow was shortened or not affected. Efficiency is dependent on patient volume, and workflow improvements are due to a shift from batch to on-line reading that is enabled by the ability of PACS to route enough examinations to keep radiologists fully occupied.

Appointments and Schedules↗

PubMed2000

Is there an interchromosomal effect in reciprocal translocation carriers? Sperm FISH studies.

Chromosome translocations have been known to affect disjunction of chromosomes unrelated to the translocation in the mouse and in Drosophila. However, in humans, an interchromosomal effect in chromosome translocations has not been demonstrated. The availability of techniques that allow the study of nondisjunction in sperm cells has permitted us to evaluate the possibility of an interchromosomal effect in male translocation heterozygotes. In this study, multicolor fluorescence in situ hybridization was used to determine levels of disomy for the clinically relevant chromosomes X, Y, 13, 18, and 21 in 332,858 spermatozoa from nine reciprocal translocation heterozygotes and nine controls with normal karyotypes. The specific translocations studied were as follows: t(10;12)(p26.1;p13.3), t(2;18)(p21;q11.2), t(3;19)(p25;q12), t(5;8)(q33;q13), t(11;22)(q23;q11), t(3;4)(p25;p16), t(8;9) (q24.2;q32), t(10;18)(q24.1;p11.2), and t(4;10)(q33;p12.2). Comparisons of disomy rates between carriers and controls were performed by using the Mann-Whitney test. Our results showed that the rates of sex chromosome hyperhaploidy were similar in controls (0.21%) and in translocation carriers (0.19%). Similarly, the frequencies of disomy for chromosomes 13, 18, and 21 did not differ significantly between controls and carriers (0.05% versus 0.08%, 0.07% versus 0.03%, and 0.14% versus 0.20%, respectively). Sex chromosome nondisjunction was more common than nondisjunction of chromosomes 13 and 18 both in controls (P=0.0057) and in carriers (P=0.0008). Similarly, the rates of chromosome disomy for chromosome 21 were higher than those for chromosomes 13 and 18 in both controls (P=0.0031) and translocation carriers (P=0.0057). In our study, the excess of chromosome 21 disomy versus disomy of the other autosomes was more pronounced in carriers than in controls. Thus, although the difference of disomy 21 between controls and carriers was not statistically significant, it is worthy of attention.

Adult↗

PubMed2000

A variant of the glucocorticoid receptor gene is not associated with adrenal androgen excess in women with polycystic ovary syndrome.

OBJECTIVE: To determine whether the frequency of the N363S variant of the glucocorticoid receptor (GRL) was increased in women with PCOS and adrenal androgen (AA) excess. DESIGN: Prospective case-control study. SETTING: University reproductive endocrinology laboratory and outpatient clinic. PATIENT(S): Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 92). INTERVENTION(S): Blood and DNA sampling before hormonal therapy. MAIN OUTCOME MEASURE(S): PCOS patient and healthy control genotypes, with the N363S allele representing a variant of GRL. RESULT(S): Fifty-four PCOS patients with (DHEAS > or = 3000 ng/mL) and 55 without (DHEAS < or = 2,500 ng/mL) AA excess, respectively, were studied. Six of 109 (5.5%) patients studied were found to be heterozygous carriers of the A-->G base pair substitution at cDNA position 1220, resulting in the missense mutation N363S. Of these six, four had excessive AA secretion (i.e., excess DHEAS levels). There was no significant difference in the allele frequency of the GRL variant between PCOS patients with and without AA excess and controls (3.7% [95% confidence interval: 1.0%-5.7%], 1.8% [0.2%-6. 0%], and 3.3% [2.3%-6.0%]). None of the subjects were found to be homozygous for the N363S allele. CONCLUSION(S): The N363S variant of GRL was an uncommon occurrence in our population of healthy women and PCOS patients and did not appear to play a major role in the genetic predisposition to PCOS or to AA excess in PCOS.

Adrenal Glands↗

PubMed2000

Multipoint estimation of genetic maps for human trisomies with one parent or other partial data.

Centromeric-mapping methods have been used to investigate the association between altered recombination and meiotic nondisjunction in humans. For trisomies, current methods are based on the genotypes from a trisomic offspring and both parents. Because it is sometimes difficult to obtain samples from both parents and because the ability to use sources of DNA previously not available (e.g., stored paraffin-embedded pathological samples) has increased, we have been interested in creating similar maps for trisomic populations in which one of the parents of the trisomic individual is unavailable for genotyping. In this paper, we derive multipoint likelihoods for both missing-parent data and conventional two-parent data. We find that likelihoods for two-parent data and for data generated without a sample from the correctly disjoining parent can be maximized in exactly the same way but also that missing-parent data has a high frequency of partial data of the same sort produced by intercross matings. Previously published centromeric-mapping methods use incorrect likelihoods for intercross matings and thus can perform poorly on missing-parent data. We wrote a FORTRAN program to maximize our multipoint likelihoods and used it in simulation studies to demonstrate the biases in the previous methods.

Algorithms↗

PubMed1999

A simple allele sharing statistic for multiple locus systems.

For complex disorders where the actions of several interacting loci must be taken into account, current methods of joint linkage analysis are problematic. We have undertaken an exploration of simultaneous search statistics originally proposed by Dupuis et al. [1995]. Additionally, we have extended these methods slightly and propose here a simple simultaneous search statistic based upon the single-point allele sharing statistic calculated from GENEHUNTER (GH). The use of conditional search techniques is also explored.

Alleles↗

PubMed1999

Multicolor fluorescence in situ hybridization analysis of the spermatozoa of a male heterozygous for a reciprocal translocation t(11;22)(q23;q11).

A reciprocal translocation between chromosomes 11 and 22 is a site-specific translocation that has been seen in many families with no common ancestry. This translocation is of particular interest because balanced carriers have a 0.7-3.7% risk of having children with the supernumerary der(22), resulting from a 3:1 segregation. We have used a three color fluorescence in situ hybridization (FISH) with specific DNA probes to determine the chromosome segregation pattern of a male carrier of a translocation t(11;22)(q23;q11). The probes selected included a centromeric marker for chromosome 11, a marker closely linked to the centromere of chromosome 22, and a third probe distal to the translocation breakpoint of chromosome 22. The results showed that 3:1 segregation is preferential in this patient, with 40.1% of spermatozoa belonging to this segregation type. Alternate segregation followed with 27.4% of analyzed spermatozoa; 17.6% resulted from adjacent 1 and 12.5% resulted from adjacent 2 segregation. We detected 0.5% of presumably diploid spermatozoa. Complementary adjacent 1 products were observed at statistically different frequencies (P = 0.02). Complementary adjacent 2 products without recombination in the interstitial segments were also seen at different frequencies (P = 0.002). In 3:1 segregation, the products containing one chromosome were observed more frequently than those with three chromosomes (P = 0.0001). The 24,+der(22) gamete was seen more frequently than all of the other gametes combined which had 24 chromosomes resulting from 3:1 segregation. The results of this study demonstrate that in this t(11;22) carrier, 3:1 segregation is preferential but not exclusive.

Adult↗