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PubMed1998

Assessing screening tests: extensions of McNemar's test.

We address the problem of comparing a new screening test to a currently available screening test in the absence of a gold standard. When both tests are given to each participant in a clinical trial, the usual analytical approach is to apply McNemar's test for equality of the off-diagonal probabilities, with rejection of the null hypothesis implying that the tests differ. For assessing equivalence, however, we consider a compound null hypothesis that the new test gives either fewer or more positive results than the standard. If both parts of this hypothesis are rejected, we assert equivalence in the rate of positive responses. We propose an extension of McNemar's test for this situation. A companion step is to construct a confidence interval for the ratio of the marginal probabilities and assert equivalence if the interval is sufficiently small. It is also important that the tests agree a large proportion of the time. This can be verified with a complementary two-tailed binomial test. Another situation arises when there is a gold standard for disease diagnosis, and we wish to compare the sensitivity and specificity of two screening tests. We show that a 2 degrees-of-freedom chi-square test based on two McNemar-like tables is an appropriate test.

Chi-Square Distribution↗
PubMed1998

Accounts of experiences of bulimia: a discourse analytic study.

OBJECTIVES: To identify the variety of versions of bulimia constructed by participants, to suggest functions and consequences of these constructions, and to examine the sociocultural ideologies evident in participants' discourse. METHODS: Ten women and one man were interviewed about their experiences of bulimia. Transcribed interviews were analyzed using a discourse analytic approach. RESULTS: Five dominant ways of talking about bulimia were identified: Individuals were constructed as victims of bulimia, women were constructed as victims of social stereotypes, bulimia was constructed as a damaging action one performs on oneself, bulimia was constructed as a personality trait of individuals, and bulimia was marginalized as abnormal and disgusting. DISCUSSION: Sociocultural ideologies evident in participants' accounts included the valuing of individual will-power and self-mastery and the construction of a mind-body dichotomy entailing the need to control the latter. The analysis emphasizes the importance of considering the sociocultural context within which psychological problems occur.

Adult↗
PubMed1999

Inheritance of LDL peak particle diameter: results from a segregation analysis in Israeli families.

Genetic and environmental determinants of LDL peak particle diameter (LDL-PPD) were investigated in a sample of 80 kindreds residing in kibbutz settlements in Israel. The sample included 182 males and 191 females ages 15-93 years. LDL-PPD levels were first adjusted for variability in sex and age. Commingling analysis demonstrated that a mixture of two normal distributions fit the adjusted LDL-PPD levels better than did a single normal distribution. Complex segregation analysis was first applied to these sex and age adjusted data but was not conclusive. However, when the regression model for sex and age allowed coefficients to be ousiotype (class) specific, the mixed environmental model was rejected while a major Mendelian model was not. These results suggest that the particular genotypes determined by the major gene, which are associated with different phenotypic variances, are likely to be more realistic, and that this analytic approach can contribute to improving our understanding of the genetics of LDL particle size.

Adolescent↗
PubMedDate not supplied

As a matter of fact: evidence-based decision-making unplugged.

The rationale of evidence-based decision-making is to inform the decision-making process with information relevant to the decisions being taken. In this paper the models of research and analytical approaches used to generate the evidence are shown to be generally not 'decision-informing'. The researcher's interest in health care interventions has led to the development and use of designs which strip the research of contextual issues and hence represent a major departure from both the underlying notions of the complex pathways to health and the empirical findings concerning the importance of population context. In this way, the evidence-based approach, dominated by a focus on health outcomes from health care interventions, overlooks the notion that society is not a 'level playing field'. Decisions based on research 'evidence' of this type risk redeploying resources inefficiently and in ways which systematically favour those groups with favourable 'prospects for health' (or non-health care determinants of health), and the conditions that those groups in society tend to suffer from, and away from those groups with less favourable prospects for health. Existing approaches to informing the decision-making process could be enhanced by broadening the scope of the research to incorporate relevant determinants of health in both the specification of the problem and the selection of methods of analysis that enable us to explore the complex pathways to health.

Decision Making↗
PubMed1999

Applications of constant denaturant capillary electrophoresis/high-fidelity polymerase chain reaction to human genetic analysis.

Constant denaturant capillary electrophoresis (CDCE) permits high-resolution separation of single-base variations occurring in an approximately 100 bp isomelting DNA sequence based on their differential melting temperatures. By coupling CDCE for highly efficient enrichment of mutants with high-fidelity polymerase chain reaction (hifi PCR), we have developed an analytical approach to detecting point mutations at frequencies equal to or greater than 10(-6) in human genomic DNA. In this article, we present several applications of this approach in human genetic studies. We have measured the point mutational spectra of a 100 bp mitochondrial DNA sequence in human tissues and cultured cells. The observations have led to the conclusion that the primary causes of mutation in human mitochondrial DNA are spontaneous in origin. In the course of studying the mitochondrial somatic mutations, we have also identified several nuclear pseudogenes homologous to the analyzed mitochondrial DNA fragment. Recently, through developments of the means to isolate the desired target sequences from bulk genomic DNA and to increase the loading capacity of CDCE, we have extended the CDCE/hifi PCR approach to study a chemically induced mutational spectrum in a single-copy nuclear sequence. Future applications of the CDCE/hifi PCR approach to human genetic analysis include studies of somatic mitochondrial mutations with respect to aging, measurement of mutational spectra of nuclear genes in healthy human tissues and population screening for disease-associated single nucleotide polymorphisms (SNPs) in large pooled samples.

Base Sequence↗
PubMed1988

Diet and cancer. Any progress in the interim?

It has been 5 years since the National Research Council (NRC) Committee on Diet, Nutrition and Cancer published "Interim Dietary Guidelines" for the nutritional prevention of cancer. The term "interim" implies that these recommendations should be regarded as temporary, pending more definitive findings from additional scientific research. This article reviews findings relevant to the connections between diet and cancer that have emerged from nutritional epidemiology subsequent to the 1982 the NRC report. Some recent research has supported the earlier work which served as a basis for the interim recommendations, some has not, and additional hypotheses have emerged. There continues to be evidence, although it is inconsistent, that dietary fat may be an important factor in colon cancer, and that something related to fruits and vegetables, perhaps carotene, may lower the risk of lung cancer. However, the hypothesized relationships between dietary fat and breast cancer and between dietary fiber and colon cancer have been less consistently supported by new findings. Meanwhile, a new hypothesis has emerged relating alcohol intake to breast cancer risk, although many important questions remain regarding the age at which alcohol use may affect risk, and the dose above which risk is increased. The last 5 years seem to have been characterized by only slow progress in our understanding of the relationship between diet and cancer. It is clear that in 1988 we are still very much in the interim. Critical methodologic assessments of the reasons for the discrepancies in findings among the various studies, and meta analytic approaches may be helpful in increasing our understanding of the set of epidemiologic research conducted to date. More important, however, are the many types of studies now underway, including more rigorously designed observational studies and chemo-preventive and dietary-preventive trials. These studies will likely provide more definitive future answers to the questions we still face in the interim.

Alcohol Drinking↗
PubMed1994

Fine needle aspiration techniques for the characterization of breast cancers.

Fine needle aspiration biopsy (FNAB) is a well established method for diagnosing breast lesions, including cancers. FNAB does not require surgery and uses only a small amount of material. FNAB can also be used to acquire material for special studies. This is especially useful with small tumors (< or = 1 cm) when most of the material is needed to make a histologic diagnosis. Immunostaining techniques can be used on FNABs to investigate proliferation by bromodeoxyuridine uptake or Ki-67 labeling. Immunostaining techniques can also be used to identify oncoprotein expression, such as of p53. Fluorescence in situ hybridization is a technique that can be used to gather cytogenetic information directly from interphase tumor cells and is well suited for use with FNAB material because the harvested nuclei are intact and no cumbersome dissociation processing is needed. Flow cytometric techniques can be applied to FNAB material to study DNA content and S-phase fraction. Material acquired by FNAB can also be analyzed by the polymerase chain reaction followed by mutation detection. In this report, the authors show the applicability of these various analytic approaches to FNAB material from primary breast cancers. They show that it is essential that the FNAB harvest is representative, ample, and well prepared for the success of these studies.

Biopsy, Needle↗
PubMed2000

Application of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to insoluble glucose oligomers in decomposed cellulose.

An analytical approach is described for the molecular weight characterization of glucose oligomers from cellulose which had been decomposed by hot-compressed water (HCW). Microcrystalline cellulose was decomposed to 18% of water insoluble fraction (WI) plus 82% of water soluble fraction (WS) by HCW (295 degrees C, 10 mL/min). The glucose oligomers in the WI were analyzed by pericullar anion exchange chromatography, and oligomers longer than pentamers were detected. These results were also confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). Many peaks derived from glucose oligomers with molecular weights less than 4000 Da were detected in the spectra. Mass differences between peaks were 162 Da, as expected for polymers composed of glucose units. This appears to be the first report concerning molecular weight determination of water or organic solvent insoluble compounds like glucose oligomers from cellulose using MALDI-TOFMS.

Cellulose↗
PubMed2001

Circulating CD33+ large mononuclear cells contain three distinct populations with phenotype of putative antigen-presenting cells including myeloid dendritic cells and CD14+ monocytes with their CD16+ subset.

BACKGROUND: In peripheral blood, myeloid markers identify a heterogeneous mixture of cells in transit from the bone marrow to peripheral tissues. Similarly, HLA-class II DR expression usually identifies mononuclear cells with the potential for developing antigen-presenting activity. We gathered putative antigen presenting cells bearing myeloid markers (My-APC) to study their composition by cell surface phenotype. METHODS: To gather and dissect My-APC phenotype while excluding lymphocytes and granulocytes, we developed a strategy based on staining red cell-lysed peripheral blood and gating cells bearing myeloid markers and physical parameters of large mononuclear cells. RESULTS: Phenotypic analysis within the My-APC gate showed three distinct populations. The largest fraction was constituted by CD14+ monocytes that extended into the other two populations, each expressing gradually lower levels of CD14 surface antigen along with increasing levels of CD16 and CD2, respectively. The CD16 and CD2 expression patterns extended from CD16+CD14+ or CD2+CD14+ double- positive intermediate cells toward each single positive subset, but they were reciprocally exclusive. Interestingly, CD2+CD14- cells within the My-APC gate were equivalent to myeloid dendritic cell precursors (pre-DC) defined previously by the absence of lineage markers and expression of HLA-DR and myeloid markers. Phenotypic analysis of each population revealed differences in the expression of costimulatory molecules and CD62L. CONCLUSIONS: This novel analytical approach allowed us to distinguish circulating My-APC in three subsets and to identify relationships between monocytes and other related myeloid populations including DC.

Antigen-Presenting Cells↗
PubMed2001

On the heating of linear conductive structures as guide wires and catheters in interventional MRI.

The interest in performing vascular interventions under magnetic resonance (MR) guidance has initiated the evaluation of the potential hazard of long conductive wires and catheters. The objective of this work is to present a simple analytical approach to address this concern and to demonstrate the agreement with experimental results. The first hypothesis is that a long conductive structure couples with the electric field of the radio frequency (RF) transmit coil. The second hypothesis is that this coupling induces high voltages near the wire ends. These voltages can cause tissue heating due to induced currents. The experimental results show an increase in coupling when moving a guide wire toward the wall of an RF transmit coil, documented with a temperature increase of a saline solution in close proximity to the tip of the guide wire. The coupling of the wire not only presents a potential hazard to the patient, but also interferes with the visualization of the wire. A safe alternative would be the use of nonconducting guide wires. J. Magn. Reson. Imaging 2001;13:105-114.

Catheterization↗
PubMed2002

Molecular interactions of glycopeptide antibiotics investigated by affinity capillary electrophoresis and bioaffinity electrospray ionization-mass spectrometry.

Many analytical approaches are available to evaluate (bio)molecular interactions, all of which have their particular advantages and disadvantages. In recent years, two relatively new techniques have emerged that may be used by the bioanalytical community to evaluate such interactions, namely affinity capillary electrophoresis (ACE) and bioaffinity electrospray ionization-mass spectrometry (ESI-MS). In this paper, we describe and evaluate the use of both these techniques for the investigation of the interactions of glycopeptide antibiotics with peptides that mimic the bacterial cell wall binding site. We focus particularly on the effect of the sugar moieties attached to the antibiotic peptide backbone and on the noncovalent dimerization of these glycopeptide antibiotics.

Anti-Bacterial Agents↗
PubMed1999

Determinants of enhanced thromboxane biosynthesis in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the rate of thromboxane biosynthesis in patients with systemic lupus erythematosus (SLE), exploring the interplay between antiphospholipid antibodies (aPL) and 2 markers of endothelial perturbation: thrombin generation and platelet activation. METHODS: A comparison of 11-dehydrothromboxane B2 (TXB2) excretion, which is a marker of in vivo platelet activation, aPL, von Willebrand factor (vWF) and tissue plasminogen activator (tPA), which are 2 circulating markers of endothelial perturbation, and plasma levels of the prothrombin fragment F1+2, which is a marker of thrombin generation, was performed in 40 SLE patients and 40 healthy subjects. Thromboxane metabolite excretion was also measured in 8 SLE patients before and after treatment with low-dose aspirin. RESULTS: SLE patients had significantly higher 11-dehydro-TXB2 excretion, plasma F1+2, vWF, and tPA levels than controls. A statistically significant correlation was found between plasma levels of vWF and tPA and excretion of thromboxane metabolite. Moreover, significantly higher 11-dehydro-TXB2 was found in patients with aPL positivity and endothelial perturbation. Low-dose aspirin suppressed 11-dehydro-TXB2 by 80%, suggesting a predominant platelet source of enhanced thromboxane biosynthesis. After a median followup of 48 months, all SLE patients who experienced major cardiovascular events had thromboxane metabolite excretion, aPL positivity, and signs of endothelial perturbation. CONCLUSION: We have characterized a sensitive marker of platelet activation, which is abnormal in SLE patients who were positive for aPL and endothelial perturbation. This analytical approach may help identify those patients at increased risk of thrombosis as potential candidates for antiplatelet therapy.

Adult↗
PubMed2004

Mortality from cardiovascular disease in relation to magnetic field exposure: findings from a study of UK electricity generation and transmission workers, 1973-1997.

BACKGROUND: Experimental and epidemiological studies have indicated that magnetic field exposure might influence heart rate variability and consequent risks of arrhythmia related deaths. METHODS: The mortality experience of a cohort of 83,997 employees of the former Central Electricity Generating Board (CEGB) of England and Wales was investigated for the period 1973-1997. Cohort members were employed for at least 6 months from 1973 to 1982. Computerized work histories were available for 79,972 study subjects for the period 1971-1993. Detailed calculations had been performed by others to enable a novel assessment to be made of exposures to magnetic fields. Two analytical approaches were used, indirect standardization (n = 83,997) and Poisson regression (n = 79,972). RESULTS: Based on serial mortality rates for England and Wales, deaths from four categories of cardiovascular disease were below expectation: arrhythmia-related disease (ICD-9 426-7), observed (obs) 32, expected (exp) 43.5, standardized mortality ratio (SMR) 74; acute myocardial infarction (ICD-9 410), obs 3,320, exp 3878.3, SMR 86; atherosclerosis (ICD-9 440), obs 25, exp 39.2, SMR 64; chronic/sub-acute coronary disease (ICD-9 411-414), obs 1,552, exp 2021.7, SMR 77). No statistically significant trends were shown for risks of any of these four disease groupings to increase either with lifetime cumulative exposure to magnetic fields or with such exposures received in the most recent 5 years. CONCLUSIONS: There are no discernible excess risks of mortality from cardiovascular diseases as a consequence of occupational exposure to magnetic fields in UK electricity generation and transmission workers.

Adult↗
PubMed1995

Association study between the dopamine D4 receptor gene and schizophrenia.

The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic clozapine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic origin matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48)n bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed.

Female↗
PubMed2006

Karyotype-phenotype insights from 11q14.1-q23.2 interstitial deletions: FZD4 haploinsufficiency and exudative vitreoretinopathy in a patient with a complex chromosome rearrangement.

We detected a unique de novo complex chromosome rearrangement (CCR) in a patient with multiple abnormalities including growth retardation, facial anomalies, exudative vitreoretinopathy (EVR), cleft palate, and minor digital anomalies. Cytogenetic analysis, fluorescent in situ hybridization, and microsatellite genotyping showed a reciprocal translocation between chromosomes 5 and 8, and a complex translocation-deletion-inversion process in the formation of derivative chromosomes 11 and 16. High-density whole-genome oligonucleotide array comparative genomic hybridization (oaCGH) defined a 35-megabase interstitial deletion of 11q14.1-q23.2 and a 1 megabase deletion of 16q22.3-q23.1. The Frizzled-4 (FZD4) gene is located within this 11q deletion. Parental studies and sequencing analysis confirmed that the patient was hemizygous for FZD4 due to the loss of a paternal allele on the derivative chromosome 11. Mutations in FZD4 are known to cause autosomal dominant exudative vitreoretinopathy (EVR1). Our patient's findings suggest that haploinsufficiency of the FZD4 gene product can also be a disease-causing mechanism for EVR1. We reviewed the clinical manifestations of 23 cases with 11q14-q23 interstitial deletions, with particular scrutiny of the present case and four reported cases characterized by molecular cytogenetics. These findings were used to construct a regional deletion map consisting of a haplosufficient segment at 11q14.3, a flanking centromeric segment at 11q14.1-q14.2, and a flanking telomeric segment at 11q21-q23.3. We propose that deletions of the FZD4 gene located within the centromeric segment cause retinal dysgenesis, while deletions within the telomeric segment account for dysmorphic craniofacial features, growth and mental retardation, and mild digital anomalies. These results provide insight into karyotype-phenotype correlations and prompt a rational analytic approach to cases with interstitial deletions of the 11q14-q23 region.

Abnormalities, Multiple↗
PubMed1990

Skeletal biological distance studies in American physical anthropology: recent trends.

Biological distance analysis, the dominant type of skeletal biological research during the 19th century, has become less visible in recent years. Although the proportion of American Journal of Physical Anthropology articles and published abstracts focusing on biodistance has remained fairly constant over the three decades between 1955 and 1985, the proportion of biodistance contributions relative to other skeletal biology studies has decreased. Emphasis in skeletal biology has shifted from the analysis of biological variation to investigations of health and diet, and within biodistance studies methodological issues have assumed prominence over purely analytical approaches. This paper investigates trends in biological distance analysis through a survey of articles and meetings abstracts published in the American Journal of Physical Anthropology from 1955 to 1985. The survey provides the historical context for five symposium papers on skeletal biological distance presented at the 1986 meeting of the American Association of Physical Anthropologists.

Anthropology, Physical↗
PubMed2006

The molecular signature of selection underlying human adaptations.

In the last decade, advances in human population genetics and comparative genomics have resulted in important contributions to our understanding of human genetic diversity and genetic adaptation. For the first time, we are able to reliably detect the signature of natural selection from patterns of DNA polymorphism. Identifying the effects of natural selection in this way provides a crucial piece of evidence needed to support hypotheses of human adaptation. This review provides a detailed description of the theory and analytical approaches used to detect signatures of natural selection in the human genome. We discuss these methods in relation to four classic human traits--skin color, the Duffy blood group, bitter-taste sensation, and lactase persistence. By highlighting these four traits we are able to discuss the ways in which analyses of DNA polymorphism can lead to inferences regarding past histories of selection. Specifically, we can infer the importance of specific regimes of selection (i.e. directional selection, balancing selection, and purifying selection) in the evolution of a trait because these different types of selection leave different patterns of DNA polymorphism. In addition, we demonstrate how these types of data can be used to estimate the time frame in which selection operated on a trait. As the field has advanced, a general issue that has come to the forefront is how specific demographic events in human history, such as population expansions, bottlenecks, and subdivision of populations, have also left a signature across the genome that can interfere with our detection of the footprint of selection at particular genes. Therefore, we discuss this general problem with respect to the four traits reviewed here, and describe the ways in which the signature of selection can be teased from a background signature of demographic history. Finally, we move from a discussion of analyses of selection motivated by a "candidate-gene" approach, in which a priori information led to the analysis of specific gene, to discussion of "genome-scanning" approaches that are directed at discovering new genes that have been under positive selection. Such scans can be designed to detect those genes that have been positively selected in our divergence from chimpanzees, as well as those genes that have been under selection as human populations have migrated, differentiated, and adapted to specific geographic environments. We predict that both approaches will be applied in the future, enabling a greater insight into human species-wide adaptations, as well as the specific adaptations of human populations.

Animals↗