Factor Structure of the Japanese Version of the Edinburgh Postnatal Depression Scale in the Postpartum Period

Background

The Edinburgh Postnatal Depression Scale (EPDS) is a widely used screening tool for postpartum depression (PPD). Although the reliability and validity of EPDS in Japanese has been confirmed and the prevalence of PPD is found to be about the same as Western countries, the factor structure of the Japanese version of EPDS has not been elucidated yet.

Methods

690 Japanese mothers completed all items of the EPDS at 1 month postpartum. We divided them randomly into two sample sets. The first sample set (n = 345) was used for exploratory factor analysis, and the second sample set was used (n = 345) for confirmatory factor analysis.

Results

The result of exploratory factor analysis indicated a three-factor model consisting of anxiety, depression and anhedonia. The results of confirmatory factor analysis suggested that the anxiety and anhedonia factors existed for EPDS in a sample of Japanese women at 1 month postpartum. The depression factor varies by the models of acceptable fit.

Conclusions

We examined EPDS scores. As a result, “anxiety” and “anhedonia” exist for EPDS among postpartum women in Japan as already reported in Western countries. Cross-cultural research is needed for future research.     

Psychometric Evaluation of the Altered States of Consciousness Rating Scale (OAV)

Background

The OAV questionnaire has been developed to integrate research on altered states of consciousness (ASC). It measures three primary and one secondary dimensions of ASC that are hypothesized to be invariant across ASC induction methods. The OAV rating scale has been in use for more than 20 years and applied internationally in a broad range of research fields, yet its factorial structure has never been tested by structural equation modeling techniques and its psychometric properties have never been examined in large samples of experimentally induced ASC.

Methodology/Principal Findings

The present study conducted a psychometric evaluation of the OAV in a sample of psilocybin (n = 327), ketamine (n = 162), and MDMA (n = 102) induced ASC that was obtained by pooling data from 43 experimental studies. The factorial structure was examined by confirmatory factor analysis, exploratory structural equation modeling, hierarchical item clustering (ICLUST), and multiple indicators multiple causes (MIMIC) modeling. The originally proposed model did not fit the data well even if zero-constraints on non-target factor loadings and residual correlations were relaxed. Furthermore, ICLUST suggested that the “oceanic boundlessness” and “visionary restructuralization” factors could be combined on a high level of the construct hierarchy. However, because these factors were multidimensional, we extracted and examined 11 new lower order factors. MIMIC modeling indicated that these factors were highly measurement invariant across drugs, settings, questionnaire versions, and sexes. The new factors were also demonstrated to have improved homogeneities, satisfactory reliabilities, discriminant and convergent validities, and to differentiate well among the three drug groups.

Conclusions/Significance

The original scales of the OAV were shown to be multidimensional constructs. Eleven new lower order scales were constructed and demonstrated to have desirable psychometric properties. The new lower order scales are most likely better suited to assess drug induced ASC.     

A Nuclear DNA Perspective on Delineating Evolutionarily Significant Lineages in Polyploids: The Case of the Endangered Shortnose Sturgeon (Acipenser brevirostrum)

The shortnose sturgeon, Acipenser brevirostrum, oft considered a phylogenetic relic, is listed as an “endangered species threatened with extinction” in the US and “Vulnerable” on the IUCN Red List. Effective conservation of A. brevirostrum depends on understanding its diversity and evolutionary processes, yet challenges associated with the polyploid nature of its nuclear genome have heretofore limited population genetic analysis to maternally inherited haploid characters. We developed a suite of polysomic microsatellite DNA markers and characterized a sample of 561 shortnose sturgeon collected from major extant populations along the North American Atlantic coast. The 181 alleles observed at 11 loci were scored as binary loci and the data were subjected to multivariate ordination, Bayesian clustering, hierarchical partitioning of variance, and among-population distance metric tests. The methods uncovered moderately high levels of gene diversity suggesting population structuring across and within three metapopulations (Northeast, Mid-Atlantic, and Southeast) that encompass seven demographically discrete and evolutionarily distinct lineages. The predicted groups are consistent with previously described behavioral patterns, especially dispersal and migration, supporting the interpretation that A. brevirostrum exhibit adaptive differences based on watershed. Combined with results of prior genetic (mitochondrial DNA) and behavioral studies, the current work suggests that dispersal is an important factor in maintaining genetic diversity in A. brevirostrum and that the basic unit for conservation management is arguably the local population.     

Population structure and eigenanalysis

Current methods for inferring population structure from genetic data do not provide formal significance tests for population differentiation. We discuss an approach to studying population structure (principal components analysis) that was first applied to genetic data by Cavalli-Sforza and colleagues. We place the method on a solid statistical footing, using results from modern statistics to develop formal significance tests. We also uncover a general “phase change” phenomenon about the ability to detect structure in genetic data, which emerges from the statistical theory we use, and has an important implication for the ability to discover structure in genetic data: for a fixed but large dataset size, divergence between two populations (as measured, for example, by a statistic like F_ST) below a threshold is essentially undetectable, but a little above threshold, detection will be easy. This means that we can predict the dataset size needed to detect structure.     

Social Determinants and the Classification of Disease: Descriptive Epidemiology of Selected Socially Mediated Disease Constellations

Background

Most major diseases have important social determinants. In this context, classification of disease based on etiologic or anatomic criteria may be neither mutually exclusive nor optimal.

Methods and Findings

Units of analysis comprised large metropolitan central and fringe metropolitan counties with reliable mortality rates – (n = 416). Participants included infants and adults ages 25 to 64 years with selected causes of death (1999 to 2006). Exposures included that residential segregation and race-specific social deprivation variables. Main outcome measures were obtained via principal components analyses with an orthogonal rotation to identify a common factor. To discern whether the common factor was socially mediated, negative binomial multiple regression models were developed for which the dependent variable was the common factor. Results showed that infant deaths, mortality from assault, and malignant neoplasm of the trachea, bronchus and lung formed a common factor for race-gender groups (black/white and men/women). Regression analyses showed statistically significant, positive associations between low socio-economic status for all race-gender groups and this common factor.

Conclusions

Between 1999 and 2006, deaths classified as “assault” and “lung cancer”, as well as “infant mortality” formed a socially mediated factor detectable in population but not individual data. Despite limitations related to death certificate data, the results contribute important information to the formulation of several hypotheses: (a) disease classifications based on anatomic or etiologic criteria fail to account for social determinants; (b) social forces produce demographically and possibly geographically distinct population-based disease constellations; and (c) the individual components of population-based disease constellations (e.g., lung cancer) are phenotypically comparable from one population to another but genotypically different, in part, because of socially mediated epigenetic variations. Additional research may produce new taxonomies that unify social determinants with anatomic and/or etiologic determinants. This may lead to improved medical management of individuals and populations.     

Common SNPs in FTO Gene Are Associated with Obesity Related Anthropometric Traits in an Island Population from the Eastern Adriatic Coast of Croatia

Background

Multiple studies have provided compelling evidence that the FTO gene variants are associated with obesity measures. The objective of the study was to investigate whether FTO variants are associated with a broad range of obesity related anthropometric traits in an island population.

Methodology/Principal Findings

We examined genetic association between 29 FTO SNPs and a comprehensive set of anthropometric traits in 843 unrelated individuals from an island population in the eastern Adriatic coast of Croatia. The traits include 11 anthropometrics (height, weight, waist circumference, hip circumference, bicondilar upper arm width, upper arm circumference, and biceps, triceps, subscapular, suprailiac and abdominal skin-fold thicknesses) and two derived measures (BMI and WHR). Using single locus score tests, 15 common SNPs were found to be significantly associated with “body fatness” measures such as weight, BMI, hip and waist circumferences with P-values ranging from 0.0004 to 0.01. Similar but less significant associations were also observed between these markers and bicondilar upper arm width and upper arm circumference. Most of these significant findings could be explained by a mediating effect of “body fatness”. However, one unique association signal between upper arm width and rs16952517 (P-value = 0.00156) could not be explained by this mediating effect. In addition, using a principle component analysis and conditional association tests adjusted for “body fatness”, two novel association signals were identified between upper arm circumference and rs11075986 (P-value = 0.00211) and rs16945088 (P-value = 0.00203).

Conclusions/Significance

The current study confirmed the association of common variants of FTO gene with “body fatness” measures in an isolated island population. We also observed evidence of pleiotropic effects of FTO gene on fat-free mass, such as frame size and muscle mass assessed by bicondilar upper arm width and upper arm circumference respectively and these pleiotropic effects might be influenced by variants that are different from the ones associated with “body fatness”.     

The Effectiveness of Three Regions in Mitochondrial Genome for Aphid DNA Barcoding: A Case in Lachininae

Background

The mitochondrial gene COI has been widely used by taxonomists as a standard DNA barcode sequence for the identification of many animal species. However, the COI region is of limited use for identifying certain species and is not efficiently amplified by PCR in all animal taxa. To evaluate the utility of COI as a DNA barcode and to identify other barcode genes, we chose the aphid subfamily Lachninae (Hemiptera: Aphididae) as the focus of our study. We compared the results obtained using COI with two other mitochondrial genes, COII and Cytb. In addition, we propose a new method to improve the efficiency of species identification using DNA barcoding.

Methodology/Principal Findings

Three mitochondrial genes (COI, COII and Cytb) were sequenced and were used in the identification of over 80 species of Lachninae. The COI and COII genes demonstrated a greater PCR amplification efficiency than Cytb. Species identification using COII sequences had a higher frequency of success (96.9% in “best match” and 90.8% in “best close match”) and yielded lower intra- and higher interspecific genetic divergence values than the other two markers. The use of “tag barcodes” is a new approach that involves attaching a species-specific tag to the standard DNA barcode. With this method, the “barcoding overlap” can be nearly eliminated. As a result, we were able to increase the identification success rate from 83.9% to 95.2% by using COI and the “best close match” technique.

Conclusions/Significance

A COII-based identification system should be more effective in identifying lachnine species than COI or Cytb. However, the Cytb gene is an effective marker for the study of aphid population genetics due to its high sequence diversity. Furthermore, the use of “tag barcodes” can improve the accuracy of DNA barcoding identification by reducing or removing the overlap between intra- and inter-specific genetic divergence values.     

A Radiographic Analysis of Major Foot Deformities

Major foot deformities were analyzed using standardized radiographic drawings of the foot in weight-bearing. Specific criteria and a classification of foot deformities by radiographic analysis are presented, utilizing “lining systems” related to the main bones of the hindfoot.The radiographic appearance of the foot is described and analyzed, as are the principal deformities such as varus and valgus heel and forefoot. The prefixes “talipes” and “pes” have been used to signify congenital and acquired deformities, respectively.Specific foot deformities, including talipes equinovarus (clubfoot), pes planovalgus (flatfoot), pes cavus, and metatarsus varus, are analyzed. This method can also be applied in the radiological analysis of any foot deformity.By using this technique, a brief, concise and simplified analysis of foot deformities is available to the student, general practitioner, and specialist.     

Resolving the Negative Potential Side (n-side) Water-accessible Proton Pathway of F-type ATP Synthase by Molecular Dynamics Simulations

The rotation of F₁F_o-ATP synthase is powered by the proton motive force across the energy-transducing membrane. The protein complex functions like a turbine; the proton flow drives the rotation of the c-ring of the transmembrane F_o domain, which is coupled to the ATP-producing F₁ domain. The hairpin-structured c-protomers transport the protons by reversible protonation/deprotonation of a conserved Asp/Glu at the outer transmembrane helix (TMH). An open question is the proton transfer pathway through the membrane at atomic resolution. The protons are thought to be transferred via two half-channels to and from the conserved cAsp/Glu in the middle of the membrane. By molecular dynamics simulations of c-ring structures in a lipid bilayer, we mapped a water channel as one of the half-channels. We also analyzed the suppressor mutant cP24D/E61G in which the functional carboxylate is shifted to the inner TMH of the c-protomers. Current models concentrating on the “locked” and “open” conformations of the conserved carboxylate side chain are unable to explain the molecular function of this mutant. Our molecular dynamics simulations revealed an extended water channel with additional water molecules bridging the distance of the outer to the inner TMH. We suggest that the geometry of the water channel is an important feature for the molecular function of the membrane part of F₁F_o-ATP synthase. The inclination of the proton pathway isolates the two half-channels and may contribute to a favorable clockwise rotation in ATP synthesis mode.     

The Pathological Buying Screener: Development and Psychometric Properties of a New Screening Instrument for the Assessment of Pathological Buying Symptoms

The study was designed to develop a new screening instrument for pathological buying (PB), and to examine its psychometric properties in a large-scale sample. By using a facet theoretical approach and based on literature as well as on clinical experience, a 20-item Pathological Buying Screener (PBS) was developed and administered to a representative German sample (n = 2,539). Valid data were available from 2,403 participants who were subjects for three subsequent empirical studies. The first study explored the factor structure using exploratory factor analyses in a subsample of 498 participants. Based on factor loadings, a 13-item version with the two factors loss of control / consequences and excessive buying behavior was revealed. This two-factor model was confirmed in study 2 by confirmatory factor analysis performed on another subsample (n = 1,905). Study 3 investigated age and gender effects and convergent validity of the PBS using the Compulsive Buying Scale (CBS) in the full sample (N = 2,403). The total PBS score was adequately correlated with the CBS score. Hierarchical regression analyses with the CBS score as the dependent variable and the two PBS factors as the predictors indicated an own incremental validity of the two factors in participants ≤ 65 years. The reliability of the total score as well as of the two subscales was good to excellent. Overall, the PBS represents a useful measure for PB. Future studies are needed to replicate the two-factor structure in clinical samples and to define a valid cutoff for PB.     

A Hybrid DNA Extraction Method for the Qualitative and Quantitative Assessment of Bacterial Communities from Poultry Production Samples

The efficacy of DNA extraction protocols can be highly dependent upon both the type of sample being investigated and the types of downstream analyses performed. Considering that the use of new bacterial community analysis techniques (e.g., microbiomics, metagenomics) is becoming more prevalent in the agricultural and environmental sciences and many environmental samples within these disciplines can be physiochemically and microbiologically unique (e.g., fecal and litter/bedding samples from the poultry production spectrum), appropriate and effective DNA extraction methods need to be carefully chosen. Therefore, a novel semi-automated hybrid DNA extraction method was developed specifically for use with environmental poultry production samples. This method is a combination of the two major types of DNA extraction: mechanical and enzymatic. A two-step intense mechanical homogenization step (using bead-beating specifically formulated for environmental samples) was added to the beginning of the “gold standard” enzymatic DNA extraction method for fecal samples to enhance the removal of bacteria and DNA from the sample matrix and improve the recovery of Gram-positive bacterial community members. Once the enzymatic extraction portion of the hybrid method was initiated, the remaining purification process was automated using a robotic workstation to increase sample throughput and decrease sample processing error. In comparison to the strict mechanical and enzymatic DNA extraction methods, this novel hybrid method provided the best overall combined performance when considering quantitative (using 16S rRNA qPCR) and qualitative (using microbiomics) estimates of the total bacterial communities when processing poultry feces and litter samples.     

Prenatal,Perinatal and Neonatal Risk Factors for Intellectual Disability: A Systemic Review and Meta-Analysis

BackgroundThe etiology of non-genetic intellectual disability (ID) is not fully known, and we aimed to identify the prenatal, perinatal and neonatal risk factors for ID.MethodPubMed and Embase databases were searched for studies that examined the association between pre-, peri- and neonatal factors and ID risk (keywords “intellectual disability” or “mental retardation” or “ID” or “MR” in combination with “prenatal” or “pregnancy” or “obstetric” or “perinatal” or “neonatal”. The last search was updated on September 15, 2015. Summary effect estimates (pooled odds ratios) were calculated for each risk factor using random effects models, with tests for heterogeneity and publication bias.ResultsSeventeen studies with 55,344 patients and 5,723,749 control individuals were eligible for inclusion in our analysis, and 16 potential risk factors were analyzed. Ten prenatal factors (advanced maternal age, maternal black race, low maternal education, third or more parity, maternal alcohol use, maternal tobacco use, maternal diabetes, maternal hypertension, maternal epilepsy and maternal asthma), one perinatal factor (preterm birth) and two neonatal factors (male sex and low birth weight) were significantly associated with increased risk of ID.ConclusionThis systemic review and meta-analysis provides a comprehensive evidence-based assessment of the risk factors for ID. Future studies are encouraged to focus on perinatal and neonatal risk factors and the combined effects of multiple factors.     

Discriminant Value of Thyroid Function Tests

Different thyroid function tests permitted a final classification of 204 consecutive patients with suspected thyroid disorders into three populations (thyrotoxic, euthyroid, and hypothyroid). Linear discriminant analysis was applied to all test results (10 variates) on adjacent population pairs. Two invitro tests (serum protein bound iodine (P.B.I.) and tri-iodothyronine (T-3) uptake values) gave good separation of thyrotoxic from euthyroid patients and fairly good distinction of hypothyroid patients. If a ¹³¹I uptake figure was then added to the in-vitro results most patients (95·5%), including thse initially classified as equivocal, were correctly diagnosed. Other tests, including clinical questionnaires, were poor discriminants.Two new techniques of utilizing the test data were devised. Firstly, the data from the two in-vitro tests were also displayed graphically, and oblique boundary lines derived from the discriminant functions gave better separation of patients than previously used limits or mathematical expressions of “free thyroxine.” Secondly, a nomogram incorporating the best four discriminants was designed as a diagnostic aid and proved to be the best means of interpreting the tests.Discriminant analysis of this kind can be used in the interpretation of diagnostic tests in any branch of medicine, and it allows the best use to be made of the available data.     

Edge Principal Components and Squash Clustering: Using the Special Structure of Phylogenetic Placement Data for Sample Comparison

Principal components analysis (PCA) and hierarchical clustering are two of the most heavily used techniques for analyzing the differences between nucleic acid sequence samples taken from a given environment. They have led to many insights regarding the structure of microbial communities. We have developed two new complementary methods that leverage how this microbial community data sits on a phylogenetic tree. Edge principal components analysis enables the detection of important differences between samples that contain closely related taxa. Each principal component axis is a collection of signed weights on the edges of the phylogenetic tree, and these weights are easily visualized by a suitable thickening and coloring of the edges. Squash clustering outputs a (rooted) clustering tree in which each internal node corresponds to an appropriate “average” of the original samples at the leaves below the node. Moreover, the length of an edge is a suitably defined distance between the averaged samples associated with the two incident nodes, rather than the less interpretable average of distances produced by UPGMA, the most widely used hierarchical clustering method in this context. We present these methods and illustrate their use with data from the human microbiome.     

Analysis of Pharmacogenomic Variants Associated with Population Differentiation

In the present study, we systematically investigated population differentiation of drug-related (DR) genes in order to identify common genetic features underlying population-specific responses to drugs. To do so, we used the International HapMap project release 27 Data and Pharmacogenomics Knowledge Base (PharmGKB) database. First, we compared four measures for assessing population differentiation: the chi-square test, the analysis of variance (ANOVA) F-test, F_st, and Nearest Shrunken Centroid Method (NSCM). F_st showed high sensitivity with stable specificity among varying sample sizes; thus, we selected F_st for determining population differentiation. Second, we divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by F_st: genes with a high level of differentiation (HD gene group) and genes with a low level of differentiation (LD gene group). Last, we conducted a gene ontology (GO) analysis and pathway analysis. Using all genes in the human genome as the background, the GO analysis and pathway analysis of the HD genes identified terms related to cell communication. “Cell communication” and “cell-cell signaling” had the lowest Benjamini-Hochberg’s q-values (0.0002 and 0.0006, respectively), and “drug binding” was highly enriched (16.51) despite its relatively high q-value (0.0142). Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with F_st values greater than 0.5. Specifically, the F_st values for rs10871454, rs6922548, rs3775289, rs1954787, and rs167771 were 0.682, 0.620, 0.573, 0.531, and 0.510, respectively. In the analysis using DR genes as the background, the HD gene group contained six significant terms. Five were related to reproduction, and one was “Wnt signaling pathway,” which has been implicated in cancer. Our analysis suggests that the HD gene group from PharmGKB is associated with cell communication and drug binding.     

A Delphi Technology Foresight Study: Mapping Social Construction of Scientific Evidence on Metagenomics Tests for Water Safety

Access to clean water is a grand challenge in the 21^st century. Water safety testing for pathogens currently depends on surrogate measures such as fecal indicator bacteria (e.g., E. coli). Metagenomics concerns high-throughput, culture-independent, unbiased shotgun sequencing of DNA from environmental samples that might transform water safety by detecting waterborne pathogens directly instead of their surrogates. Yet emerging innovations such as metagenomics are often fiercely contested. Innovations are subject to shaping/construction not only by technology but also social systems/values in which they are embedded, such as experts’ attitudes towards new scientific evidence. We conducted a classic three-round Delphi survey, comprised of 107 questions. A multidisciplinary expert panel (n = 24) representing the continuum of discovery scientists and policymakers evaluated the emergence of metagenomics tests. To the best of our knowledge, we report here the first Delphi foresight study of experts’ attitudes on (1) the top 10 priority evidentiary criteria for adoption of metagenomics tests for water safety, (2) the specific issues critical to governance of metagenomics innovation trajectory where there is consensus or dissensus among experts, (3) the anticipated time lapse from discovery to practice of metagenomics tests, and (4) the role and timing of public engagement in development of metagenomics tests. The ability of a test to distinguish between harmful and benign waterborne organisms, analytical/clinical sensitivity, and reproducibility were the top three evidentiary criteria for adoption of metagenomics. Experts agree that metagenomic testing will provide novel information but there is dissensus on whether metagenomics will replace the current water safety testing methods or impact the public health end points (e.g., reduction in boil water advisories). Interestingly, experts view the publics relevant in a “downstream capacity” for adoption of metagenomics rather than a co-productionist role at the “upstream” scientific design stage of metagenomics tests. In summary, these findings offer strategic foresight to govern metagenomics innovations symmetrically: by identifying areas where acceleration (e.g., consensus areas) and deceleration/reconsideration (e.g., dissensus areas) of the innovation trajectory might be warranted. Additionally, we show how scientific evidence is subject to potential social construction by experts’ value systems and the need for greater upstream public engagement on metagenomics innovations.     

Whole Genome Sequencing Investigation of a Tuberculosis Outbreak in Port-au-Prince,Haiti Caused by a Strain with a “Low-Level” rpoB Mutation L511P – Insights into a Mechanism of Resistance Escalation

The World Health Organization recommends diagnosing Multidrug-Resistant Tuberculosis (MDR-TB) in high burden countries by detection of mutations in Rifampin (RIF) Resistance Determining Region of Mycobacterium tuberculosis rpoB gene with rapid molecular tests GeneXpert MTB/RIF and Hain MTBDRplus. Such mutations are found in >95% of Mycobacterium tuberculosis strains resistant to RIF by conventional culture-based drug susceptibility testing (DST). However routine diagnostic screening with molecular tests uncovered specific “low level” rpoB mutations conferring resistance to RIF below the critical concentration of 1 μg/ml in some phenotypically susceptible strains. Cases with discrepant phenotypic (susceptible) and genotypic (resistant) results for resistance to RIF account for at least 10% of resistant diagnoses by molecular tests and urgently require new guidelines to inform therapeutic decision making. Eight strains with a “low level” rpoB mutation L511P were isolated by GHESKIO laboratory between 2008 and 2012 from 6 HIV-negative and 2 HIV-positive patients during routine molecular testing. Five isolates with a single L511P mutation and two isolates with double mutation L511P&M515T had MICs for RIF between 0.125 and 0.5 μg/ml and tested susceptible in culture-based DST. The eighth isolate carried a double mutation L511P&D516C and was phenotypically resistant to RIF. All eight strains shared the same spoligotype SIT 53 commonly found in Haiti but classic epidemiological investigation failed to uncover direct contacts between the patients. Whole Genome Sequencing (WGS) revealed that L511P cluster isolates resulted from a clonal expansion of an ancestral strain resistant to Isoniazid and to a very low level of RIF. Under the selective pressure of RIF-based therapy the strain acquired mutation in the M306 codon of embB followed by secondary mutations in rpoB and escalation of resistance level. This scenario highlights the importance of subcritical resistance to RIF for both clinical management of patients and public health and provides support for introducing rpoB mutations as proxy for MICs into laboratory diagnosis of RIF resistance. This study illustrates that WGS is a promising multi-purpose genotyping tool for high-burden settings as it provides both “gold standard” sequencing results for prediction of drug susceptibility and a high-resolution data for epidemiological investigation in a single assay.     

A review of family-based tests for linkage disequilibrium between a quantitative trait and a genetic marker

Quantitative trait transmission/disequilibrium tests (quantitative TDTs) are commonly used in family-based genetic association studies of quantitative traits. Despite the availability of various quantitative TDTs, some users are not aware of the properties of these tests and the relationships between them. This review aims at outlining the broad features of the various quantitative TDT procedures carried out in the frequently used QTDT and FBAT packages. Specifically, we discuss the “Rabinowitz” and the “Monks-Kaplan” procedures, as well as the various “Abecasis” and “Allison” regression-based procedures. We focus on the models assumed in these tests and the relationships between them. Moreover, we discuss what hypotheses are tested by the various quantitative TDTs, what testing procedures are best suited to various forms of data, and whether the regression-based tests overcome population stratification problems. Finally, we comment on power considerations in the choice of the test to be used. We hope this brief review will shed light on the similarities and differences of the various quantitative TDTs.     

Contribution of the ELFG Test in Algorithms of Non-Invasive Markers towards the Diagnosis of Significant Fibrosis in Chronic Hepatitis C

Background and Aims

We aimed to determine the best algorithms for the diagnosis of significant fibrosis in chronic hepatitis C (CHC) patients using all available parameters and tests.

Patients and Methods

We used the database from our study of 507 patients with histologically proven CHC in which fibrosis was evaluated by liver biopsy (Metavir) and tests: Fibrometer®, Fibrotest®, Hepascore®, Apri, ELFG, MP3, Forn''s, hyaluronic acid, tissue inhibitor of metalloproteinase-1 (TIMP1), MMP1, collagen IV and when possible Fibroscan™. For the first test we used 90% negative predictive value to exclude patients with F≤1, next an induction algorithm was applied giving the best tests with at least 80% positive predictive value for the diagnosis of F≥2. The algorithms were computed using the R Software C4.5 program to select the best tests and cut-offs. The algorithm was automatically induced without premises on the part of the investigators. We also examined the inter-observer variations after independent review of liver biopsies by two pathologists. A medico-economic analysis compared the screening strategies with liver biopsy.

Results

In “intention to diagnose” the best algorithms for F≥2 were Fibrometer ®, Fibrotest®, or Hepascore® in first intention with the ELFG score in second intention for indeterminate cases. The percentage of avoided biopsies varied between 50% (Fibrotest® or Fibrometer®+ELFG) and 51% (Hepascore®+ELFG). In “per-analysis” Fibroscan™+ELFG avoided liver biopsy in 55% of cases. The diagnostic performance of these screening strategies was statistically superior to the usual combinations (Fibrometer® or Fibrotest®+Fibroscan™) and was cost effective. We note that the consensual review of liver biopsies between the two pathologists was mainly in favor of F1 (64–69%).

Conclusion

The ELFG test could replace Fibroscan in most currently used algorithms for the diagnosis of significant fibrosis including for those patients for whom Fibroscan™ is unusable.