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PubMed1984

Auditory brainstem evoked potential latency-intensity functions: a corrective algorithm.

The dynamic changes in the latency of the components of the auditory brainstem evoked potentials (ABEP) were analyzed and correlated with the psychophysical magnitude estimates of the stimuli evoking the potentials. This study included the reanalysis of the results originally reported by Pratt and Sohmer (1977, Electroencephalogr. Clin. Neurol., 43, 802-812), this time with correction for asymptote of the latency-intensity functions. The results of reanalyzing latency-intensity power functions have yielded exponents that were very similar across components, closer to the exponent of magnitude estimates and accounting for a higher amount of variance for all of the ABEP components. This procedure may also prove useful for clinical evaluation of auditory function.

Algorithms↗

PubMedDate not supplied

Detected heroin use in an Australian methadone maintenance program.

A reanalysis was undertaken of survey and retrospective urinalysis data on patients remaining in an abstinence-oriented, public methadone maintenance program in Sydney, Australia. A comparison of urinalysis results with those of previous reports of Australian methadone programs suggests that the clinic's disciplinary program failed to reduce detected heroin use; morphine was detected in 27% of urine specimens. Women, those with a partner in methadone maintenance, and exprisoners were significantly more likely to submit morphine positive urines. When account was taken of subjects' General Health Questionnaire scores in a second logistic regression model, the more psychologically disturbed patients were one fifth as likely to submit a morphine positive specimen as the less disturbed. This and other findings are interpreted as indicating that psychologically disturbed patients who continued to use heroin were more likely to be expelled from or otherwise leave treatment than the less psychologically disturbed who continued to use heroin.

Adult↗

PubMed1990

Can decision analysis adequately represent clinical problems?

A major weakness of medical decision analysis has been the inability of the commonly used single attribute utility models to adequately represent clinical decision making situations. To illustrate this problem, I reanalyzed a well known decision analysis that is widely interpreted as proof that two decision alternatives are equivalent in all clinically meaningful respects. The reanalysis was based on a more representative decision model made possible by the use of the analytic hierarchy process (AHP), a multiobjective decision making technique. The use of this model resulted in the identification of a clearly preferred alternative, indicating that the results of the original analysis have been widely misinterpreted. The degree to which a decision model represents clinical reality influences the correct interpretation of a decision analysis. Limited decision models can yield only limited conclusions. The use of more representative multiobjective decision models would improve the clinical usefulness of medical decision analyses.

Decision Support Techniques↗

PubMed1992

Split decomposition: a new and useful approach to phylogenetic analysis of distance data.

In order to analyze the structure inherent to a matrix of dissimilarities (such as evolutionary distances) we propose to use a new technique called split decomposition. This method accurately dissects the given dissimilarity measure as a sum of elementary "split" metrics plus a (small) residue. The split summands identify related groups which are susceptible to further interpretation when casted against the available biological information. Reanalysis of previously published ribosomal RNA data sets using split decomposition illustrate the potential of this approach.

Animals↗

PubMed1996

Drug therapy for vertebral fractures in osteoporosis: evidence that decreases in bone turnover and increases in bone mass both determine antifracture efficacy.

The conventional belief is that osteopenia is the major cause of vertebral fractures and that drug therapy must induce a substantial increase in vertebral bone mineral density (BMD) before the vertebral fracture rate (VFR) is decreased. We hypothesized that the increased bone turnover in osteoporosis also is a major cause of vertebral fractures because of its adverse effects on the microarchitecture of the vertebrae and, thus, that normalization of bone turnover by antiresorptive drug therapy will decrease VFR substantially. This hypothesis is supported by our reanalysis of data from previous clinical trials with fluoride and with estrogen therapy in postmenopausal osteoporotic women. As evident from computer-generated three-dimensional graphic plots of data from osteoporotic women treated with placebo, VFR increased as bone turnover increased or as vertebral BMD decreased. Estrogen therapy decreased the bone turnover rate to normal and eliminated the relationship between VFR and bone turnover, whereas the inverse relationship with vertebral BMD persisted. In osteoporotic women treated with fluoride, VFR decreased as vertebral BMD increased, provided that patients with high (toxic) serum fluoride levels were not included in the comparison. Over the range of values in the data set, increased vertebral BMD and decreased bone turnover had approximately equal effects in decreasing VFR. Thus, both formation-stimulating and resorption-inhibiting drugs can substantially decrease VFR but do so by different mechanisms.

Bone Density↗

PubMed2005

Variability in observer performance studies experimental observations.

RATIONALE AND OBJECTIVES: The aim of the study is to assess variance components in observer performance studies and the possible impact on study results and conclusions. MATERIALS AND METHODS: Two previously performed retrospective receiver operating characteristic-type observer performance studies to evaluate the performance of seven radiologists in detecting interstitial disease on conventional posteroanterior chest films and nine radiologists in detecting interstitial disease on a high-resolution workstation were reanalyzed by using the Beiden, Wagner, and Campbell nine-component model to estimate the different variance components. We estimated case-, reader-, and mode-related components of the variance for the group as a whole and after excluding (round robin) each reader. Overall variance was evaluated, and the effect of individual readers on overall study conclusions was assessed. RESULTS: Overall results and conclusions of the reanalysis agreed with the original one in that, as a group, radiologists performed significantly better when using conventional films (P < .05) in both studies. Reader variability was large compared with all other components, and in one study, it was substantially larger for the workstation reading mode. Reader variability was affected substantially by one observer in each study, and in one study, reader-by-mode variability was affected by another reader who performed better on the workstation. CONCLUSION: Estimates of variance components can shed light on the appropriateness of study design, as well as the sensitivity of results to the inclusion (or exclusion) of individual observers.

Humans↗

PubMed2004

Negative alcohol consumption outcome associations in young and mature adult social drinkers: a route to drinking restraint?

Alcohol 'cognitions' were explored using an implicit methodology [Stacy, Leigh and Weingardt, 1994]. In Study 1, an Associations Questionnaire was developed with young adult undergraduates (median=20 years) comprising culturally available (i.e., high-frequency occurrence) and idiosyncratic (i.e., low-frequency occurrence) positive and negative alcohol consumption outcomes and positive and negative outcomes of behaviors-other-than-alcohol consumption. In Study 2, the relationship was explored between the alcohol consumption of young adult undergraduates (median age = 19 years) and implicit alcohol-related associations made through the Associations Questionnaire. A significant positive relationship was found between consumption and positive and negative culturally available (experimental) outcomes but not for the other two types of (control) outcome. In Study 3, the relationship between alcohol consumption and alcohol-related associations was explored in mature adults (median = 45 years) with many more years' drinking experience. The results of Study 1 were replicated except that a significant positive relationship between consumption and some control outcomes was now found--e.g., negative outcomes of what where hitherto behaviors-other-than-alcohol consumption. In Study 4, however, using the same techniques that were used to develop the Associations Questionnaire in Study 1, an extended set of negative alcohol consumption outcomes was found in mature adults (median = 44 years) that included a proportion of the negative outcomes of behaviors-other-than-alcohol consumption that had served as controls in Studies 2 and 3. A reanalysis of the data from Study 3, with such items removed from the controls and designated 'new' negative alcohol consumption outcomes, showed a positive relationship between consumption and implicit alcohol-related associations made through these 'new' items of the Associations Questionnaire. The changing profile of associations with negative outcomes of consumption is discussed and related to negative expectancy research and drinking restraint.

Adult↗

PubMed2004

Baseline risk factors for the development of primary open-angle glaucoma in the Ocular Hypertension Treatment Study.

PURPOSE: Higher baseline pattern standard deviation (PSD) and larger vertical cup-to-disk ratio (VC/D) were factors in the predictive model for the development of primary open-angle glaucoma (POAG) in the Ocular Hypertension Treatment Study. Because early changes in PSD and VC/D may be indicative of early POAG damage, we repeated the prediction model excluding PSD and VC/D. DESIGN: Reanalysis of baseline factors for the development of POAG. METHODS: We compared the hazard ratios for baseline factors predictive of POAG in the multivariate Cox proportional hazards model that included PSD and VC/D and in the model that excluded them. RESULTS: Hazard ratios for baseline factors predictive of POAG in Ocular Hypertension Treatment Study were not substantially affected by the inclusion or exclusion of PSD and VC/D in the proportional hazards model. CONCLUSION: Whether PSD or VC/D was included in the Cox proportional hazards model, the same baseline factors were statistically significant and their hazard ratios were essentially similar.

Glaucoma, Open-Angle↗

PubMed2005

Random-effects models in investigating the effect of vitamin A in childhood diarrhea.

PURPOSE: By adopting more appropriate and powerful statistical methods that fully exploit longitudinal structure, we re-analyze and extend previously published results from a large community trial to investigate the effect of vitamin A supplementation on the prevalence and severity of diarrhea in young children. METHODS: Generalized linear mixed models were used to allow for repeated measures in a reanalysis of a double-blind, randomized, placebo-controlled community trial conducted in a cohort of children in northeastern Brazil during 1 year. The response variable was weekly number of days with diarrhea for each child, and Markov Chain Monte Carlo methods were used to estimate model parameters. RESULTS AND CONCLUSIONS: Random effects suitably accounted for the underlying heterogeneity between and within children, and our longitudinal analysis shows a significant beneficial effect of vitamin A supplementation that was inconclusive in previously reported simple summary analyses of these data. Risk for diarrhea infection was estimated to be 1.57 times greater for a child administered a placebo as opposed to vitamin A (95% credible interval, 1.17-2.12). Additionally, we identified previously unreported temporal effects in these data, showing a decreasing daily probability of diarrhea for both groups during the trial and treatment-time interaction.

Bayes Theorem↗

PubMed2006

Big brown dog or brown big dog? An electrophysiological study of semantic constraints on prenominal adjective order.

Event-related brain potentials (ERPs) were recorded while participants read and made acceptability judgments about sentences containing three types of adjective sequences: (1) normal sequences--e.g., Jennifer rode a huge gray elephant; (2) reversed sequences that violate grammatical-semantic constraints on linear order--e.g., *Jennifer rode a gray huge elephant; and (3) contradictory sequences that violate lexical-semantic constraints on compositionality--e.g., *Jennifer rode a small huge elephant. Relative to the control condition, the second adjective elicited a reduced N400 and an enhanced P600 in both the reversal condition and the contradiction condition. We present several alternative accounts of these two effects, but favor an interpretation which treats them as reflecting semantic and syntactic aspects of a temporary reanalysis of the adjective order construction. Furthermore, relative to the control condition, the final noun elicited a robust N400 in the contradiction condition but not in the reversal condition. We suggest that this effect indexes the full registration of the lexical-semantic incompatibility of the two adjectives in the contradiction condition. Finally, we discuss how all of these findings fit into the broader context of recent ERP studies that have reported atypical N400s and robust P600s in response to certain types of semantic anomalies.

Adult↗

PubMed2004

Human SULT1A3 pharmacogenetics: gene duplication and functional genomic studies.

Sulfotransferase (SULT) 1A3 catalyzes the sulfate conjugation of catecholamines. Inheritance is an important factor responsible for individual variation in SULT1A3 activity, and gene resequencing studies have shown the presence of one functionally significant SULT1A3 nonsynonymous cSNP. However, following completion of the Human Genome Project, it appeared that SULT1A3 might be duplicated. We used specific PCR-based assays and fluorescence in situ hybridization to verify that 2 SULT1A3 genes-SULT1A3 and SULT1A4-were present on chromosome 16 in all human DNA samples studied. Furthermore, reanalysis of previous gene resequencing data confirmed the presence of the SULT1A3 SNPs identified previously, but also revealed 11 novel polymorphisms, including 3 nonsynonymous cSNPs. Functional genomic studies showed that two of those cSNPs, C302T, and C302A, resulted in decreased enzyme activity without striking changes in substrate kinetics but with parallel changes in levels of immunoreactive protein. In addition, RT-PCR revealed that both SULT1A3 and SULT1A4 can be transcriptionally active. The duplication of SULT1A3 will have to be taken into account in future efforts to understand individual variation in SULT1A3 activity or properties.

Arylsulfotransferase↗

PubMed2026

Robust error-minimization in the genetic code across physicochemical metrics and variant codes: A graph-theoretic analysis in GF(2)6.

The standard genetic code reduces the impact of point mutations, but the robustness of this property across physicochemical metrics, naturally occurring variant codes, and codon-reassignment mechanisms remains incompletely quantified. Embedding the 64 codons in GF(2)6 represents the hypercube Q6 as a coordinate-dependent subgraph of the encoding-independent single-nucleotide mutation graph H(3,4), and enables continuous ρ-interpolation between the two. Under a quartet-pattern shuffle null (n=10,000), the standard code is significantly low-cost across four established, code-independent physicochemical distance metrics with partially overlapping content (Grant ham p=0.0062; Miyata p<0.001; Woese polar requirement p=0.003; Kyte-Doolittle hydropathy p=0.001), and the signal strengthens monotonically as ρ moves Q6→H(3,4). A structure-aware sensitivity analysis under the alignment-derived ProtSub matrix (Jia & Jernigan 2021) yields the most extreme percentile of any measure tested (p=0.0004; all five p-values pass Bonferroni at α=0.05). Across the 27 NCBI translation tables, near-optimality is preserved: 11 of 12 informative-distance variants retain top-5% placement after BH-FDR correction. Natural codon reassignments avoid disrupting codon-family connectivity: under the encoding-independent H(3,4) adjacency, observed events are topology-breaking at relative risk 0.32 versus the candidate landscape (permutation p≤10-4). The H(3,4) result is stable by construction; the Q6 decomposition is representation-specific and fails to show depletion under 8 of 24 base-to-bit encodings, so we report H(3,4) as the primary test and Q6 as a sensitivity. Event-level conditional-logit modelling shows that topology avoidance and local physicochemical cost provide complementary, only weakly correlated signal (rs=0.15), and that topology adds explanatory value beyond physicochemistry under both Q6 and encoding-independent H(3,4) adjacency. Retrospective reanalysis of nine genome-recoding datasets is consistent with codon-family topology operating as an evolutionary-trajectory constraint distinct from acute engineering fitness. The contribution is the second axis: code evolution is jointly constrained by physicochemical smoothness and codon-family topological integrity, and these two constraints are partly independent.

Codon reassignment↗

PubMed2004

Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy.

The structural basis for the reduction in vertebral and nonvertebral fracture risk in patients using anti-resorptive therapy is not well understood. As reduced bone mineral density (BMD) increases the risk for fracture and anti-resorptive agents increase BMD, it was commonly held that the increase in BMD explained the fracture risk reduction until several meta-analyses either failed to detect a significant association between vertebral fracture risk reduction and the incremental increase in BMD or reported that only a small proportion of the vertebral fracture risk reduction was explained by changes in BMD. Recently, it was reported that the risk of nonvertebral fractures decreased when an increase in BMD accompanied anti-resorptive treatment [J. Clin. Endrocrinol. Metab. 87 (2002) 1586]. However, a reanalysis of the data, using the same statistical methods after correcting for discrepancies in the reported BMD and person-year data, suggested that the magnitude of reductions in nonvertebral fracture risk was not associated with the magnitude of increases in BMD at the end of the first year or at completion of the studies. We infer that only a small proportion of risk reduction in vertebral and nonvertebral fractures observed with anti-resorptive drug therapy is explained by the increase in BMD. Further studies are needed to define the structural basis of the fracture risk reduction.

Bone Density↗

PubMed2006

Multilocus analysis of estrogen-related genes in Spanish postmenopausal women suggests an interactive role of ESR1, ESR2 and NRIP1 genes in the pathogenesis of osteoporosis.

Osteoporosis is a common disease with multiple environmental and genetic risk factors involved. Using a marker-by-marker approach, the role of different estrogen-related genes has been analyzed in different populations, but most of these studies ignore the complex multigenic nature of human osteoporosis. Looking for markers related to osteoporosis, we have analyzed five single nucleotide polymorphisms located in genes related to the estrogen pathway, Follicle Stimulating Hormone Receptor (FSHR) gene, the CYP19 aromatase (CYP19A1) gene, the Estrogen Receptor alpha (ESR1) gene, the Estrogen Receptor beta (ESR2) gene and the Nuclear Receptor Interacting Protein 1 (NRIP1) gene in 265 unrelated postmenopausal women. We have obtained nominal P values for the NRIP1 Gly75Gly and ESR2 *39A>G markers (P=0.013 and P=0.02 respectively), but no gene seems to be associated after multiple test corrections. Reanalysis of this study using 437 postmenopausal women confirmed our results and only detect marginal effects for ESR2 marker (P=0.045). By contrast, multilocus analysis predicted epistatic interactions between ESR1, ESR2 and NRIP1 loci and its involvement in postmenopausal osteoporosis (P=0.003). We detected two digenic genotypes involving ESR2-NRIP1 and ESR2-ESR1 genes strongly associated with osteoporosis (P=0.007). Replication of multilocus studies using 437 patients confirmed the detected interactions (P<0.01). We proposed a non-additive non-multiplicative oligogenic model including ESR2 AG genotype modulated by NRIP1 A+ or ESR1 TT genotypes involved in osteoporosis. Our results reaffirm the polygenic nature and the genetic complexity of osteoporosis trait adding a new candidate gene (NRIP1) for association studies of bone-related traits.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Estrogen and combined estrogen-progestogen therapy in the menopause and breast cancer.

Most of the data on menopausal hormone therapy (HT) and breast cancer risk available up to the mid-1990s were included in a collaborative reanalysis based on over 52,000 women with and 108,000 without breast cancer. HT increased the risk of breast cancer by about 2.3% per year of use. Subsequent studies have confirmed that breast cancer risk is elevated in current and recent (but not past) HT users and that the relative risk (RR) is higher for users of combined estrogen-progestin treatment than for users of estrogen only, and this higher RR is seen with various types of preparations and different routes of administration. With reference to intervention studies, information on combined HT derives from the Women's Health Initiative (WHI). After 7 years of follow-up, 166 breast cancer cases were recorded in the HT group, as against 124 in the placebo group, corresponding to a RR of 1.24. Data from two other, smaller, randomized studies are available. In a combined analysis of the three randomized trials, 205 cases of breast cancer were observed in the treated groups as against 154 in the placebo groups, corresponding to a pooled RR of 1.27. However, in the estrogen-only component of the WHI population, at 8 years of follow-up 94 cases were observed in the estrogen group, opposed to 124 in the placebo group (RR=0.77). The results recorded in the WHI and the Million Women Study do not confirm the suggestion that breast cancers in women using HT have a more favorable prognosis. HT has also been related to an increased risk of recurrent breast cancer.

Adult↗

PubMed2026

Discordant neoplasms in monozygotic twins with a germline RECQL5 variant.

RECQL5 is a member of the RecQ helicase family involved in DNA replication, homologous recombination, and maintenance of genomic stability. While germline pathogenic variants in other RecQ helicases cause established cancer predisposition syndromes, the role of RECQL5 in human cancer susceptibility remains uncertain. We report monozygotic adolescent twins with distinct tumors: dysembryoplastic neuroepithelial tumor in one twin and Burkitt lymphoma in the other. Clinical genome sequencing was initially nondiagnostic, but reanalysis identified a rare heterozygous nonsense variant in RECQL5 (NM_004259.7:c.2698C>T, p.(Gln900Ter)), present in both twins and their unaffected mother. The variant is predicted to undergo nonsense-mediated mRNA decay or produce a truncated protein lacking the C-terminal SRI (Set2-Rpb1 interacting) domain, which mediates interaction with RNA polymerase II. However, tumor sequencing data were not available to evaluate loss of heterozygosity or second somatic events. Given the unaffected carrier parent, lack of tumor molecular confirmation, and the biological heterogeneity of the tumors, a causal relationship for this variant cannot be established. This case highlights the challenges of interpreting rare germline variants in genes with emerging but incompletely characterized disease associations. Although the available evidence is insufficient to establish a definitive causal relationship, the identification of a shared loss-of-function RECQL5 variant in monozygotic twins with distinct tumors is noteworthy and adds to the limited clinical evidence suggesting a potential role for RECQL5 in cancer susceptibility. Additional functional studies, tumor-based analyses and the accumulation of well-characterized clinical cases will be essential to determine whether RECQL5 contributes to hereditary cancer predisposition.

Adolescent↗

PubMed2005

Asymmetric glycosylation of soybean seed coat peroxidase.

Reanalysis of the tryptic digests of soybean seed coat peroxidase (SBP) and its carboxyamidated peptide derivatives in the light of more complete sequence data has thrown light on the diglycosylated tryptic peptides, TP13 (Leu[183-205]Arg) and TP15 (Cys[208-231]Arg). Matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analyses indicate that although all potential sites carry some glycan substituents, not all sites are fully occupied. Tryptic glycopeptide TP13, carrying two N-glycosylation consensus sequons (Asn185 and Asn197), occurs mainly (85-90%) as the diglycosylated species, the remainder (10-15%) being monoglycosylated. In contrast, tryptic peptide TP15, also with two N-glycosylation sites (Asn211 and Asn216), is primarily monoglycosylated (approximately 90%), with the remainder (10%) being diglycosylated. No non-glycosylated TP13 or TP15 was observed. Some artifacts are noted in the reactions of N-terminal cysteine residues and aspartate/asparagines residues in glycopeptide TP15. Mapping the glycans onto the crystal structure of SBP shows that these are asymmetrically distributed on the molecule, occurring primarily on the substrate-channel face of the enzyme. In contrast, the glycans of HRP, isozyme c, are more uniformly distributed over the enzyme surface.

Amides↗

PubMed2005

Health Watch exposure estimates: do they underestimate benzene exposure?

A nested case-control study found that the excess of leukemia, identified among the male members of the Health Watch cohort, was associated with benzene exposure. Exposure had been retrospectively estimated for each individual occupational history using an algorithm in a relational database. Benzene exposure measurements, supplied by Australian petroleum companies, were used to estimate exposure for specific tasks. The tasks carried out within each job, the products handled, and the technology used, were identified from structured interviews with contemporary colleagues. More than half of the subjects started work after 1965 and had an average exposure period of 20 years. Exposure was low; nearly 85% of the cumulative exposure estimates were at or below 10 ppm-years. Matched analyses showed that leukemia risk increased with increasing cumulative benzene exposures and with increasing exposure intensity of the highest-exposed job. Non-Hodgkin lymphoma and multiple myeloma were not associated with benzene exposure. A reanalysis reported here, showed that for the 7 leukemia case-sets with greater than 16 ppm-years cumulative exposure, the odds ratio was 51.9 (5.6-477) when compared to the 2 lowest exposed categories combined to form a new reference category. The addition of occasional high exposures, e.g. as a result of spillages, increased exposure for 25% of subjects but for most, the increase was less than 5% of total exposure. The addition of these exposures reduced the odds ratios. Cumulative exposures did not range as high as those in comparable studies; however, the recent nature of the cohort and local handling practices can explain these differences.

Air Pollutants, Occupational↗