Assessing the effects of cooperation bias and attrition in behavioral genetic research using data-weighting

Because twins and adoptees are a rare resource, they are often studied repeatedly over a period of many years. Differential attrition, and in some studies initial cooperation bias, have the potential to lead to serious biases to estimates of genetic and environmental parameters. Since non-response is often influenced by multiple binary or categorical sociodemographic variables, maximum-likelihood methods are not easily adapted to adjust for such effects. In this brief note we illustrate the use of data-weighting to assess the likely effects of cooperation bias or attrition both on measures of mean or prevalence, and on twin pair correlations or concordances, using data from the Australian twin panel 1981 survey and alcohol challenge studies. Participants in the alcohol challenge study were on average younger, more socially nonconforming, heavier drinkers, more likely to be unmarried, and less likely to report their religion as Other Protestant. Reweighting the alcohol challenge sample to have the same distribution on these variables as the Australian twin panel 1981 survey respondents confirmed that individuals who would feel very intoxicated after a challenge dose of alcohol were underrepresented in the study. However, pairwise data-weighting indicated that this cooperation bias was leading to only a slight underestimation of the importance of genetic effects on subjective intoxication.     

Pseudomonas aeruginosa as a cause of infectious diarrhoea

Pseudomonas aeruginosa is not generally considered a cause of infectious diarrhoea. However, it was the predominant organism isolated from the faeces of 23 unrelated, hospital outpatients investigated in the course of a year for persistent (> 1 week duration) diarrhoea. To investigate the possible aetiological role of P. aeruginosa, these patient histories were reviewed and a selection of their faecal isolates were investigated in vitro (n > or = 10) and in vivo (n = 2) for virulence. The patients had a mean age of 60 years, were receiving antibiotics and/or had an underlying illness. Extensive microbiological investigations identified no other potential or recognized enteropathogen in the faeces of 20 of these patients. More than 40% of the isolates tested were able to adhere to HEp-2 cells and exhibited twitching motility (type IV pili), properties indicative of their ability to colonize the human intestine. Cytotoxic activity was demonstrated in bacterium-free cell supernatants of over 80% of isolates; supernatants of four isolates tested in infant mice were weakly enterotoxigenic. Two isolates intragastrically inoculated into clindamycin pre-treated rats established persistent infections and induced signs and symptoms of enteritis. Overall these findings suggest that P. aeruginosa can cause diarrhoea particularly in immunodeficient individuals.     

Type-1 plasminogen-activator inhibitor -- conformational differences between latent, active, reactive-centre-cleaved and plasminogen-activator-complexed forms, as probed by proteolytic susceptibility

We have analysed the susceptibility of latent, active, reactive-centre-cleaved and plasminogen-activator-complexed type-1 plasminogen-activator inhibitor (PAI-1) to the non-target proteinases trypsin, endoproteinase Asp-N, proteinase K and subtilisin. This analysis has allowed us to detect conformational differences between the different forms of PAI-1 outside the reactive-centre loop and beta-sheet A. Proteinase-hypersensitive sites were clustered in three regions. Firstly, susceptibility was observed in the region around alpha-helix E, beta-strand 1A, and the flanking loops, which are believed to form flexible joints during movements of beta-sheet A. Secondly, hypersensitive sites were observed in the loop between alpha-helix I and beta-strand 5A. Thirdly, the gate region, encompassing beta-strands 3C and 4C, was highly susceptible to trypsin in latent PAI-1, but not in the other conformations. The digestion patterns differed among all four forms of PAI-1, indicating that each represents a unique conformation. The differential proteolytic susceptibility of the flexible-joint region may be coupled to the differential affinity to vitronectin, binding in the same region. The analysis also allowed detection of conformational differences between reactive-centre-cleaved forms produced under different solvent conditions. The digestion pattern of plasminogen-activator-complexed PAI-1 was different from that of active PAI-1, but indistinguishable from that of one of the reactive-centre-cleaved forms, as the complexed and this particular cleaved PAI-1 were completely resistant to all the non-target proteinases tested. This observation is in agreement with the notion that complex formation involves reactive-centre cleavage and a large degree of insertion of the reactive-centre loop into beta-sheet A. Our analysis has allowed the identification of some flexible regions that appear to be implicated in the conformational changes during the movements of beta-sheet A and during the inhibitory reaction of serpins with their target proteinases.     

Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA

Viruses have long been suggested to be involved in the etiology of multiple sclerosis (MS). This suggestion is based on (1) epidemiological evidence of childhood exposure to infectious agents and increase in disease exacerbations with viral infection; (2) geographic association of disease susceptibility with evidence of MS clustering; (3) evidence that migration to and from high-risk areas influences the likelihood of developing MS; (4) abnormal immune responses to a variety of viruses; and (5) analogy with animal models and other human diseases in which viruses can cause diseases with long incubation periods, a relapsing-remitting course, and demyelination. Many of these studies involve the demonstration of increased antibody titers to a particular virus, whereas some describe isolation of virus from MS material. However, no virus to date has been definitively associated with this disease. Recently, human herpesvirus 6 (HHV-6), a newly described beta-herpes virus that shares homology with cytomegalovirus (CMV), has been reported to be present in active MS plaques. In order to extend these observations, we have demonstrated increased IgM serum antibody responses to HHV-6 early antigen (p41/38) in patients with relapsing-remitting MS (RRMS), compared with patients with chronic progressive MS (CPMS), patients with other neurologic disease (OND), patients with other autoimmune disease (OID), and normal controls. Given the ubiquitous nature of this virus and the challenging precedent of correlating antiviral antibodies with disease association, these antibody studies have been supported by the detection of HHV-6 DNA from samples of MS serum as a marker of active viral infection.     

Activity of liposomal nystatin against disseminated Aspergillus fumigatus infection in neutropenic mice

The purpose of this study was to examine the activity of liposomal nystatin against a disseminated Aspergillus fumigatus infection in neutropenic mice. Mice were made neutropenic with 5-fluorouracil and were administered the antifungal drug intravenously for 5 consecutive days beginning 24 h following infection. Liposomal nystatin, at doses as low as 2 mg/kg of body weight/day, protected neutropenic mice against Aspergillus-induced death in a statistically significant manner at the 50-day time point compared to either the no-treatment, the saline, or the empty-liposome group. This protection was approximately the same as that for free nystatin, a positive control. Histopathological results showed that liposomal nystatin cleared the lungs, spleen, pancreas, kidney, and liver of Aspergillus and that there was no organ damage at the day 5 time point, which was after only three doses of liposomal nystatin. Based on these results in mice, it is probable that liposomal nystatin will be effective against Aspergillus infection in humans.     

Tissue-factor antigen and activity in human coronary atherosclerotic plaques

BACKGROUND: Coronary atherosclerotic-plaque thrombosis is a key event in the pathogenesis of unstable angina and myocardial infarction. Although plaque rupture or fissuring frequently occurs in atherosclerosis, only a small proportion of ruptured plaques develop thromboses. METHODS: Tissue-factor antigen and activity were measured in atherectomy samples from 50 consecutive patients with coronary artery disease (stable angina n = 19, unstable angina n = 24, and myocardial infarction n = 7). FINDINGS: Median tissue-factor antigen and activity concentrations were significantly higher in plaques from patients with unstable angina and myocardial infarction than in those from patients with stable angina (antigen: 66.1 pg/mg [interquartile range 43.8-82.5] vs 32.4 pg/mg [9.8-43.4], p = 0.0001; activity: 0.22 mU/mg [0.17-0.41] vs 0.13 mU/mg [0.05-0.16], p = 0.0004). INTERPRETATION: Tissue-factor, an initiator of the coagulation cascade, may account for the different thrombotic responses to the rupture of human coronary atherosclerotic plaques.     

Age differences in mental multiplication: evidence for peripheral but not central decrements

This study reports two mental multiplication experiments that were designed to measure age differences in central and peripheral processes. Experiment 1 varied task type (verification vs production), and Experiment 2 varied exposure duration (presentation until response, 600 ms, and 300 ms) on a production task. Neither experiment showed evidence of age differences in central processes (e.g., retrieval speed); however, there was some evidence of a peripheral-process (e.g., encoding) decrement for older adults. Specifically, there were no Age X Problem Size interactions for either experiment. Experiment 2 revealed decreasing age differences as problem difficulty increased. Indeed, for the 300-ms exposure duration, there were no age differences in RT or error rate. These results suggest that the magnitude of age differences in central processing speed are significantly less extreme than are age differences for peripheral processing speed for this type of mental arithmetic task. Also, older adults, in general, may have a higher skill level for basic fact retrieval in mental arithmetic than do young adults.     

Gender differences in social desirability and social approval bias in dietary self-report

Social desirability (the tendency to respond in such a way as to avoid criticism) and social approval (the tendency to seek praise) are two prominent response set biases evident in answers on structured questionnaires. These biases were tested by comparing nutrient intakes as estimated from a single 24-hour diet recall interview (24 HR) and a 7-day dietary recall (7DDR). Data were collected as part of the Worcester Area Trial for Counseling in Hyperlipidemia, a randomized, physician-delivered nutrition intervention trial for hypercholesterolemic patients conducted in Worcester, Massachusetts, from 1991 to 1995. Of the 1,278 total study subjects, 759 had complete data for analysis. Men overestimated their fat and energy intakes on the 7DDR as compared with the 24HR according to social approval: One unit increase in the social approval score was associated with an overestimate of 21.5 kcal/day in total energy intake and 1.2 g/day in total fat intake. Women, however, underestimated their dietary intakes on the 7DDR relative to the 24HR according to social desirability: One unit increase in the social desirability score was associated with an underestimate of 19.2 kcal/day in energy intake and 0.8 g/day in total fat. The results from the present study indicate that social desirability and social approval biases appear to vary by gender. Such biases may lead to misclassification of dietary exposure estimates resulting in a distortion in the perceived relation between health-related outcomes and exposure to specific foods or nutrients. Because these biases may vary according to the perceived demands of research subjects, it is important that they be assessed in a variety of potential research study populations.