Mendelian randomization in health research: Using appropriate genetic variants and avoiding biased estimates

Mendelian randomization methods, which use genetic variants as instrumental variables for exposures of interest to overcome problems of confounding and reverse causality, are becoming widespread for assessing causal relationships in epidemiological studies. The main purpose of this paper is to demonstrate how results can be biased if researchers select genetic variants on the basis of their association with the exposure in their own dataset, as often happens in candidate gene analyses. This can lead to estimates that indicate apparent “causal” relationships, despite there being no true effect of the exposure. In addition, we discuss the potential bias in estimates of magnitudes of effect from Mendelian randomization analyses when the measured exposure is a poor proxy for the true underlying exposure. We illustrate these points with specific reference to tobacco research.     

Colposcopy services in the West Midlands region.

A survey of all 72 consultant gynaecologists in the West Midlands region was carried out to determine their views on colposcopy services. All districts provided a colposcopy service and 47 consultants practised colposcopy. The consultants differed considerably in their views on criteria for referring women for investigation after smears. All but one thought that a positive smear result was an indication for immediate referral but whereas 55 thought that women with one or more inflammatory smear should be referred, 17 did not believe this to be necessary. Sixty seven consultants thought a preoperative colposcopic assessment desirable, but 10 had to ration referrals because of limited resources. Four forms of treatment were used: 17 districts had a carbon dioxide laser, eight used low voltage diathermy loop excision, two had only a cold coagulator, and one used only cold cautery. There was widespread dissatisfaction with resources and about the increasing amount of time spent on the service at the expense of other work. Consultants were also concerned about the relevance of much of what was done to the aim of the screening programme--reducing mortality from cervical cancer. Although additional resources are needed in some districts, referral policies, indications for colposcopic assessment, training, choice of treatment, and the value of follow up need to be reviewed if the service is to be improved.     

Free anonymous screening consultation and clinical management of HIV infection

In France, since 1988, anonymous and free consultations (called CDAG) have been settled in the country to facilitate an individual and volunteer approach for HIV screening. At the time, there are more than 380 CDAG with newly defined objectives. CDAG are supposed to encourage early screening, facilitate access to precarious persons and persons at risk for sexually transmitted diseases, and reinforce prevention, helping consultants to define a personal preventive strategy. CDAG are also supposed to play a role in prevention of both hepatitis B and C, and syphilis. They may help to link screening and healthcare. Their activity is increasing and the rate of positive test is twice that of private laboratories. Patients consulting those facilities are younger and more at risk than general population. Between 1000 and 2000 HIV positive tests are detected in CDAG each year (11 % of positive tests in the country). The real impact on prevention and screening at the national level is unknown, in part because of anonymity. To improve the characterization of consultants, data collection will be modified in 2004, and a network of selected and volunteer centres will collect continuously more accurate data.     

Traits émotionnels, intelligence émotionnelle: intÉrêt de ces concepts et Étude de leurs interrelations

Studies on personality traits conducted during the past decade indicate that there is a set of emotion-related traits on which individuals differ. Moreover, other studies showed that there are some abilities related to the processing of both emotions and emotional information, referred to as the concept of emotional intelligence. The authors of the article evaluated one hundred adults (ranging in age from 20–50) using the French version of a series of scales to measure stable emotionrelated traits and emotional intelligence. The results showed that these instruments provide accurate internal consistency and reliability, and that there are significant relationships between the individual emotional characteristics observed. A factorial analysis conducted with varimax rotation underlined five primary factors identified as: Clear-sightedness of emotions, Emotional richness, Identification, Understanding and Emotional control. The average emotional profiles based on these five primary factors depend on gender and age. In particular, the female and the oldest participants showed a greater emotional richness. The examination of these five factors should lead to a better understanding of the relationships which exist between these emotional characteristics and cognitive performances, and their involvement in clinical syndromes.     

Molecular phylogeny of north mediterranean freshwater barbs (genus Barbus: cyprinidae) inferred from cytochrome b sequences: biogeographic and systematic implications

We investigated phylogenetic relationships among north Mediterranean species of the genus Barbus using sequences of the cytochrome b gene. Our results indicate that the species belong to two major clades that are consistent with those previously defined from morphological features. The first clade includes species ranging from France to the Black Sea. In this clade, there is a well-supported monophyletic group of large-sized fluvio-lacustrine barbs; however, the monophyly of the small-sized rheophilic species is not clear. The second clade comprises species found in Spain, Greece, and Asia Minor and probably represents the oldest group present in the north Mediterranean rivers. In general, there is good concordance between geography and phylogenetic relationships. These results are compared to those from previous morphological- and allozyme-based studies and demonstrate widespread discordance and polyphyly in the traditional taxonomy of the genus Barbus. This study is one of the first reporting the phylogenetic and biogeographic relationships of a genus that is widely distributed in European rivers and contains species that are a major component of the European ichthyofauna.     

Parental Decision-Making and Acceptance of Newborn Bloodspot Screening: An Exploratory Study

Objective

Newborn bloodspot screening is an internationally established public health measure. Despite this, there is a paucity of information relating to the decision-making process that parents go through when accepting newborn screening. This is important as screening panels are expanding; potentially leading to an increasing amount of complex information. This study sought to understand the factors that influence parental decisions and roles they play in the decision-making process.

Patients and Methods

Qualitative thematic evaluation of semi structured interviews with parents whose children had recently undergone newborn screening in the Merseyside and Cheshire region of England, UK.

Results

Eighteen interviews with first time parents (n = 12) and those with previous children (n = 6). Seven factors were identified as being either explicitly or implicitly related to parental decision-making: Experience, Attitudes to medicine, Information-seeking behaviour, Perceived knowledge, Attitudes to screening, and Perceived choice, all of which ultimately impact on Perceived decisional quality.

Conclusions

These results indicate that while content is important, other contextual factors such as personal experience, perceived choice, and general attitudes toward medicine, are also highly influential. In particular, relationships with key healthcare professionals are central to information collection, attitudes toward screening, and the level of deliberation that is invested in decisions to accept newborn bloodspot screening.     

Dispersal, Environmental Correlation, and Spatial Synchrony in Population Dynamics

Many species exhibit widespread spatial synchrony in population fluctuations. This pattern is of great ecological interest and can be a source of concern when the species is rare or endangered. Both dispersal and spatial correlations in the environment have been implicated as possible causes of this pattern, but these two factors have rarely been studied in combination. We develop a spatially structured population model, simple enough to obtain analytic solutions for the population correlation, that incorporates both dispersal and environmental correlation. We ask whether these two synchronizing factors contribute additively to the total spatial population covariance. We find that there is always an interaction between these two factors and that this interaction is small only when one or both of the environmental correlation and the dispersal rate are small. The interaction is opposite in sign to the environmental correlation; so, in the normal case of positive environmental correlation across sites, the population synchrony will be lower than predicted by simply adding the effects of dispersal and environmental correlation. We also find that population synchrony declines as the strength of population regulation increases. These results indicate that dispersal and environmental correlation need to be considered in combination as explanations for observed patterns of population synchrony.     

Evolutionary patterns and genetic structure in localized and widespread species in the Stylidium caricifolium complex (Stylidiaceae)

The Stylidium caricifolium (Stylidiaceae) complex consists of seven currently recognized species and a taxon of putative hybrid origin endemic to southwest Western Australia. These taxa vary in geographical distribution from widespread, extending over a range of 500 km, to extremely localized, covering a range of only 0.5 km. Patterns of allozyme variation were investigated in 61 populations covering all taxa and two closely related species. Measures of genetic diversity were consistently lower and in some cases significantly lower in four rare and geographically restricted taxa compared with their widespread relatives. In contrast, genetic diversity in two other localized taxa was comparable or higher than in the widespread taxa. The level of divergence among populations was moderate to high, with a significant trend of higher F(ST) values for the widespread species to lower values for the geographically restricted and rare taxa. Phylogenetic relationships and levels of divergence indicate that most taxa are probably relictual rather than recently evolved. Geographical localization and rarity in this complex can be attributed to a range of factors associated with habitat specificity, historical and ecological processes that characterize the southwest region, and mode of origin.     

The influence of artificial cranial vault deformation on the expression of cranial nonmetric traits: its importance in the study of evolutionary relationships

Nonmetric cranial traits have been commonly used in evolutionary relationship studies. They develop during the growth and development of an individual, and for this reason its expression presents different sources of genetic and nongenetic variation. However, the use of these features in evolutionary relationship studies carries the implicit assumption that much of the nonmetric trait variation is essentially genetic. Among the nonheritable factors, cranial vault deformation has been the most studied in human populations. Because of the widespread distribution and elevated rate of artificial cranial vault deformation found in America, and the importance of nonmetric traits in evolutionary relationship studies in this area, the objectives of this paper are as follows: (a) to study the influence of artificial cranial vault deformation on the presence of nonmetric traits within samples of human craniofacial remains; and (b) to establish artificial cranial vault deformation influence on evolutionary relationships between local populations on a regional scale. Our results indicate that artificial cranial vault deformations alter the variation and covariation of metric and nonmetric traits in some samples. Wormian bones, placed in cranial vault sutures, are the most influenced by this factor. However, our results suggest that when all nonmetric traits were used the artificial cranial vault deformation did not influence the basic pattern of variation among samples. The exclusion or inclusion of wormians bones in evolutionary relationships analysis did not modify the results, but using only wormians bones lead to inconsistent results indicating that these traits have little value on these kind of studies.     

Frequency of inborn errors of metabolism,especially PKU,in some representative newborn screening centers around the world

Conclusions It becomes quite clear, by comparing reliable data about frequencies of some inborn errors of metabolism in newborn populations scattered around the world, that the frequency of PKU is significantly different in different nations and races. For several of these differences the relationships and dissimilarities in the origin of present-day nations can be presumed as explanations. The examples of intra-Irish differences and those between Ashkenazi Jews and other European nations, demonstrate the possible effect of religious and social barriers. In Galactosemia by transferase deficiency, comparable observations can be made, although technical problems produce artefacts. At present there is no indication that Histidinemia has a different frequency in different parts of the world, but more data are needed. This is true also for Arginino-succinic-aciduria and Hartnup's disease where interesting differences in frequency have been observed but in too few screening centers.The observation of significant differences in frequency of PKU and Galactosemia within such small countries as Ireland and Austria seems to indicate that comparison of frequencies in total newborn populations may only mask interesting differences by intranational equilibration. A politically defined modern nation need not necessarilly represent a genetic entity.The study shows that the comparison of frequencies of inborn errors of metabolism is a valuable and inexpensive means of elucidating genetic relationships and dissimilarities between modern populations and of recognizing influences which define genetic compartments. This side effect of newborn screening programs could become much more fruitful if screening centers were spread more evenly arround the globe; the reliability of certain test procedures could be ensured and the number of generally sought—for disorders could be increased.     

Practitioner versus participant perspectives on conservation tenders

Extensive clearing of native vegetation on rural properties throughout Australia over the last century has generated significant damage to biodiversity. Conservation tenders have been broadly used to reduce the detrimental impact of such widespread clearance. To date, Australian conservation tender research has largely been limited to program evaluations and landholder surveys. This analysis differs by comparing and contrasting the views of non-landholders involved with these programs with those of participant landholders. The non-landholder group consists of individuals with involvement in conservation tenders across Australia. By contrast, the landholder group consists of individuals with participation experience in a series of Victorian tender initiatives. Each group is surveyed to investigate the drivers of cost-effectiveness within tender programs and landholder participation. This analysis explores these two perspectives, revealing important convergences and divergences in opinion. Both practitioners and landholders indicate that programs supported by close agency–landholder relationships and offering flexibility to landholders are most likely to succeed, particularly where landholders perceive the tender instrument to be fair. Whilst practitioners emphasise the role of transaction costs issues and program characteristics in achieving cost-effective biodiversity outcomes, landholders indicate that these factors are less important to participation rates. This research is important to guide future implementation of tender programs both in Australia and internationally.     

Exemplary family physicians and consultants: empirical definition of contemporary medical practice.

To identify the characteristics of exemplary family physicians and consultants, we interviewed 25 family physicians and 25 consultants (5 each in the specialties of internal medicine, obstetrics and gynecology, pediatrics, psychiatry and surgery) selected by their peers as being exemplary in their own practice setting. The results indicated that the participants had well-formulated concepts of exemplary practitioners, defining five main categories of performance: clinical competence, relationship with patients, availability, family physician-consultant relationship and a fifth category that included organizational ability and personality attributes. The family physicians and the consultants placed different values on these categories and indicated that these values might change under different clinical circumstances. Their concepts appear to be compatible with, but not restricted to, a model of contemporary medical practice based on an ethic specific to medicine.     

Molecular phylogeny of the Cheilodactylidae and Latridae (Perciformes: Cirrhitoidea) with notes on taxonomy and biogeography

Phylogenetic relationships among cheilodactylid and latrid fishes were estimated from cytochrome oxidase I and cytochrome b mitochondrial DNA sequences. Two South African cheilodactylids, Cheilodactylus fasciatus and Cheilodactylus pixi, were divergent from the remaining members of their genus and family, and the monophyly of these groups was rejected based on parametric bootstrap analysis. As C. fasciatus is the nominal species for the genus and family, widespread taxonomic reassignment is implicated for the remaining 12 and 17 members of these groups, respectively. As these 17 cheilodactylids are not genetically or morphologically distinct from the latrids, it is proposed that the Latridae should be expanded to encompass them. The inferred relationships among those Cheilodactylus requiring generic reassignment were largely unresolved, and hence few recommendations can be made regarding their placement. Divergence time estimates indicate that chance oceanic dispersal subsequent to Gondwanan fragmentation best explains the Southern Hemisphere radiation of cheilodactylids.     

Prevalence of intraspecific relationships between range size and abundance in Danish birds

In this study, we investigate patterns in the prevalence of dynamic range–abundance relationships of the Danish avifauna, using breeding bird atlases from 1971 to 1974 and from 1993 to 1996. We focus on differences between common and rare species by dividing the assemblage into range-size quartiles. The trend in total population size was determined using an index. Range was determined as grid cell occupancy and standardized to facilitate comparisons between common and rare species. While narrow-ranging species showed strong and consistent range–abundance relationships, the relationships for widespread species were weak and exhibited considerable variation. This may be due to differences in patterns of resource use, since widespread species generally have wider niches, and so may be less affected by resource-based factors linking range and abundance. Since a tight and dynamic relationship is upheld for rare species, monitoring strategies based on range size surveys seem viable.     

Attitudes to Psychiatry in the General Hospital

A survey of consultant attitudes to psychiatry in six general hospitals is presented and compared with reported findings in general practitioners and medical students.Psychological factors were accepted as important in a variety of medical conditions. Different specialties differed little in their attitudes to neurotic patients and to psychiatrists, younger consultants tending to be more critical. Consultants had a lower level of neuroticism than the general population and medical students, and physicians were less extraverted than surgeons; these personality factors were not related to expressed attitudes.The results suggest that other specialties accept the role of psychiatry, and its integration into the general hospital is not likely to meet with antagonism.     

Constraints on HIV-1 diversity from protein structure

The high rate of HIV-1 evolution contributes to immune escape, enables the virus to escape drug therapy, and may underlie the difficulty of producing an effective vaccine. Identifying constraints on HIV evolution is therefore of prime importance. To investigate this problem, we examined the relationships between sequence diversity, selection, and protein structure. We found that while there was an increase in sequence diversity over time, this variation had a tendency to be limited to specific structural regions. When individual sites were analyzed, there was, in contrast, substantial and widespread evolutionary constraint over gag and env. This constraint was present even in the highly variable envelope proteins. The evolutionary significance of an individual site is indicated by the change in selection pressure along the time course: increasing entropy indicates that the site is evolving predominantly in a more "clock"-like manner, low entropy values with no increase indicate a high degree of constraint, and high entropy values indicate a lack of constraint. Few sites display high degrees of turnover. Mapping these sites onto the three-dimensional protein structure, we found a significant difference between evolutionary rates for regions buried in the core of the protein and those on the surface. This constraint did not change over the time period analyzed and was not subtype dependent, as similar results were found for subtypes B and C. This link between sequence and structure not only demonstrates the limits of recent HIV-1 evolution but also highlights the origins of evolutionary constraint on viral change.     

Interspecific differences in intraspecific abundance-range size relationships of British breeding birds

A general positive interspecific relationship between local abundance and geographic range size in animals has prompted speculation that a similar relationship might exist intraspecifically, such that a species is widespread at times when it is locally abundant, and more restricted in distribution when it is locally rare. Current evidence suggests that intraspecific relationships often are positive, but that there is considerable variation in the pattern exhibited by species. Here, we use data on British birds to test the hypotheses that species showing a high mean or wide spread of local densities or range sizes will be more likely to show strong intraspecific relationships between abundance and geographic range size. These data show only inconsistent support for an effect of the range of densities or of occupancies on intraspecific abundance-range size relationships. However, the strength of an intraspecific relationship does seem to be related to the mean occupancy of species, and whether or not a species exhibits temporal trends in density, with the strongest relationships found in species with simultaneous trends in both density and occupancy. We suggest that these results are explained by time lags in the loss or gain of species at occupied sites in response to reductions or increases in density.     

Regional variation in nonmedical factors affecting family physicians' decisions about referral for consultation

OBJECTIVE: To determine whether there is regional variation in environmental (non-medical) factors affecting referral decisions of family physicians (FPs). DESIGN: Cross-sectional interview survey. SETTING: Nova Scotia. PARTICIPANTS: A random sample of 125 FPs grouped into 1 of 5 functionally defined geographic regions of Nova Scotia (25 in each group). Groupings were based on access to general hospital beds through active staff hospital appointments or to specialist consultants in the community, or both. Participants were personally interviewed on site. No physician refused an interview. In 9 cases the physician indicated that he or she did not fit the profile of the assigned group; the physician was excluded from the study and the next doctor on the list was substituted. OUTCOME MEASURES: The questionnaire was designed to test several hypotheses about factors known to potentially influence decisions about referral. Geographic differences in factors affecting referral and in decisions about 5 hypothetical cases were assessed with the use of significance tests for proportions that were sensitive to specific orders across groups. RESULTS: Three factors affecting referral showed unequivocal variation across the 5 groups. Access to hospital facilities and remoteness from specialist care, leading to local styles of practice or treatment policies, and the FP''s relationship with specialist consultants appeared to be important nonmedical factors affecting referral decisions. For similar case scenarios the physicians living in rural areas would refer only half as often overall as those living in urban areas with tertiary care hospitals; for some cases, such as a severe asthma attack, the difference was more than 7-fold. CONCLUSIONS: Significant differences in nonmedical factors affecting referral, and in referral decisions about hypothetical cases, were found between the groups of FPs. Differences in access to resources, creating local styles of practice, appeared to explain most of the variation. The results may account for previously observed differences in actual rates of referral for these particular groups.     

Determinants of teenage pregnancies: The case of Busia District in Kenya

Sub-Saharan Africa has one of the highest levels of teenage pregnancies in the world. In spite of that, there is paucity of empirical research on causes of teenage pregnancies in African countries. This paper investigates the determinants of teenage pregnancies based on a case study of Busia District in Kenya. The data are from a household survey conducted in 1998/1999. Empirical results indicate that girls' education level has significant influence on the probability of teenage birth, with non-schooling adolescents and those with primary school level education being more vulnerable. Among the variables used as proxies for access to sex education, availability of church forums that educate adolescents about sex and family life issues reduce probability of teenage pregnancy. Age is positively related to teenage pregnancies, with older adolescents being more predisposed to pregnancies. Though use of contraceptives is found to have a positive effect, only a small proportion of adolescents were using modern contraceptives and, supply side factors such as quality and availability were not accounted for. Other key factors as outlined by the adolescents themselves include peer pressure and social environment-related factors like inappropriate forms of recreation, which act as rendezvous for pre-marital sex, as well as lack of parental guidance and counselling. Overall, lack of access to education opportunities, sex education and information regarding contraceptives, as well the widespread poverty predispose girls to teenage pregnancies. The problem of teenage pregnancies should be viewed within the broader socio-economic and socio-cultural environment in which the adolescents operate. For instance, lack of parental guidance on issues of sexuality and sex education was reinforced by cultural taboos that inhibit such discussions. Adolescents should be equipped with the relevant knowledge to enable them make informed choices regarding sexual relationships. This should be complemented with broader programmes aimed at promoting girl education and poverty alleviation.