Causal mediation analysis with multiple mediators.

In diverse fields of empirical research-including many in the biological sciences-attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from "single mediator theory" to "multiple mediator practice," highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed

Causal mediation analysis with multiple mediators

In diverse fields of empirical research - including many in the biological sciences - attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from single mediator theory to multiple mediator practice, highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed

A case-control study of the impact of improved sanitation on diarrhoea morbidity in Lesotho.

A health impact evaluation of the Rural Sanitation Pilot Project in Mohale's Hoek district, Lesotho, was conducted from October 1987 to September 1988. A clinic-based case-control design was used to investigate the impact of improved sanitation on diarrhoea morbidity in young children. The results indicate that under-5-year-olds from households with a latrine may experience 24% fewer episodes of diarrhoea than such children from households without a latrine (odds ratio = 0.76; 95% confidence interval, 0.58-1.01). The impact of latrines on diarrhoea was greater in those households that used more water, practised better personal hygiene, and where the mothers had a higher level of education or worked outside the home. In common with studies conducted in Malawi, Philippines, and Sri Lanka, little evidence was found that the relationship between latrine ownership and diarrhoea was confounded by socioeconomic status or environmental variables. For a sample of cases and controls, data on exposure status (presence or absence of a latrine) that were collected by interview at the clinics agreed closely with those obtained by observation during a home visit

IFN-gamma is associated with risk of Schistosoma japonicum infection in China.

Before the start of the schistosomiasis transmission season, 129 villagers resident on a Schistosoma japonicum-endemic island in Poyang Lake, Jiangxi Province, 64 of whom were stool-positive for S. japonicum eggs by the Kato method and 65 negative, were treated with praziquantel. Forty-five days later the 93 subjects who presented for follow-up were all stool-negative. Blood samples were collected from all 93 individuals. S. japonicum soluble worm antigen (SWAP) and soluble egg antigen (SEA) stimulated IL-4, IL-5 and IFN-gamma production in whole-blood cultures were measured by ELISA. All the subjects were interviewed nine times during the subsequent transmission season to estimate the intensity of their contact with potentially infective snail habitats, and the subjects were all re-screened for S. japonicum by the Kato method at the end of the transmission season. Fourteen subjects were found to be infected at that time. There was some indication that the risk of infection might be associated with gender (with females being at higher risk) and with the intensity of water contact, and there was evidence that levels of SEA-induced IFN-gamma production were associated with reduced risk of infection

Red-dot card test of the paracentral field as a screening test for optic nerve disease in onchocerciasis.

A new screening test for optic nerve pathology is described, consisting of a series of four red targets presented at an angle of 12 degrees in the paracentral field above and below the horizontal meridian. Nonperception and desaturation of the targets are recorded. Inter-observer variability studies found a kappa value = 0.8. A total of 6831 individuals aged > or = 5 years in communities that were mesoendemic for savanna onchocerciasis in Kaduna State, northern Nigeria, were screened using the test. Of the participants 22% were unable to complete the test; almost two-thirds of these (62%) were aged 5-8 years. After exclusion of those visually impaired or blind according to WHO criteria and those unable to complete the test, the test showed a sensitivity of 40% and a specificity of 98% for optic nerve disease when inability to visualize one or more targets was used as the definition of test failure. The sensitivity increased to 54% with a specificity of 96% when the criterion for failure included desaturation of one or more targets. These values compare favourably with those for other available screening methods. The test took 1-2 minutes to perform and was readily accepted by patients and nurses

Impact of annual dosing with ivermectin on progression of onchocercal visual field loss.

Reported are the results of a randomized, double-masked, placebo-controlled trial of annual ivermectin dosing in 34 rural communities, Kaduna State, northern Nigeria, where guinea savanna onchocerciasis is mesoendemic. A total of 939 individuals underwent Friedmann field analysis at the first examination and saw at least 19 spots in at least one eye. Of these, 636 (68%) completed a subsequent Friedmann field analysis 2-3 years later. The adjusted incidence rate ratio for the ivermectin group versus the placebo group was 0.64 (95% confidence interval (CI): 0.42-0.98). There was some evidence that the impact of ivermectin was greatest among those who had received one dose of ivermectin. The majority of the deteriorations occurred in eyes that gave evidence of optic atrophy at the first examination. An analysis restricted to individuals with optic atrophy at baseline indicated a reduction of 45% in the incidence of visual field deterioration in the ivermectin group (95% CI: 8-67%). Previous findings have shown that ivermectin has an impact on the incidence of optic atrophy. Our results indicate, for the first time, that ivermectin has a substantial impact on the progression of visual field loss among those with pre-existing optic atrophy

Strengthening the Reporting of Observational Studies in Epidemiology for Newborn Infection (STROBE-NI): an extension of the STROBE statement for neonatal infection research.

Neonatal infections are estimated to account for a quarter of the 2·8 million annual neonatal deaths, as well as approximately 3% of all disability-adjusted life-years. Despite this burden, few data are available on incidence, aetiology, and outcomes, particularly regarding impairment. We aimed to develop guidelines for improved scientific reporting of observational neonatal infection studies, to increase comparability and to strengthen research in this area. This checklist, Strengthening the Reporting of Observational Studies in Epidemiology for Newborn Infection (STROBE- NI), is an extension of the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. STROBE-NI was developed following systematic reviews of published literature (1996-2015), compilation of more than 130 potential reporting recommendations, and circulation of a survey to relevant professionals worldwide, eliciting responses from 147 professionals from 37 countries. An international consensus meeting of 18 participants (with expertise in infectious diseases, neonatology, microbiology, epidemiology, and statistics) identified priority recommendations for reporting, additional to the STROBE statement. Implementation of these STROBE-NI recommendations, and linked checklist, aims to improve scientific reporting of neonatal infection studies, increasing data utility and allowing meta-analyses and pathogen-specific burden estimates to inform global policy and new interventions, including maternal vaccines

Uncertainty in the Tail of the Variant Creutzfeldt-Jakob Disease Epidemic in the UK

Despite low case numbers the variant Creutzfeldt-Jakob disease epidemic poses many challenges for public health planning due to remaining uncertainties in disease biology and transmission routes. We develop a stochastic model for variant CJD transmission, taking into account the known transmission routes (food and red-cell transfusion) to assess the remaining uncertainty in the epidemic. We use Bayesian methods to obtain scenarios consistent with current data. Our results show a potentially long but uncertain tail in the epidemic, with a peak annual incidence of around 11 cases, but the 95% credibility interval between 1 and 65 cases. These cases are predicted to be due to past food-borne transmissions occurring in previously mostly unaffected genotypes and to transmissions via blood transfusion in all genotypes. However, we also show that the latter are unlikely to be identifiable as transfusion-associated cases by case-linking. Regardless of the numbers of future cases, even in the absence of any further control measures, we do not find any self-sustaining epidemics

A polymorphism in the regulatory region of PRNP is associated with increased risk of sporadic Creutzfeldt-Jakob disease

Background: Creutzfeldt-Jakob disease (CJD) is a rare transmissible neurodegenerative disorder. An important determinant for CJD risk and phenotype is the M129V polymorphism of the human prion protein gene (PRNP), but there are also other coding and non-coding polymorphisms inside this gene.Methods: We tested whether three non-coding polymorphism located inside the PRNP regulatory region (C-101G, G310C and T385C) were associated with risk of CJD and with age at onset in a United Kingdom population-based sample of 131 sporadic CJD (sCJD) patients and 194 controls.Results: We found no disease association for either PRNP C-101G or PRNP T385C. Although the crude analysis did not show a significant association between PRNP G310C and sCJD (OR: 1.5; 95%CI = 0.7 to 2.9), after adjusting by PRNP M129V genotype, it resulted that being a C allele carrier at PRNP G310C was significantly (p = 0.03) associated with a 2.4 fold increased risk of developing sCJD (95%CI = 1.1 to 5.4). Additionally, haplotypes carrying PRNP 310C coupled with PRNP 129M were significantly overrepresented in patients (p = 0.02) compared to controls. Cases of sCJD carrying a PRNP 310C allele presented at a younger age (on average 8.9 years younger than those without this allele), which was of statistical significance (p = 0.05). As expected, methionine and valine homozygosity at PRNP M129V increased significantly the risk of sCJD, alone and adjusted by PRNP G310C (OR MM/MV = 7.3; 95%CI 3.9 to 13.5 and OR VV/MV = 4.0; 95%CI 1.7 to 9.3).Conclusions: Our findings support the hypothesis that genetic variations in the PRNP promoter may have a role in the pathogenesis of sCJD

The impact of helminths on the response to immunization and on the incidence of infection and disease in childhood in Uganda: design of a randomized, double-blind, placebo-controlled, factorial trial of deworming interventions delivered in pregnancy and early childhood [ISRCTN32849447]

BACKGROUND: Helminths have profound effects on the immune response, allowing long-term survival of parasites with minimal damage to the host. Some of these effects "spill-over", altering responses to non-helminth antigens or allergens. It is suggested that this may lead to impaired responses to immunizations and infections, while conferring benefits against inflammatory responses in allergic and autoimmune disease. These effects might develop in utero, through exposure to maternal helminth infections, or through direct exposure in later life. PURPOSE: To determine the effects of helminths and their treatment in pregnancy and in young children on immunological and disease outcomes in childhood. METHODS: The trial has three randomized, double-blind, placebo-controlled interventions at two times, in two people: a pregnant woman and her child. Pregnant women are randomized to albendazole or placebo and praziquantel or placebo. At age 15 months their children are randomized to three-monthly albendazole or placebo, to continue to age five years. The proposed designation for this sequence of interventions is a 2 x 2(x2) factorial design. Children are immunized with BCG and against polio, Diphtheria, tetanus, Pertussis, Haemophilus, hepatitis B and measles. Primary immunological outcomes are responses to BCG antigens and tetanus toxoid in whole blood cytokine assays and antibody assays at one, three and five years of age. Primary disease outcomes are incidence of malaria, pneumonia, diarrhoea, tuberculosis, measles, vertical HIV transmission, and atopic disease episodes, measured at clinic visits and twice-monthly home visits. Effects on anaemia, growth and intellectual development are also assessed. CONCLUSION: This trial, with a novel design comprising related interventions in pregnant women and their offspring, is the first to examine effects of helminths and their treatment in pregnancy and early childhood on immunological, infectious disease and allergic disease outcomes. The results will enhance understanding of both detrimental and beneficial effects of helminth infection and inform policy