Mediation analysis of time-to-event endpoints accounting for repeatedly measured mediators subject to time-varying confounding

In this article, we will present statistical methods to assess to what extent the effect of a randomised treatment (versus control) on a time-to-event endpoint might be explained by the effect of treatment on a mediator of interest, a variable that is measured longitudinally at planned visits throughout the trial. In particular, we will show how to identify and infer the path-specific effect of treatment on the event time via the repeatedly measured mediator levels. The considered proposal addresses complications due to patients dying before the mediator is assessed, due to the mediator being repeatedly measured, and due to posttreatment confounding of the effect of the mediator by other mediators. We illustrate the method by an application to data from the LEADER cardiovascular outcomes trial.     

Perceived discrimination In Primary Healthcare in Europe: evidence from the cross‐sectional QUALICOPC study

Recent figures show that discrimination in healthcare is still persistent in the European Union. Research has confirmed these results but focused mainly on the outcomes of perceived discrimination. Studies that take into account socioeconomic determinants of discrimination limit themselves to either ethnicity, income or education. This article explores the influence of several socioeconomic indicators (e.g. gender, age, income, education and ethnicity) on perceived discrimination in 30 European countries. Data from the QUALICOPC study were used. These data were collected between October 2011 and December 2013 in the participating countries. In total, 7183 GPs (general practitioners) and 61932 patients participated in the study, which had an average response rate of 74.1%. Data collection was co‐ordinated by NIVEL (Dutch Institute for Research of Health Care). Bivariate binomial logistic regressions were used to estimate the impact of each socioeconomic indicator on perceived discrimination. Multivariate logistic regressions were used to estimate the unique effect of each indicator. Results indicate that in Europe, overall 7% of the respondents felt discriminated, ranging between 1.4% and 12.8% at the country level. With regard to socioeconomic determinants in perceived discrimination, income and age are both important indicators, with lower income groups and younger people having a higher chance to feel discriminated. In addition, we find significant influences of education, gender, age and ethnicity in several countries. In most countries, higher educated people, older people, women and the indigenous population appeared to feel less discriminated. In conclusion, perceived discrimination in healthcare is reported in almost all European countries, but there is large variation between European countries. A high prevalence of perceived discrimination within a country also does not imply a correlation between socioeconomic indicators and perceived discrimination.     

Translational optical imaging in diagnosis and treatment of cancer

In cancer imaging, many different modalities are used that each have their specific features, leading to the combined use of different techniques for the detection, staging and treatment evaluation of cancer. Optical imaging using near-infrared fluorescence light is a new imaging modality that has recently emerged in the field of cancer imaging. After extensive preclinical research, the first steps of translation to the clinical practice are currently being made. In this article, we discuss the preclinical and clinical results of near-infrared optical imaging for non-invasive detection and classification of tumors, therapy monitoring, sentinel lymph node procedures, and image-guided cancer surgery. Widespread availability of imaging systems and optical contrast agents will enable larger studies on their clinical benefit and can help establish a definitive role in clinical practice.     

Rational Use of Protein Supplements in the Elderly—Relevance of Gastrointestinal Mechanisms

Protein supplements are increasingly used by older people to maintain nutrition and prevent or treat loss of muscle function. Daily protein requirements in older people are in the range of 1.2 gm/kg/day or higher. Many older adults do not consume this much protein and are likely to benefit from higher consumption. Protein supplements are probably best taken twice daily, if possible soon after exercise, in doses that achieve protein intakes of 30 gm or more per episode. It is probably not important to give these supplements between meals, as we have shown no suppressive effects of 30 gm whey drinks, and little if any suppression of 70 gm given to older subjects at varying time intervals from meals. Many gastrointestinal mechanisms controlling food intake change with age, but their contributions to changes in responses to protein are not yet well understood. There may be benefits in giving the supplement with rather than between meals, to achieve protein intakes above the effective anabolic threshold with lower supplement doses, and have favourable effects on food-induced blood glucose increases in older people with, or at risk of developing, type 2 diabetes mellitus; combined protein and glucose drinks lower blood glucose compared with glucose alone in older people.     

Preoperative Nutrition Status and Postoperative Outcome in Elderly General Surgery Patients

Background: Poor nutrition status is considered a risk factor for postoperative complications in the adult population. In elderly patients, who often have a poor nutrition status, this relationship has not been substantiated. Thus, the aim of this systematic review was to assess the merit of preoperative nutrition parameters used to predict postoperative outcome in elderly patients undergoing general surgery. Methods: A systematic literature search of 10 consecutive years, 1998–2008, in PubMed, EMBASE, and Cochrane databases was performed. Search terms used were nutrition status, preoperative assessment, postoperative outcome, and surgery (hip or general), including their synonyms and MeSH terms. Limits used in the search were human studies, published in English, and age (65 years or older). Articles were screened using inclusion and exclusion criteria. All selected articles were checked on methodology and graded. Results: Of 463 articles found, 15 were included. They showed profound heterogeneity in the parameters used for preoperative nutrition status and postoperative outcome. The only significant preoperative predictors of postoperative outcome in elderly general surgery patients were serum albumin and ≥10% weight loss in the previous 6 months. Conclusions: This systematic review revealed only 2 preoperative parameters to predict postoperative outcome in elderly general surgery patients: weight loss and serum albumin. Both are open to discussion in their use as a preoperative nutrition parameter. Nonetheless, serum albumin seems a reliable preoperative parameter to identify a patient at risk for nutrition deterioration and related complicated postoperative course.     

Mendelian randomization analysis of case-control data using structural mean models

'Instrumental Variable' (IV) methods provide a basis for estimating an exposure's causal effect on the risk of disease. In Mendelian randomization studies, where genetic information plays the role of the IV, IV analyses are routinely performed on case-control data, rather than prospectively collected observational data. Although it is a well-appreciated fact that ascertainment bias may invalidate such analyses, ad hoc assumptions and approximations are made to justify their use. In this paper we attempt to explain and clarify why they may fail and show how they can be adjusted for improved performance. In particular, we propose consistent estimators of the causal relative risk and odds ratio if a priori knowledge is available regarding either the population disease prevalence or the population distribution of the IV (e.g. population allele frequencies). We further show that if no such information is available, approximate estimators can be obtained under a rare disease assumption. We illustrate this with matched case-control data from the recently completed EPIC study, from which we attempt to assess the evidence for a causal relationship between C-reactive protein levels and the risk of Coronary Artery Disease.     

A weighting approach to causal effects and additive interaction in case-control studies: marginal structural linear odds models

Estimates of additive interaction from case-control data are often obtained by logistic regression; such models can also be used to adjust for covariates. This approach to estimating additive interaction has come under some criticism because of possible misspecification of the logistic model: If the underlying model is linear, the logistic model will be misspecified. The authors propose an inverse probability of treatment weighting approach to causal effects and additive interaction in case-control studies. Under the assumption of no unmeasured confounding, the approach amounts to fitting a marginal structural linear odds model. The approach allows for the estimation of measures of additive interaction between dichotomous exposures, such as the relative excess risk due to interaction, using case-control data without having to rely on modeling assumptions for the outcome conditional on the exposures and covariates. Rather than using conditional models for the outcome, models are instead specified for the exposures conditional on the covariates. The approach is illustrated by assessing additive interaction between genetic and environmental factors using data from a case-control study.     

Influence of matching for exposure time on estimates of attributable mortality caused by nosocomial bacteremia in critically ill patients.

OBJECTIVE: To evaluate the influence of matching on exposure time on estimates of attributable mortality of nosocomial bacteremia as assessed by matched cohort studies. DESIGN: Two retrospective, pairwise-matched (1:2) cohort studies. SETTING: A 54-bed intensive care unit (ICU) in a university hospital. PATIENTS: Patients with nosocomial Escherichia coli bacteremia (n = 68) and control-patients without nosocomial bacteremia (n = 136 for each matched cohort study). INTERVENTION: In both matched cohort studies, the same set of bacteremic patients was matched with control-patients using the APACHE II system. In the first study, control-patients were required to have an ICU stay at least as long as the respective bacteremic patient prior to onset of bacteremia (matching on exposure time). In the second study, control-patients were required to have an ICU stay shorter than the stay prior to the development of bacteremia in the respective bacteremic patient (no matching on exposure time). RESULTS: For bacteremic patients, the mean ICU stay before onset of the bacteremia was 9 days (median, 6 days). In the first matched cohort study, hospital mortality was not different between bacteremic patients and control-patients (44.1% vs 43.4%; P = .999). In the second study, mortality of bacteremic patients and control-patients was also not different (44.1% vs 47.8%; P = .657). Mortality rates between control groups were not different (43.4% vs 47.8%; P = .543). CONCLUSION: Matching or not matching on exposure time did not alter the estimate of attributable mortality for ICU patients with E. coli bacteremia.     

Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer: A prospective pilot study

Background: Clearance of viable tumour cells in mediastinal lymph nodes (MLN) by induction chemotherapy (IC) – so-called MLN downstaging – is an important aspect of combined-modality treatment of N2-NSCLC. Reassessment of MLN after IC by CT is far from accurate, while re-mediastinoscopy is often technically difficult. Based on our previous results with FDG-PET in the initial staging of N2 disease, we investigated whether PET after IC could be helpful in predicting MLN downstaging and therapeutic outcome.Patients and methods: Patients underwent a first PET before IC. After three cycles of platinum-based IC, a second PET was performed before locoregional therapy, either surgery or radiotherapy. PET results were correlated with pathology of the MLN when available, and with survival.Results: Fifteen surgically staged N2-NSCLC patients were prospectively included. Locoregional therapy after IC consisted of surgery in nine and radiotherapy in six. Correlation with pathology of the nine resection specimens revealed that the accuracy of PET in predicting MLN downstaging was 100% (six true negatives; three true positives), whereas for CT it was only 67% (two false pos; one false neg). Reassessment with PET after IC was correlated with the outcome after the entire combined modality treatment. Survival was significantly better in patients with mediastinal clearance (P = 0.01) or with a greater than 50% decrease in the Standardised Uptake Value (SUV) of the primary tumour (P = 0.03) after IC.Conclusions: Mediastinal PET after IC accurately assesses pathologic MLN downstaging in N2-NSCLC. The data suggest a possible correlation of early survival with mediastinal clearance and an important decrease of SUV in the primary tumour. Confirmation of these preliminary findings would establish PET as a useful non-invasive tool to select patients for intensive locoregional treatment after IC.     

A re-evaluation of k0 and related nuclear data for the 555.8 keV gamma-line emitted by the Rh-Rh mother–daughter pair for use in NAA

A re-evaluation is made of the k₀-factor and related nuclear data for the 555.8 keV gamma-ray of the ^104mRh-¹⁰⁴Rh mother–daughter pair that are important in neutron activation analysis (NAA). This study considers that the relevant level is also fed by the 4.34 min ^104mRh mother (with an absolute gamma-ray emission probability γ₂=0.13%) and not only, as assumed in former work, by the 42.3 s ¹⁰⁴Rh daughter isotope (with γ₃=2.0%). In view of this, generalised equations were developed for both the experimental determination and the analytical use of the k₀-factor and of the associated parameters k₀(m)/k₀(g), Q₀(m) and Q₀(g) [(m):^104mRh; (g): ¹⁰⁴Rh], requiring the introduction of the γ₂ and γ₃ data and also of the ^104mRh→¹⁰⁴Rh fractional decay factor F₂(=0.9987). The experimental determinations were based on irradiations performed in the BR1 reactor in Mol and the WWR-M reactor in Budapest. Furthermore, considering the special formation of the 555.8 keV gamma-ray, the procedure for true-coincidence correction was revised as well. All this led to the compilation and recommendation of a new set of ‘k₀-NAA’ data.