Likelihood for generally coarsened observations from multi-state or counting process models

We consider first the mixed discrete-continuous scheme of observation in multistate models; this is a classical pattern in epidemiology because very often clinical status is assessed at discrete visit times while times of death or other events are observed exactly. A heuristic likelihood can be written for such models, at least for Markov models; however, a formal proof is not easy and has not been given yet. We present a general class of possibly non-Markov multistate models which can be represented naturally as multivariate counting processes. We give a rigorous derivation of the likelihood based on applying Jacod's formula for the full likelihood and taking conditional expectation for the observed likelihood. A local description of the likelihood allows us to extend the result to a more general coarsening observation scheme proposed by Commenges & G\'egout-Petit. The approach is illustrated by considering models for dementia, institutionalization and death

The impact of population-based faecal occult blood test screening on colorectal cancer mortality:a matched cohort study

BACKGROUND: Randomised trials show reduced colorectal cancer (CRC) mortality with faecal occult blood testing (FOBT). This outcome is now examined in a routine, population-based, screening programme. METHODS: Three biennial rounds of the UK CRC screening pilot were completed in Scotland (2000–2007) before the roll out of a national programme. All residents (50–69 years) in the three pilot Health Boards were invited for screening. They received a FOBT test by post to complete at home and return for analysis. Positive tests were followed up with colonoscopy. Controls, selected from non-pilot Health Boards, were matched by age, gender, and deprivation and assigned the invitation date of matched invitee. Follow-up was from invitation date to 31 December 2009 or date of death if earlier. RESULTS: There were 379 655 people in each group (median age 55.6 years, 51.6% male). Participation was 60.6%. There were 961 (0.25%) CRC deaths in invitees, 1056 (0.28%) in controls, rate ratio (RR) 0.90 (95% confidence interval (CI) 0.83–0.99) overall and 0.73 (95% CI 0.65–0.82) for participants. Non-participants had increased CRC mortality compared with controls, RR 1.21 (95% CI 1.06–1.38). CONCLUSION: There was a 10% relative reduction in CRC mortality in a routine screening programme, rising to 27% in participants

Inconsistency of the MLE for the joint distribution of interval censored survival times and continuous marks

This paper considers the nonparametric maximum likelihood estimator (MLE) for the joint distribution function of an interval censored survival time and a continuous mark variable. We provide a new explicit formula for the MLE in this problem. We use this formula and the mark specific cumulative hazard function of Huang and Louis (1998) to obtain the almost sure limit of the MLE. This result leads to necessary and sufficient conditions for consistency of the MLE which imply that the MLE is inconsistent in general. We show that the inconsistency can be repaired by discretizing the marks. Our theoretical results are supported by simulations.Comment: 27 pages, 4 figure

Survival Analysis of Patients with Heart Failure: Implications of Time-Varying Regression Effects in Modeling Mortality

Background: Several models have been designed to predict survival of patients with heart failure. These, while available and widely used for both stratifying and deciding upon different treatment options on the individual level, have several limitations. Specifically, some clinical variables that may influence prognosis may have an influence that change over time. Statistical models that include such characteristic may help in evaluating prognosis. The aim of the present study was to analyze and quantify the impact of modeling heart failure survival allowing for covariates with time-varying effects known to be independent predictors of overall mortality in this clinical setting. Methodology: Survival data from an inception cohort of five hundred patients diagnosed with heart failure functional class III and IV between 2002 and 2004 and followed-up to 2006 were analyzed by using the proportional hazards Cox model and variations of the Cox's model and also of the Aalen's additive model. Principal Findings: One-hundred and eighty eight (188) patients died during follow-up. For patients under study, age, serum sodium, hemoglobin, serum creatinine, and left ventricular ejection fraction were significantly associated with mortality. Evidence of time-varying effect was suggested for the last three. Both high hemoglobin and high LV ejection fraction were associated with a reduced risk of dying with a stronger initial effect. High creatinine, associated with an increased risk of dying, also presented an initial stronger effect. The impact of age and sodium were constant over time. Conclusions: The current study points to the importance of evaluating covariates with time-varying effects in heart failure models. The analysis performed suggests that variations of Cox and Aalen models constitute a valuable tool for identifying these variables. The implementation of covariates with time-varying effects into heart failure prognostication models may reduce bias and increase the specificity of such models.CNPq Brazilian Foundation for Scientific and Technological DevelopmentCNPq - Brazilian Foundation for Scientific and Technological Development [150653/2008-5

More breast cancer genes?

A new gene associated with a high risk of breast cancer, termed BRCAX, may exist on chromosome 13q. Tumours from multicase Nordic breast cancer families, in which mutations in BRCA1 and BRCA2 had been excluded, were analyzed using comparative genomic hybridization in order to identify a region of interest, which was apparently confirmed and refined using linkage analysis on an independent sample. The present commentary discusses this work. It also asks why there should exist genetic variants associated with susceptibility to breast cancer other than mutations in BRCA1 and BRCA2, and what might be their modes of inheritance, allele frequencies and risks. Replication studies will be needed to clarify whether there really is a tumour suppressor gene other than BRCA2 on chromosome 13q

An exploratory randomised controlled trial of a premises-level intervention to reduce alcohol-related harm including violence in the United Kingdom

<b>Background</b><p></p> To assess the feasibility of a randomised controlled trial of a licensed premises intervention to reduce severe intoxication and disorder; to establish effect sizes and identify appropriate approaches to the development and maintenance of a rigorous research design and intervention implementation.<p></p> <b>Methods</b><p></p> An exploratory two-armed parallel randomised controlled trial with a nested process evaluation. An audit of risk factors and a tailored action plan for high risk premises, with three month follow up audit and feedback. Thirty-two premises that had experienced at least one assault in the year prior to the intervention were recruited, match paired and randomly allocated to control or intervention group. Police violence data and data from a street survey of study premises’ customers, including measures of breath alcohol concentration and surveyor rated customer intoxication, were used to assess effect sizes for a future definitive trial. A nested process evaluation explored implementation barriers and the fidelity of the intervention with key stakeholders and senior staff in intervention premises using semi-structured interviews.<p></p> <b>Results</b><p></p> The process evaluation indicated implementation barriers and low fidelity, with a reluctance to implement the intervention and to submit to a formal risk audit. Power calculations suggest the intervention effect on violence and subjective intoxication would be raised to significance with a study size of 517 premises.<p></p> <b>Conclusions</b><p></p> It is methodologically feasible to conduct randomised controlled trials where licensed premises are the unit of allocation. However, lack of enthusiasm in senior premises staff indicates the need for intervention enforcement, rather than voluntary agreements, and on-going strategies to promote sustainability

Multiple primary tumours: incidence estimation in the presence of competing risks

<p>Abstract</p> <p>Background</p> <p>Estimating the risk of developing subsequent primary tumours in a population is difficult since the occurrence probability is conditioned to the survival probability.</p> <p>Methods</p> <p>We proposed to apply Markov models studying the transition intensities from first to second tumour with the Aalen-Johansen (AJ) estimators, as usually done in competing risk models. In a simulation study we applied the proposed method in different settings with constant or varying underlying intensities and applying age standardisation. In addition, we illustrated the method with data on breast cancer from the Piedmont Cancer Registry.</p> <p>Results</p> <p>The simulation study showed that the person-years approach led to a sensibly wider bias than the AJ estimators. The largest bias was observed assuming constantly increasing incidence rates. However, this situation is rather uncommon dealing with subsequent tumours incidence. In 9233 cases with breast cancer occurred in women resident in Turin, Italy, between 1985 and 1998 we observed a significant increased risk of 1.91 for subsequent cancer of corpus uteri, estimated with the age-standardised Aalen-Johansen incidence ratio (AJ-IR^stand), and a significant increased risk of 1.29 for cancer possibly related to the radiotherapy of breast cancer. The peak of occurrence of those cancers was observed after 8 years of follow-up.</p> <p>Conclusion</p> <p>The increased risk of a cancer of the corpus uteri, also observed in other studies, is usually interpreted as the common shared risk factors such as low parity, early menarche and late onset of menopause. We also grouped together those cancers possibly associated to a previous local radiotherapy: the cumulative risk at 14 years is still not significant, however the AJ estimators showed a significant risk peak between the eighth and the ninth year. Finally, the proposed approach has been shown to be reliable and informative under several aspects. It allowed for a correct estimation of the risk, and for investigating the time trend of the subsequent cancer occurrence.</p

Evaluation of energy and dietary intake estimates from a food frequency questionnaire using independent energy expenditure measurement and weighed food records

<p>Abstract</p> <p>Background</p> <p>We have developed a food frequency questionnaire (FFQ) for the assessment of habitual diet, with special focus on the intake of fruit, vegetables and other antioxidant-rich foods and beverages. The aim of the present study was to evaluate the relative validity of the intakes of energy, food and nutrients from the FFQ.</p> <p>Methods</p> <p>Energy intake was evaluated against independent measures of energy expenditure using the ActiReg^®system (motion detection), whereas 7-days weighed food records were used to study the relative validity of food and nutrient intake. The relationship between methods was investigated using correlation analyses and cross-classification of participants. The visual agreement between the methods was evaluated using Bland-Altman plots.</p> <p>Results</p> <p>We observed that the FFQ underestimated the energy intake by approximately 11% compared to the energy expenditure measured by the ActiReg^®. The correlation coefficient between energy intake and energy expenditure was 0.54 and 32% of the participants were defined as under-reporters. Compared to the weighed food records the percentages of energy from fat and added sugar from the FFQ were underestimated, whereas the percentage of energy from total carbohydrates and protein were slightly overestimated. The intake of foods rich in antioxidants did not vary significantly between the FFQ and weighed food records, with the exceptions of berries, coffee, tea and vegetables which were overestimated. Spearman's Rank Order Correlations between FFQ and weighed food records were 0.41 for berries, 0.58 for chocolate, 0.78 for coffee, 0.61 for fruit, 0.57 for fruit and berry juices, 0.40 for nuts, 0.74 for tea, 0.38 for vegetables and 0.70 for the intake of wine.</p> <p>Conclusions</p> <p>Our new FFQ provides a good estimate of the average energy intake and it obtains valid data on average intake of most antioxidant-rich foods and beverages. Our study also showed that the FFQs ability to rank participants according to intake of total antioxidants and most of the antioxidant-rich foods was good.</p