Statistical controversies in clinical research: futility analyses in oncology-lessons on potential pitfalls from a randomized controlled trial.

BACKGROUND: Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses. MATERIALS AND METHODS: LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS. RESULTS: At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis. CONCLUSIONS: Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate. TRIAL NUMBER: NCT00806819.

Combined dynamic predictions using joint models of two longitudinal outcomes and competing risk data.

Nowadays there is an increased medical interest in personalized medicine and tailoring decision making to the needs of individual patients. Within this context our developments are motivated from a Dutch study at the Cardio-Thoracic Surgery Department of the Erasmus Medical Center, consisting of patients who received a human tissue valve in aortic position and who were thereafter monitored echocardiographically. Our aim is to utilize the available follow-up measurements of the current patients to produce dynamically updated predictions of both survival and freedom from re-intervention for future patients. In this paper, we propose to jointly model multiple longitudinal measurements combined with competing risk survival outcomes and derive the dynamically updated cumulative incidence functions. Moreover, we investigate whether different features of the longitudinal processes would change significantly the prediction for the events of interest by considering different types of association structures, such as time-dependent trajectory slopes and time-dependent cumulative effects. Our final contribution focuses on optimizing the quality of the derived predictions. In particular, instead of choosing one final model over a list of candidate models which ignores model uncertainty, we propose to suitably combine predictions from all considered models using Bayesian model averaging.

A steep ramp test is valid for estimating maximal power and oxygen uptake during a standard ramp test in type 2 diabetes.

A short maximal steep ramp test (SRT, 25 W/10 s) has been proposed to guide exercise interventions in type 2 diabetes, but requires validation. This study aims to (a) determine the relationship between Wmax and V˙O2peak reached during SRT and the standard ramp test (RT); (b) obtain test-retest reliability; and (c) document electrocardiogram (ECG) abnormalities during SRT. Type 2 diabetes patients (35 men, 26 women) performed a cycle ergometer-based RT (women 1.2; men 1.8 W/6 s) and SRT on separate days. A random subgroup (n = 42) repeated the SRT. ECG, heart rate, and V˙O2 were monitored. Wmax during RT: 193 ± 63 (men) and 106 ± 33 W (women). Wmax during SRT: 193 ± 63 (men) and 188 ± 55 W (women). The relationship between RT and SRT was described by men RT V˙O2peak (mL/min) = 152 + 7.67 × Wmax SRT1 (r: 0.859); women RT V ˙ O 2 p e a k (mL/min) = 603 + 4.75 × Wmax SRT1 (r: 0.771); intraclass correlation coefficients between first (SRT1) and second SRT Wmax (SRT2) were men 0.951 [95% confidence interval (CI) 0.899-0.977] and women 0.908 (95% CI 0.727-0.971). No adverse events were noted during any of the exercise tests. This validation study indicates that the SRT is a low-risk, accurate, and reliable test to estimate maximal aerobic capacity during the RT to design exercise interventions in type 2 diabetes patients.

Is tightly controlled disease activity possible with online patient-reported outcomes?

OBJECTIVE: To evaluate the performance of patient-reported outcomes (PRO) as primary indices for identification and prediction of a 28-joint Disease Activity Score (DAS28)>3.2 among patients with rheumatoid arthritis (RA). METHODS: Patients with RA completed monthly online PRO [Health Assessment Questionnaire (HAQ), Rheumatoid Arthritis Disease Activity Index (RADAI), visual analog scale (VAS) fatigue] and were clinically assessed every 3 months using the DAS28. Simple descriptive statistics, logistic regression, and the Bayesian joint modeling approach were used to analyze the data. The Bayesian joint model combines the scores and changes in the scores of 3 PRO to predict a DAS28>3.2 at the subsequent timepoint. RESULTS: A group of 159 patients with RA participated. Stratified summaries of the PRO by DAS28 categories at baseline provided incremental values of the PRO for more active disease. However, on an individual level, the DAS28 and the PRO fluctuated over time. The prediction of subsequent DAS score by a single instrument at single timepoints resulted in moderate sensitivity and specificity. Using the intercept and slope of the combined PRO of the first 3 measurements to predict the DAS28 state at 3 months resulted in a sensitivity of 0.81 and a specificity of 0.92. After 10-fold cross validation, the model had a sensitivity of 0.61 and specificity of 0.75 to identify patients with a DAS28>3.2. CONCLUSION: PRO showed fluctuating levels of disease activity over time, while on a group level disease activity stayed the same. Using the changes in RADAI, HAQ, and VAS fatigue over time to predict future DAS28>3.2 resulted in moderate performance after the internal cross-validation of the model (sensitivity 0.61, specificity 0.75).

Bayesian meta-analysis of diagnostic tests allowing for imperfect reference standards.

There is an increasing interest in meta-analyses of rapid diagnostic tests (RDTs) for infectious diseases. To avoid spectrum bias, these meta-analyses should focus on phase IV studies performed in the target population. For many infectious diseases, these target populations attend primary health care centers in resource-constrained settings where it is difficult to perform gold standard diagnostic tests. As a consequence, phase IV diagnostic studies often use imperfect reference standards, which may result in biased meta-analyses of the diagnostic accuracy of novel RDTs. We extend the standard bivariate model for the meta-analysis of diagnostic studies to correct for differing and imperfect reference standards in the primary studies and to accommodate data from studies that try to overcome the absence of a true gold standard through the use of latent class analysis. Using Bayesian methods, improved estimates of sensitivity and specificity are possible, especially when prior information is available on the diagnostic accuracy of the reference test. In this analysis, the deviance information criterion can be used to detect conflicts between the prior information and observed data. When applying the model to a dataset of the diagnostic accuracy of an RDT for visceral leishmaniasis, the standard meta-analytic methods appeared to underestimate the specificity of the RDT.

The history of Belgian assisted reproduction technology cycle registration and control: a case study in reducing the incidence of multiple pregnancy.

STUDY QUESTION: What is the effect of a legal limitation of the number of embryos that can be transferred in an assisted reproductive technology (ART) cycle on the multiple delivery rate? SUMMARY ANSWER: The Belgian national register shows that the introduction of reimbursement of ART laboratory costs in July 2003, and the imposition of a legal limitation of the number of embryos transferred in the same year, were associated with a >50% reduction of the multiple pregnancy rate from 27 to 11% between 2003 and the last assessment in 2010, without any reduction of the pregnancy rate per cycle. WHAT IS KNOWN ALREADY: Individual Belgian IVF centres have published their results since the implementation of the law, and these show a decrease in the multiple pregnancy rate on a centre by centre basis. However, the overall national picture remains unpublished. STUDY DESIGN, SIZE, DURATION: Cohort study from 1990 to 2010 of all ART cycles in Belgium (2685 cycles in 1990 evolving to 19 110 cycles in 2010), with a retrospective analysis from 1990 to 2000 and prospective online data collection since 2001. PARTICIPANTS/MATERIALS, SETTING, METHODS: Registration evolved from paper written reports per centre to a compulsory online registration of all ART cycles. From 2001 up to mid-2009, data were collected from Excel spread sheets or MS Access files into an MS Access database. Since mid-2009, data collection is done via a remote and secured web-based system (www.belrap.be) where centres can upload their data and get immediate feedback about missing data, errors and inconsistencies. MAIN RESULTS AND THE ROLE OF CHANCE: National Belgian registration data show that reimbursement of IVF laboratory costs in July 2003, coupled to a legal limitation in the number of embryos transferred in utero, were associated with a 50% reduction of the multiple pregnancy rate from 27 to 11% without reduction of the pregnancy rate per cycle, and with an increase in the number of fresh and frozen ART cycles due to improved access to treatment. LIMITATIONS, REASONS FOR CAUTION: There is potential underreporting of complications of ART treatment, pregnancy outcome and neonatal health. WIDER IMPLICATIONS OF THE FINDINGS: Over the 20 years of registration, the pregnancy rate has remained constant, despite the reduction in the number of embryos transferred, optimization of laboratory procedures and stimulation protocols, introduction of quality systems and implementation of the EU Tissue Directive over the period 2004-2010. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. None of the authors has any conflict of interest to declare.

Correction for misclassification of caries experience in the absence of internal validation data.

OBJECTIVES: To quantify the effects of risk factors and/or determinants on disease occurrence, it is important that the risk factors as well as the variable that measures the disease outcome are recorded with the least error as possible. When investigating the factors that influence a binary outcome, a logistic regression model is often fitted under the assumption that the data are collected without error. However, most categorical outcomes (e.g., caries experience) are accompanied by misclassification and this needs to be accounted for. The aim of this research was to adjust for binary outcome misclassification using an external validation study when investigating factors influencing caries experience in schoolchildren. MATERIALS AND METHODS: Data from the Signal Tandmobiel(®) study were used. A total of 500 children from the main and 148 from the validation study were included in the analysis. Regression models (with several covariates) for sensitivity and specificity were used to adjust for misclassification in the main data. RESULTS: The use of sensitivity and specificity modeled as functions of several covariates resulted in a better correction compared to using point estimates of sensitivity and specificity. Age, geographical location of the school to which the child belongs, dentition type, tooth type, and surface type were significantly associated with the prevalence of caries experience. CONCLUSIONS: Sensitivity and specificity calculated based on an external validation study may resemble those obtained from an internal study if conditioned on a rich set of covariates. CLINICAL RELEVANCE: Main data can be corrected for misclassification using information obtained from an external validation study when a rich set of covariates is recorded during calibration.

A periconceptional energy-rich dietary pattern is associated with early fetal growth: the Generation R study.

OBJECTIVE: To identify periconceptional maternal dietary patterns associated with crown-rump length (CRL), estimated fetal weight (EFW) and birthweight. DESIGN: Population-based prospective birth cohort study. SETTING: Rotterdam, the Netherlands. PARTICIPANTS: For this study, 847 pregnant Dutch women were eligible. Women were included between 2001 and 2005. METHODS: Information on nutritional intake was collected by a semiquantitative food frequency questionnaire. For extracting dietary patterns, principal component factor analysis was used. Fetal growth was assessed using ultrasound measurements. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used. MAIN OUTCOME MEASURES: Crown-to-rump length, estimated fetal weight in second and third trimester and birthweight. RESULTS: An 'energy-rich dietary pattern' was identified, characterised by high intakes of bread, margarine and nuts. A significant association was shown between a high adherence to this dietary pattern (difference, mm: 2.15, 95% confidence interval 0.79-3.50) and CRL (linear trend analyses P = 0.015). No association was revealed between increasing adherence to this dietary pattern and EFW in second or third trimester, or birthweight. CONCLUSION: This study suggests that increasing adherence to an energy-rich dietary pattern is associated with increased CRL in the first trimester.

Suspected bacterial endophthalmitis following intravitreal anti-VEGF injection: case series and literature review.

AIM: To report an up-to-date overview of all patients reported in the literature with suspected bacterial endophthalmitis following anti-VEGF injection. Secondly, to identify specific symptoms and signs to differentiate between infectious and noninfectious endophthalmitis. METHODS: A Pubmed search retrieved 12 retrospective case series which had included a total of 118 patients with suspected bacterial endophthalmitis after anti-VEGF injection. Data of 15 patients from the Rotterdam Eye Hospital were added. Patients were divided into three groups: those who did not receive intravitreal antibiotics (group A), patients who received intravitreal antibiotics with biopsy-negative cultures (group B) and those with biopsy-positive cultures (group C). RESULTS: The median time between anti-VEGF injection and presentation with suspected bacterial endophthalmitis was 1 day in group A compared to 3 days in groups B and C. At presentation, patients of group A had a better median visual acuity (logMAR 1.0) compared to those in groups B and C (logMAR 2.1 and 2.5, respectively). CONCLUSION: This study suggests that patients presenting with a visual acuity of 20/200 (logMAR 1.0) or less and later than 24 h after injection are more likely to have bacterial endophthalmitis. To prevent undertreatment in these patients, the threshold to proceed to vitreous biopsy and empirical intravitreous antibiotics should be low.

Assessment of caries experience in epidemiological surveys: a review.

OBJECTIVES: To review aspects of methods for assessing caries experience (CE) in epidemiological surveys. METHOD: A search of English language literature published between January 2000 and December 2008 was undertaken using 'epidemiology', 'dental caries' and 'assessment' as search terms. Information on criteria for CE assessment, materials and settings, diagnostic threshold, training of examiners and validation of the screening results was extracted from the reports. RESULTS: Eighty-nine reports met the inclusion criteria. In 9 of the reports (10%) no reference was made to existing standardisation criteria for assessment of CE. Light condition applied (60 reports, 67%) and the use of a probe (60 reports, 67%) were frequently reported. Most reports mentioned that training and calibration of examiners took place, but the outcome of reliability checks were often not presented (48 reports, 54%). Only 28 of the reports (32%) specified that cleaning took place before the examination. Journals with Impact Factor (IF) provided specific information on methods more frequently than journals without. The WHO Basic Methods for Oral Health Surveys were most often applied (52 surveys, 58%). However, deviations from the original description were found especially for measurement and reporting of reliability measurement (24, 46% and 29, 56% respectively), type of probe used (27, 52%) and light condition (16, 31%). All of these hamper the (external) validity of the obtained results. CONCLUSIONS: There is a clear need for improvement of the reporting and application of methods for assessing CE in epidemiological surveys. A check-list of aspects of methods to be included in reports of surveys assessing CE is proposed by the authors.

Bayesian latent variable models for spatially correlated tooth-level binary data in caries research.

Analysis of dental caries is traditionally based on aggregated scores, which are summaries of caries experience for each individual. A well-known example of such scores is the decayed, missing and filled teeth or tooth surfaces index introduced in the 1930s. Although these scores have improved our understanding of the pattern of dental caries, there are still some fundamental questions that remain unanswered. As an example, it is well believed among dentists that there are spatial symmetries in the mouth with respect to caries, but this has never been evaluated in a statistical sense. An answer to this question requires the analysis to be performed at subunits within the mouth, which necessitates the use of methods for correlated data. We propose a Bayesian generalized latent variable model coupled with an undirected graphical model to investigate the unique spatial distribution of tooth-level caries outcomes in the mouth. Data from the Signal Tandmobiel(®) study in Flanders, a dental longitudinal survey, are used to illustrate the methodology.

Correcting for misclassification for a monotone disease process with an application in dental research.

Motivated by a longitudinal oral health study, we evaluate the performance of binary Markov models in which the response variable is subject to an unconstrained misclassification process and follows a monotone or progressive behavior. Theoretical and empirical arguments show that the simple version of the model can be used to estimate the prevalence, incidences, and misclassification parameters without the need of external information and that the incidence estimators associated with the model outperformed approaches previously proposed in the literature. We propose an extension of the simple version of the binary Markov model to describe the relationship between the covariates and the prevalence and incidence allowing for different classifiers. We implemented a Bayesian version of the extended model and show that, under the settings of our motivating example, the parameters can be estimated without any external information. Finally, the analyses of the motivating problem are presented.

An application of Harrell's C-index to PH frailty models.

Frailty models are encountered in many medical applications, yet little research has been devoted to develop measures that quantify the predictive ability of these models. In this paper, we elaborate on the concept of the concordance probability to clustered data, resulting in an 'Overall Conditional C-index' or bfC(O, C) and an 'Overall Marginal C-index' or C(O, M) . Both Overall C-indices can be split up into a 'Between Conditional' or C(B, C) and a 'Between Marginal C-index' or C(B, M) and into a 'Within Conditional' or C(W, C) and a 'Within Marginal C-index' or C(W, M) . For PH frailty models of the power variance family, C(W, C) and C(W, M) are equivalent resulting in one 'Within C-index' C(W) . We propose an application of Harrell's C-index to estimate the proposed indices within a likelihood and a Bayesian context and the performances of their point estimates and confidence/credible intervals are compared in an extensive simulation study. This simulation study shows that the point estimates of C(W) and C(B, M) perform good within both a likelihood and Bayesian context but that the point estimates of C(B, C) show less bias for the Bayesian approach than for the likelihood approach. The 95 per cent confidence/credible intervals also possess good coverage properties, given that the point estimates perform good. The performance of the C-indices is evaluated on a real data set.

Factors that influence data quality in caries experience detection: a multilevel modeling approach.

Caries experience detection is prone to misclassification. For this reason, calibration exercises which aim at assessing and improving the scoring behavior of dental raters are organized. During a calibration exercise, a sample of children is examined by the benchmark scorer and the dental examiners. This produces a 2 × 2 contingency table with the true and possibly misclassified responses. The entries in this misclassification table allow to estimate the sensitivity and the specificity of the raters. However, in many dental studies, the uncertainty with which sensitivity and specificity are estimated is not expressed. Further, caries experience data have a hierarchical structure since the data are recorded for the surfaces nested in the teeth within the mouth. Therefore, it is important to report the uncertainty using confidence intervals and to take the clustering into account. Here we apply a Bayesian logistic multilevel model for estimating the sensitivity and specificity. The main goal of this research is to find the factors that influence the true scoring of caries experience accounting for the hierarchical structure in the data. In our analysis, we show that the dentition type and tooth or surface type affect the quality of caries experience detection.

Establishing the relationship between nurse staffing and hospital mortality using a clustered discrete-time logistic model.

Studies based on aggregated hospital outcome data have established that there is a relationship between nurse staffing and adverse events. However, this result could not be confirmed in Belgium where 96 per cent of the variability of nurse staffing levels over nursing units (belonging to different hospitals) is explained by within-hospital variability. To better appreciate the possible impact of nurse staffing levels on adverse events, we propose a multilevel approach reflecting the complex nature of the data. In particular we suggest a clustered discrete-time logistic model that captures the risks associated with a given unit in the patient's trajectory through the hospital. The model also allows for nurse staffing levels to affect the current and subsequent nursing unit (carry-over effect). In the model 'time' is represented by the sequential number of the nursing unit that the patient is passing through. The model incorporates hospital and nursing unit random effects to express that patients treated in the same hospital and taken care of by nurses of the same unit share a common environment. In this study we used Belgian national administrative databases for the year 2003 to assess the relationship between nurse staffing levels and nurse education variables with in-hospital mortality. The analysis was restricted to elective cardiac surgery patients. Lower nursing unit staffing levels in the general nursing units were associated with high in-hospital mortality in units past the traditional cardiac surgery nursing units.

Measuring oral health behaviour in Flemish health care workers: an application of the theory of planned behaviour.

OBJECTIVE: This study describes the development and validation of a questionnaire to measure the determinants of oral health related behaviour in health care workers, based on the Theory of Planned Behaviour (TPB). RESEARCH DESIGN: A preliminary questionnaire was drafted containing 78 self report items measuring three behaviours related to oral health (i.e. dietary habits, oral hygiene habits and dental attendance), as well as the attitudes, perceived social norms and self-efficacy for each behaviour. The questionnaire was completed by 201 health care workers for the initial validation and 966 other health care workers for a replication. OUTCOMES: A principal component analysis with Procrustes rotation toward an a priori three component structure on the original sample yielded high congruence measures for reported dental attendance, but not for dietary habits and oral hygiene habits. Subsequent exploratory Varimax rotations and discarding of redundant items resulted in three component solutions explaining 43% of the variance in dietary habits, 57% in oral hygiene habits and 66% in dental attendance, respectively. For all three behaviours, these components corresponded to the dimensions of the TPB. Internal consistency of the scales was satisfactory, with Chronbach's alpha's ranging from 0.51 to 0.87. Scale scores accounted for a significant proportion of the variance in the intention to avoid sweet snacks, to brush teeth, and to attend dental check-ups, and of the frequency of consumption of sweet drinks and frequency of brushing. A confirmatory factor analysis on the larger sample of 966 health care workers provided excellent goodness of fit indices, confirming the construct validity of the scales.

Semi-parametric modelling of the distribution of the baseline risk in meta-analysis.

In meta-analysis of clinical trials, often meta-regression analyses are performed to explain the heterogeneity in treatment effects that usually exist between trials. A popular explanatory variable is the risk observed in the control group, the baseline risk. The relationship between the treatment effect and the baseline risk is investigated by fitting a linear model that allows randomness on the true baseline risk by assuming a normal distribution with unknown mean and variance. However, the normality assumption could be too strong to adequately describe the underlying distribution. Therefore, we developed a new semi-parametric method that relaxes the normality assumption to a more flexible and general distribution. We applied a penalized Gaussian mixture distribution to represent the baseline risk distribution. Furthermore, a bivariate hierarchical model is formulated in order to take into account the correlation between the baseline and treatment effect. To fit the proposed model, a penalized likelihood function is maximized by an Expectation Maximization (EM) algorithm. We illustrate our method on a number of simulated data sets and on a published meta-analysis data set.

Caries patterns in primary dentition in 3-, 5- and 7-year-old children: spatial correlation and preventive consequences.

This study aimed to contribute to the descriptive information of oral health status in the primary dentition, especially concerning the distribution and spatial correlation of lesions. Data were obtained from two surveys. In the Signal-Tandmobiel project 4,468 7-year-old children in Flanders (Belgium) were selected by a stratified clustered random sample. In the Tandje de Voorste - Smile for Life (TDV) project, data were obtained from 1,291 3-year-old and 1,315 5-year-old children. The children were examined by trained dentists, using standardized and widely accepted criteria, based on the British Association for the Study of Community Dentistry criteria. At the population level, symmetry in the prevalence of caries experience across the midline was tested at the tooth and tooth surface levels using generalized estimating equations and alternating logistic regression (ALR) approaches. Individual symmetry was tested using an approach described by Hujoel et al. [J Dent Res 1994;73:1575-1580]. Descriptive observations suggested a symmetrical distribution of caries experience at the population level. The null hypothesis of symmetry could not be rejected at a 0.05 level, suggesting that caries experience might be symmetric in the deciduous dentition. Based on the ALR approach, 2 x 2 associations of caries experience at the tooth and surface levels, both in 5- and 7-year-olds, appeared to be strongest for the left-right pairs in the mandible, followed by the left-right pairs in the maxilla. At the individual level the hypothesis of random caries pattern was rejected (p < 0.0001). In conclusion, at the population level the null hypothesis of left-right symmetry could not be rejected, while at the individual level lesions tended to cluster on one side of the mouth.

The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin.

AIMS: Cytokeratin (CK) 7 and CK19 expression, present in hepatic progenitor cells (HPCs) and in cholangiocytes but not in normal hepatocytes, has been reported in some hepatocellular carcinomas (HCCs); however, the incidence and relevance of this expression in HCC in Caucasians is not known. Therefore, our aim was to study the occurrence and clinicopathological characteristics of HCC expressing CK7 and/or CK19 in 109 Caucasian patients. METHODS AND RESULTS: The expression of hepatocellular differentiation markers (Hepar, canalicular polyclonal carcinoembryonic antigen), biliary/progenitor cell markers (CK7, CK19), alpha-fetoprotein (AFP), p53 and beta-catenin in HCC was semiquantitatively assessed by immunohistochemistry. Of 109 HCCs, 78 were CK7-/CK19- (72%), 13 CK7+/CK19- (12%), seven CK7-/CK19+ (6%), 11 CK7+/CK19+ (10%). CK19 expression was significantly associated with elevated serum AFP (400 ng/ml) (P = 0.023), tumour AFP expression (P < 0.0001), presence in serum of anti-hepatitis B core (P = 0.016), less fibrosis in non-neoplastic parenchyma (P = 0.009) and less nuclear beta-catenin expression (P = 0.021). CK7 expression was significantly associated with elevated serum bilirubin (> 2 mg/dl) (P = 0.0005) and less nuclear beta-catenin expression (P = 0.003). HCC expressing CK19 had a higher rate of recurrence (P = 0.009, hazard ratio 12.5, n = 31) after liver transplantation compared with CK19- tumours. CONCLUSIONS: In our series, 28% of HCCs contained cells expressing CK7 and/or CK19. They potentially derive from HPCs. The higher recurrence rate of CK19+ HCC after transplantation suggests a worse prognosis for these HCCs compared with CK19- HCC.

Effect of caries experience in primary molars on cavity formation in the adjacent permanent first molar.

This study sought to address the influence of a sound versus affected first and/or second deciduous molar on the incidence of visible caries experience in the adjacent permanent first molar. Clinical and questionnaire data were obtained from a 6-year prospective oral health screening project in Flanders, Belgium (Signal-Tandmobiel project), where 4,468 children (born in 1989) were examined annually during their primary school time. A multiple survival model allowing for dependent data with possible censoring was applied. The impact of timing of tooth emergence (determining the period at risk), gender, presence of sealants and reported oral hygiene habits was also considered. Cavity formation in permanent first molars was clearly influenced by the status of the adjacent primary molars;the effect of the second deciduous molar was most pronounced. Moreover, if both deciduous molars experienced caries and the child presented with poor oral hygiene, a peak in cavity formation of the permanent first molar 1-2 years after emergence was noticed. On the other hand, if a child presented with good oral hygiene, no peak was observed; caries risk increased slightly over time. No significant benefit from restoring primary molars could be demonstrated, possibly because of methodological limitations.