Integrating Latent Classes in the Bayesian Shared Parameter Joint Model of Longitudinal and Survival Outcomes

Cystic fibrosis is a chronic lung disease which requires frequent patient monitoring to maintain lung function over time and minimize onset of acute respiratory events known as pulmonary exacerbations. From the clinical point of view it is important to characterize the association between key biomarkers such as $FEV_1$ and time-to first exacerbation. Progression of the disease is heterogeneous, yielding different sub-groups in the population exhibiting distinct longitudinal profiles. It is desirable to categorize these unobserved sub-groups (latent classes) according to their distinctive trajectories. Accounting for these latent classes, in other words heterogeneity, will lead to improved estimates of association arising from the joint longitudinal-survival model. The joint model of longitudinal and survival data constitutes a popular framework to analyze such data arising from heterogeneous cohorts. In particular, two paradigms within this framework are the shared parameter joint models and the joint latent class models. The former paradigm allows one to quantify the strength of the association between the longitudinal and survival outcomes but does not allow for latent sub-populations. The latter paradigm explicitly postulates the existence of sub-populations but does not directly quantify the strength of the association. We propose to integrate latent classes in the shared parameter joint model in a fully Bayesian approach, which allows us to investigate the association between $FEV_1$ and time-to first exacerbation within each latent class. We, furthermore, focus on the selection of the optimal number of latent classes

Integrating latent classes in the Bayesian shared parameter joint model of longitudinal and survival outcomes

Cystic fibrosis is a chronic lung disease requiring frequent lung-function monitoring to track acute respiratory events (pulmonary exacerbations). The association between lung-function trajectory and time-to-first exacerbation can be characterized using joint longitudinal-survival modeling. Joint models specified through the shared parameter framework quantify the strength of association between such outcomes but do not incorporate latent sub-populations reflective of heterogeneous disease progression. Conversely, latent class joint models explicitly postulate the existence of sub-populations but do not directly quantify the strength of association. Furthermore, choosing the optimal number of classes using established metrics like deviance information criterion is computationally intensive in complex models. To overcome these limitations, we integrate latent classes in the shared parameter joint model through a fully Bayesian approach. To choose the optimal number of classes, we construct a mixture model assuming more latent classes than present in the data, thereby asymptotically “emptying” superfluous latent classes, provided the Dirichlet prior on class proportions is sufficiently uninformative. Model properties are evaluated in simulation studies. Application to data from the US Cystic Fibrosis Registry supports the existence of three sub-populations corresponding to lung-function trajectories with high initial forced expiratory volume in 1 s (FEV1), rapid FEV1 decline, and low but steady FEV1 progression. The association between FEV1 and hazard of exacerbation was negative in each class, but magnitude varied

Prevalence of permanent neonatal hearing impairment: systematic review and Bayesian meta-analysis

Objective: To investigate the variance in reported prevalence rates of permanent neonatal hearing impairment (HI) worldwide. Design: A systematic review and meta-analysis was performed on reported prevalence rates of sensorineural and permanent conductive or mixed HI worse than 40 dB in neonates, detected as a result of a screening programme or audiometric study. Study sample: For meta-analysis, 35 articles were selected, 25 from high-income countries and 10 from middle-income countries according to the world bank classification system. Results: The prevalence rate of permanent uni- and bilateral HI worse than 40 dB in neonates varied from 1 to 6 per 1000, the overall prevalence was 2.21 per 1000 [1.71, 2.8]. In NICU populations the prevalence rate was higher with a larger fraction of bilateral cases. Although not significant, prevalence rates were slightly higher in Asia compared to Europe and the number of infants lost to follow-up appeared higher in countries with lower gross national income. Conclusion: Substantial variations exist in prevalence rates of neonatal permanent HI across countries and regions. There is a strong need for more data from low-income countries to identify demographic factors that account for this variability in reported prevalence rates. Reporting these data in a uniform way is advocated

Development of a local dose-response relationship for osteoradionecrosis within the mandible

Purpose: Osteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy of the head and neck, but not all regions of the mandible may be equally at risk. Therefore our goal was to explore a local dose response relationship for subregions of the mandible. Materials and methods: All oropharyngeal cancer patients treated at our hospital between 2009 and 2016 were reviewed. Follow-up was cut-off at 3 years. For patients that developed ORN, the ORN volume was delineated on the planning CT. Each mandible was divided into 16 volumes of interest (VOIs) based on the location of the dental elements and the presence of ORN in each was scored. Generalized estimating equations were used to build a model for the probability of developing ORN in an element VOI. Results: Of the 219 included patients, 22 developed ORN in 89 element VOIs. Mean dose to the element VOI (odds ratio (OR) = 1.05 per Gy, 95% confidence interval (CI): (1.04,1.07)), pre-radiotherapy extractions of an element ipsilateral to element of interest (OR = 2.81, 95% CI: (1.12,7.05)), and smoking at start of radiotherapy (OR = 3.37, 95% CI: (1.29,8.78)) were significantly associated with an increased probability of ORN in the VOI. Conclusion: The developed dose-response model indicates that the probability of ORN varies within the mandible and strongly depends on the local dose, the location of extractions, and smoking.</p

Diagnosis of bronchiectasis and airway wall thickening in children with cystic fibrosis: Objective airway-artery quantification

Objectives: To quantify airway and artery (AA)-dimensions in cystic fibrosis (CF) and control patients for objective CT diagnosis of bronchiectasis and airway wall thickness (AWT). Methods: Spirometer-guided inspiratory and expiratory CTs of 11 CF and 12 control patients were collected retrospectively. Airway pathways were annotated semi-automatically to reconstruct three-dimensional bronchial trees. All visible AA-pairs were measured perpendicular to the airway axis. Inner, outer and AWT (outer−inner) diameter were divided by the adjacent artery diameter to compute AinA-, AoutA- and AWTA-ratios. AA-ratios were predicted using mixed-effects models including disease status, lung volume, gender, height and age as covariates. Results: Demographics did not differ significantly between cohorts. Mean AA-pairs CF: 299 inspiratory; 82 expiratory. Controls: 131 inspiratory; 58 expiratory. All ratios were significantly larger in inspiratory compared to expiratory CTs for both groups (p<0.001). AoutA- and AWTA-ratios were larger in CF than in controls, independent of lung volume (p<0.01). Difference of AoutA- and AWTA-ratios between patients with CF and controls increased significantly for every following airway generation (p<0.001). Conclusion: Diagnosis of bronchiectasis is highly dependent on lung volume and more reliably diagnosed using outer airway diameter. Difference in bronchiectasis and AWT severity between the two cohorts increased with each airway generation. Key points: • More peripheral airways are visible in CF patients compared to controls.• Structural lung changes in CF patients are greater with each airway generation.• Number of airways visualized on CT could quantify CF lung disease.• For objective airway disease quantification on CT, lung volume standardization is required

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin:a systematic review and meta-analysis

Background: Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy. Methods: Embase, MEDLINE, Web of Science and Cochrane were searched for articles studying the use of repeated administration of palliative intraperitoneal chemotherapy in patients with gastric cancer and peritoneal metastases, published up to January 2024. The primary outcome was overall survival. Results: Twenty-three studies were included, representing a total of 999 patients. The pooled median overall survival was 14.5 months. The pooled hazard ratio of the two RCTs using intraperitoneal paclitaxel and docetaxel favoured the intraperitoneal chemotherapy arm. The median overall survival of intraperitoneal paclitaxel, intraperitoneal docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.4 months, 13.2 months and 9.0 months. All treatment methods had a relatively safe toxicity profile. Conversion surgery after completion of intraperitoneal therapy was performed in 16% of the patients.Conclusions: Repeated intraperitoneal chemotherapy, regardless of method of administration, is safe for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a subset of patients.</p

Predicting hemoglobin levels in whole blood donors using transition models and mixed effects models

Background: To optimize the planning of blood donations but also to continue motivating the volunteers it is important to streamline the practical organization of the timing of donations. While donors are asked to return for donation after a suitable period, still a relevant proportion of blood donors is deferred from donation each year due to a too low hemoglobin level. Rejection of donation may demotivate the candidate donor and implies an inefficient planning of the donation process. Hence, it is important to predict the future hemoglobin level to improve the planning of donors' visits to the blood bank. Methods. The development of the hemoglobin prediction rule is based on longitudinal (panel) data from blood donations collected by Sanquin (the only blood product collecting and supplying organization in the Netherlands). We explored and contrasted two popular statistical models, i.e. the transition (autoregressive) model and the mixed effects model as plausible models to account for the dependence among subsequent hemoglobin levels within a donor. Results: The predictors of the future hemoglobin level are age, season, hemoglobin levels at the previous visits, and a binary variable indicating whether a donation was made at the previous visit. Based on cross-validation, the areas under the receiver operating characteristic curve (AUCs) for male donors are 0.83 and 0.81 for the transition model and the mixed effects model, respectively; for female donors we obtained AUC values of 0.73 and 0.72 for the transition model and the mixed effects model, respectively. Conclusion: We showed that the transition models and the mixed effects models provide a much better prediction compared to a multiple linear regression model. In general, the transition model provides a somewhat better prediction than the mixed effects model, especially at high visit numbers. In addition, the transition model offers a better trade-off between sensitivity and specificity when varying the cut-off values for eligibility in predicted values. Hence transition models make the prediction of hemoglobin level more precise and may lead to less deferral from donation in the future

Protocol description of the HOVON 141/VISION trial: a prospective, multicentre, randomised phase II trial of ibrutinib plus venetoclax in patients with creatinine clearance >= 30 mL/min who have relapsed or refractory chronic lymphocytic leukaemia (RR-CLL) with or without TP53 aberrations

Introduction Literature is scarce on the combination treatment of ibrutinib and venetoclax (IV) is scarce in relapsed or refractory chronic lymphocytic leukaemia (RR-CLL). Especially, the possibility of stopping ibrutinib in RR-CLL patients in deep remission is unclear.Methods and analysis In the HOVON 141/VISION trial, patients with RR-CLL are treated with 12 cycles of IV after a short induction with ibrutinib. Patients reaching undetectable minimal residual disease (uMRD) after 12 cycles of IV are randomised 1:2 to continue ibrutinib or stop treatment. The persistence of uMRD after stopping IV is studied. In addition, in patients who become positive for MRD again after stopping, IV treatment is reinitiated. The efficacy of this approach with regard to progression-free survival 12 months after randomisation is the primary endpoint of the study.Ethics and dissemination This protocol respects the Helsinki declaration and has been approved by the ethical committee of the Amsterdam Medical Center. Study findings will be disseminated through peer-reviewed papers. All patients who fulfil the inclusion criteria and no-exclusion criteria, and have signed the informed consent form are included in the study.</div