A methodology to extract outcomes from routine healthcare data for patients with locally advanced non-small cell lung cancer

BACKGROUND: Outcomes for patients in UK with locally advanced non-small cell lung cancer (LA NSCLC) are amongst the worst in Europe. Assessing outcomes is important for analysing the effectiveness of current practice. However, data quality is inconsistent and regular large scale analysis is challenging. This project investigates the use of routine healthcare datasets to determine progression free survival (PFS) and overall survival (OS) of patients treated with primary radical radiotherapy for LA NSCLC. METHODS: All LA NSCLC patients treated with primary radical radiotherapy in a 2 year period were identified and paired manual and routine data generated for an initial pilot study. Manual data was extracted information from hospital records and considered the gold standard. Key time points were date of diagnosis, recurrence, death or last clinical encounter. Routine data was collected from various data sources including, Hospital Episode Statistics, Personal Demographic Service, chemotherapy data, and radiotherapy datasets. Relevant event dates were defined by proxy time points and refined using backdating and time interval optimization. Dataset correlations were then tested on key clinical outcome indicators to establish if routine data could be used as a reliable proxy measure for manual data. RESULTS: Forty-three patients were identified for the pilot study. The manual data showed a median age of 67 years (range 46- 89 years) and all patients had stage IIIA/B disease. Using the manual data, the median PFS was 10.78 months (range 1.58-37.49 months) and median OS was 16.36 months (range 2.69-37.49 months). Based on routine data, using proxy measures, the estimated median PFS was 10.68 months (range 1.61-31.93 months) and estimated median OS was 15.38 months (range 2.14-33.71 months). Overall, the routine data underestimated the PFS and OS of the manual data but there was good correlation with a Pearson correlation coefficient of 0.94 for PFS and 0.97 for OS. CONCLUSIONS: This is a novel approach to use routine datasets to determine outcome indicators in patients with LA NSCLC that will be a surrogate to analysing manual data. The ability to enable efficient and large scale analysis of current lung cancer strategies has a huge potential impact on the healthcare system

The development and validation of prognostic models for overall survival in the presence of missing data in the training dataset: a strategy with a detailed example.

Background The United Kingdom Myeloma Research Alliance (UK-MRA) Myeloma Risk Profile is a prognostic model for overall survival. It was trained and tested on clinical trial data, aiming to improve the stratification of transplant ineligible (TNE) patients with newly diagnosed multiple myeloma. Missing data is a common problem which affects the development and validation of prognostic models, where decisions on how to address missingness have implications on the choice of methodology. Methods Model building The training and test datasets were the TNE pathways from two large randomised multicentre, phase III clinical trials. Potential prognostic factors were identified by expert opinion. Missing data in the training dataset was imputed using multiple imputation by chained equations. Univariate analysis fitted Cox proportional hazards models in each imputed dataset with the estimates combined by Rubin’s rules. Multivariable analysis applied penalised Cox regression models, with a fixed penalty term across the imputed datasets. The estimates from each imputed dataset and bootstrap standard errors were combined by Rubin’s rules to define the prognostic model. Model assessment Calibration was assessed by visualising the observed and predicted probabilities across the imputed datasets. Discrimination was assessed by combining the prognostic separation D-statistic from each imputed dataset by Rubin’s rules. Model validation The D-statistic was applied in a bootstrap internal validation process in the training dataset and an external validation process in the test dataset, where acceptable performance was pre-specified. Development of risk groups Risk groups were defined using the tertiles of the combined prognostic index, obtained by combining the prognostic index from each imputed dataset by Rubin’s rules. Results The training dataset included 1852 patients, 1268 (68.47%) with complete case data. Ten imputed datasets were generated. Five hundred twenty patients were included in the test dataset. The D-statistic for the prognostic model was 0.840 (95% CI 0.716–0.964) in the training dataset and 0.654 (95% CI 0.497–0.811) in the test dataset and the corrected D-Statistic was 0.801. Conclusion The decision to impute missing covariate data in the training dataset influenced the methods implemented to train and test the model. To extend current literature and aid future researchers, we have presented a detailed example of one approach. Whilst our example is not without limitations, a benefit is that all of the patient information available in the training dataset was utilised to develop the model. Trial registration Both trials were registered; Myeloma IX-ISRCTN68454111, registered 21 September 2000. Myeloma XI-ISRCTN49407852, registered 24 June 2009

A methodology to extract outcomes from routine healthcare data for patients with locally advanced non-small cell lung cancer

BACKGROUND: Outcomes for patients in UK with locally advanced non-small cell lung cancer (LA NSCLC) are amongst the worst in Europe. Assessing outcomes is important for analysing the effectiveness of current practice. However, data quality is inconsistent and regular large scale analysis is challenging. This project investigates the use of routine healthcare datasets to determine progression free survival (PFS) and overall survival (OS) of patients treated with primary radical radiotherapy for LA NSCLC. METHODS: All LA NSCLC patients treated with primary radical radiotherapy in a 2 year period were identified and paired manual and routine data generated for an initial pilot study. Manual data was extracted information from hospital records and considered the gold standard. Key time points were date of diagnosis, recurrence, death or last clinical encounter. Routine data was collected from various data sources including, Hospital Episode Statistics, Personal Demographic Service, chemotherapy data, and radiotherapy datasets. Relevant event dates were defined by proxy time points and refined using backdating and time interval optimization. Dataset correlations were then tested on key clinical outcome indicators to establish if routine data could be used as a reliable proxy measure for manual data. RESULTS: Forty-three patients were identified for the pilot study. The manual data showed a median age of 67 years (range 46- 89 years) and all patients had stage IIIA/B disease. Using the manual data, the median PFS was 10.78 months (range 1.58-37.49 months) and median OS was 16.36 months (range 2.69-37.49 months). Based on routine data, using proxy measures, the estimated median PFS was 10.68 months (range 1.61-31.93 months) and estimated median OS was 15.38 months (range 2.14-33.71 months). Overall, the routine data underestimated the PFS and OS of the manual data but there was good correlation with a Pearson correlation coefficient of 0.94 for PFS and 0.97 for OS. CONCLUSIONS: This is a novel approach to use routine datasets to determine outcome indicators in patients with LA NSCLC that will be a surrogate to analysing manual data. The ability to enable efficient and large scale analysis of current lung cancer strategies has a huge potential impact on the healthcare system

Marketing a tourism industry in late stage decline: The case of the Isle of Man

Qualitative interviews in the Isle of Man uncovered local perceptions of a tourism industry in late stage decline. Social impacts of decline are pronounced including facilities loss, cultural changes and a heightening of perceived peripherality: which taken together undermine local identity. Tourists are welcomed as they help to affirm the pride residents have in their island in creating a more active atmosphere, provide social interaction opportunities and to combat negative stereotyping. Thus findings emphasise the diverse, unique and persistent benefits of tourism in the Isle of Man, despite its decline. Destination marketing recommendations are therefore made to better address the experiences and desires of communities experiencing decline

How is overall survival assessed in randomised clinical trials in cancer and are subsequent treatment lines considered? A systematic review

Background Overall survival is the “gold standard” endpoint in cancer clinical trials. It plays a key role in determining the clinical- and cost-effectiveness of a new intervention and whether it is recommended for use in standard of care. The assessment of overall survival usually requires trial participants to be followed up for a long period of time. In this time, they may stop receiving the trial intervention and receive subsequent anti-cancer treatments, which also aim to extend survival, during trial follow-up. This can potentially change the interpretation of overall survival in the context of the clinical trial. This review aimed to determine how overall survival has been assessed in cancer clinical trials and whether subsequent anti-cancer treatments are considered. Methods Two searches were conducted using MEDLINE within OVID© on the 9th of November 2021. The first sought to identify papers publishing overall survival results from randomised controlled trials in eight reputable journals and the second to identify papers mentioning or considering subsequent treatments. Papers published since 2010 were included if presenting or discussing overall survival in the context of treating cancer. Results One hundred and thirty-four papers were included. The majority of these were presenting clinical trial results (98, 73%). Of these, 45 (46%) reported overall survival as a (co-) primary endpoint. A lower proportion of papers including overall survival as a (co-) primary endpoint compared to a secondary endpoint were published in recent years. The primary analysis of overall survival varied across the papers. Fifty-nine (60%) mentioned subsequent treatments. Seven papers performed additional analysis, primarily when patients in the control arm received the experimental treatment during trial follow-up (treatment switching). Discussion Overall survival has steadily moved from being the primary to a secondary endpoint. However, it is still of interest with papers presenting overall survival results with the caveat of subsequent treatments, but little or no investigation into their effect. This review shows that there is a methodological gap for what researchers should do when trial participants receive anti-cancer treatment during trial follow-up. Future research will identify the stakeholder opinions, on how this methodological gap should be addressed

Hypersensitivity reactions to human papillomavirus vaccine in Australian schoolgirls: retrospective cohort study

Objective To describe the outcomes of clinical evaluation, skin testing, and vaccine challenge in adolescent schoolgirls with suspected hypersensitivity to the quadrivalent human papillomavirus vaccine introduced in Australian schools in 2007

Single-crystal to cingle-crystal addition of H2to [Ir(iPr-PONOP)(propene)][BArF4] and comparison between solid-state and solution reactivity

The EPSRC (EP/M024210/2, EP/T019867/1), SCG Chemicals, The Clarendon Trust, The Leverhulme Trust (RPG-2020-184), Diamond Light Source for funding (PhD studentship to AM).The reactivity of the Ir(I) PONOP pincer complex [Ir(iPr-PONOP)(η2-propene)][BArF4], 6, [iPr-PONOP = 2,6-(iPr2PO)2C6H3N, ArF= 3,5-(CF3)2C6H3] was studied in solution and the solid state, both experimentally, using molecular density functional theory (DFT) and periodic-DFT computational methods, as well as in situ single-crystal to single-crystal (SC-SC) techniques. Complex 6 is synthesized in solution from sequential addition of H2and propene, and then the application of vacuum, to [Ir(iPr-PONOP)(η2-COD)][BArF4], 1, a reaction manifold that proceeds via the Ir(III) dihydrogen/dihydride complex [Ir(iPr-PONOP)(H2)H2][BArF4], 2, and the Ir(III) dihydride propene complex [Ir(iPr-PONOP)(η2-propene)H2][BArF4], 7, respectively. In solution (CD2Cl2) 6 undergoes rapid reaction with H2to form dihydride 7 and then a slow (3 d) onward reaction to give dihydrogen/dihydride 2 and propane. DFT calculations on the molecular cation in solution support this slow, but productive, reaction, with a calculated barrier to rate-limiting propene migratory insertion of 24.8 kcal/mol. In the solid state single-crystals of 6 also form complex 7 on addition of H2in an SC-SC reaction, but unlike in solution the onward reaction (i.e., insertion) does not occur, as confirmed by labeling studies using D2. The solid-state structure of 7 reveals that, on addition of H2to 6, the PONOP ligand moves by 90° within a cavity of [BArF4]-anions rather than the alkene moving. Periodic DFT calculations support the higher barrier to insertion in the solid state (ΔG‡= 26.0 kcal/mol), demonstrating that the single-crystal environment gates onward reactivity compared to solution. H2addition to 6 to form 7 is reversible in both solution and the solid state, but in the latter crystallinity is lost. A rare example of a sigma amine-borane pincer complex, [Ir(iPr-PONOP)H2(η1-H3B·NMe3)][BArF4], 5, is also reported as part of these studies.Peer reviewe

A comprehensive evaluation of the accuracy of CBCT and deformable registration based dose calculation in lung proton therapy

The uncertainties in water equivalent thickness (WET) and accuracy of dose estimation using a virtual CT (vCT), generated from deforming the planning CT (pCT) onto the daily cone-beam CT (CBCT), were comprehensively evaluated in the context of lung malignancies and passive scattering proton therapy. The validation methodology utilized multiple CBCT datasets to generate the vCTs of twenty lung cancer patients. A correction step was applied to the vCTs to account for anatomical modifications that could not be modeled by deformation alone. The CBCT datasets included a regular CBCT (rCBCT) and synthetic CBCTs created from the rCBCT and rescan CT (rCT), which minimized the variation in setup between the vCT and the gold-standard image (i.e., rCT). The uncertainty in WET was defined as the voxelwise difference in WET between vCT and rCT, and calculated in 3D (planning target volume, PTV) and 2D (distal and proximal surfaces). The uncertainty in WET based dose warping was defined as the difference between the warped dose and a forward dose recalculation on the rCT. The overall root mean square (RMS) uncertainty in WET was 3.6 ± 1.8, 2.2 ± 1.4 and 3.3 ± 1.8 mm for the distal surface, proximal surface and PTV, respectively. For the warped dose, the RMS uncertainty of the voxelwise dose difference was 6% ± 2% of the maximum dose (%mD), using a 20% cut-off. The rCBCT resulted in higher uncertainties due to setup variability with the rCT; the uncertainties reported with the two synthetic CBCTs were similar. The vCT followed by a correction step was found to be an accurate alternative to rCT

The relative effects of prey availability, anthropogenic pressure and environmental variables on lion (Panthera leo) site use in Tanzania's Ruaha landscape during the dry season

African lion (Panthera leo) populations have been reduced by almost half in the past two decades, with national parks and game reserves maintaining vital source populations, particularly in East Africa. However, much of the habitats necessary to support lion populations occur in unprotected lands surrounding protected areas. There is an ongoing need for understanding the ecological determinants of lion occurrence in these unprotected habitats, where lions are most vulnerable to extinction. This study evaluated variations in lion site use along a gradient of anthropogenic pressure encompassing the Ruaha National Park, Pawaga‐Idodi Wildlife Management Area (WMA) and unprotected village lands via camera‐trapping. We collected lion occurrence data in the dry seasons of 2014 and 2015, and modelled lion site use as a function of environmental and anthropogenic variables under a Bayesian framework. We recorded 143 lion detections within the national park, 14 in the WMA and no detections in village lands. This result does not imply that lions never use the village lands, but rather that we did not detect them in our surveys during the dry season. Our findings suggest that lion site use was primarily associated with high seasonal wild prey biomass in protected areas. Thus, we infer that human‐induced prey depletion and lion mortality are compromising lion site use of village lands. Seasonal prey movements, and a corresponding concentration inside the park during sampling, could also play an important role in lion site use. These findings reinforce the need to secure large‐bodied prey base to conserve lions, and the importance of protected areas as key refugia for the species