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  ["project_title"]=>
  string(108) "Methods for Staging disease activity In ulcerative colitis; A comparison of endoscopy and Histology (MESIAH)"
  ["project_narrative_summary"]=>
  string(703) "It is essential tests accurately gauge inflammation for ulcerative colitis. Endoscopy is the best test, but calprotectin (stool test) is an alternative. This study will use data from clinical trials to identify:
-calprotectin thresholds for endoscopic inflammation
-if calprotectin can monitor response to medication
-factors influencing calprotectin results
- Combine symptoms, blood and calprotectin to create a model to predict endoscopic inflammation.
Calprotectin and the proposed model are inexpensive, less invasive and more accessible than endoscopy; potentially improving patient outcomes. Findings will inform design and interpretation of therapeutic drug trials." ["project_learn_source"]=> string(12) "scien_public" ["project_learn_source_exp"]=> string(115) "New research question toe examine accuracy of diagnostic methods based on secondary analysis of clinical trial data" ["project_key_personnel"]=> array(3) { [0]=> array(6) { ["p_pers_f_name"]=> string(5) "Mehul" ["p_pers_l_name"]=> string(5) "Patel" ["p_pers_degree"]=> string(22) "MBBS, BSc, PhD Student" ["p_pers_pr_affil"]=> string(35) "King's College Hospital, London, UK" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } [1]=> array(6) { ["p_pers_f_name"]=> string(5) "Bilal" ["p_pers_l_name"]=> string(6) "Mateen" ["p_pers_degree"]=> string(9) "MBBS, BSc" ["p_pers_pr_affil"]=> string(29) "University College London, UK" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } [2]=> array(6) { ["p_pers_f_name"]=> string(10) "Bu'Hussain" ["p_pers_l_name"]=> string(5) "Hayee" ["p_pers_degree"]=> string(9) "MBBS, PhD" ["p_pers_pr_affil"]=> string(44) "King's College Hospital NHS Foundation Trust" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } } ["project_ext_grants"]=> array(2) { ["value"]=> string(68) "No external grants or funds are being used to support this research." ["label"]=> string(68) "No external grants or funds are being used to support this research." } ["project_funding_source"]=> string(0) "" ["project_assoc_trials"]=> array(2) { [0]=> object(WP_Post)#4702 (24) { ["ID"]=> int(1144) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2014-09-22 11:06:00" ["post_date_gmt"]=> string(19) "2014-09-22 11:06:00" ["post_content"]=> string(0) "" ["post_title"]=> string(252) "NCT00487539 - A Phase 2/3 Multicenter, Randomized, Placebo-controlled, Double blind Study to Evaluate the Safety and Efficacy of Golimumab Induction Therapy, Administered Subcutaneously, in Subjects with Moderately to Severely Active Ulcerative Colitis" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(193) "nct00487539-a-phase-2-3-multicenter-randomized-placebo-controlled-double-blind-study-to-evaluate-the-safety-and-efficacy-of-golimumab-induction-therapy-administered-subcutaneously-in-subjects-w" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2024-04-22 10:30:28" ["post_modified_gmt"]=> string(19) "2024-04-22 14:30:28" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(242) "https://dev-yoda.pantheonsite.io/clinical-trial/nct00487539-a-phase-2-3-multicenter-randomized-placebo-controlled-double-blind-study-to-evaluate-the-safety-and-efficacy-of-golimumab-induction-therapy-administered-subcutaneously-in-subjects-w/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } [1]=> object(WP_Post)#4701 (24) { ["ID"]=> int(1583) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2017-01-04 14:53:00" ["post_date_gmt"]=> string(19) "2017-01-04 14:53:00" ["post_content"]=> string(0) "" ["post_title"]=> string(252) "NCT00488631 - A Phase 3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Golimumab Maintenance Therapy, Administered Subcutaneously, in Subjects With Moderately to Severely Active Ulcerative Colitis" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(193) "nct00488631-a-phase-3-multicenter-randomized-placebo-controlled-double-blind-study-to-evaluate-the-safety-and-efficacy-of-golimumab-maintenance-therapy-administered-subcutaneously-in-subjects-w" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-02-06 13:23:37" ["post_modified_gmt"]=> string(19) "2023-02-06 13:23:37" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(242) "https://dev-yoda.pantheonsite.io/clinical-trial/nct00488631-a-phase-3-multicenter-randomized-placebo-controlled-double-blind-study-to-evaluate-the-safety-and-efficacy-of-golimumab-maintenance-therapy-administered-subcutaneously-in-subjects-w/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } } ["project_date_type"]=> string(91) "Individual Participant-Level Data, which includes Full CSR and all supporting documentation" ["property_scientific_abstract"]=> string(1410) "Background: Endoscopic and histological remission for ulcerative colitis (UC) is associated with successful steroid tapering; reduced hospitalisation, surgery and cancer. This highlights the need for robust makers to stage inflammation in response to treatment. Endoscopy is the gold standard, but is invasive, expensive and can delay treatment decisions due to availability. Objective: To identify the utility of non-invasive markers of disease activity of UC. Specifically: thresholds of calprotectin for endoscopic activity; serial calprotectin results to determine treatment response; and ultimately, create a model that combines markers (symptom, serum markers, calprotectin) to predict endoscopic activity. Study Design: This study will use prospectively collected data from therapeutic clinical trials available on the YODA and Vivli platforms to address the objectives and validate findings. Participants: patients enrolled in therapeutic clinical trials with established UC. Main Outcome: endoscopic remission (mayo endoscopic subscore = 0/1) and histological remission (absence of neutrophils). Statistical analysis: agreement statistics (Fleiss? and Cohen?s Kappa), statistics for diagnostic accuracy (sensitivity, specificity, positive predictive value, negative predictive value, receiver operator curve analysis), regression analysis, decision curve analysis and predictive modelling experiments." ["project_brief_bg"]=> string(1164) "Ulcerative colitis (UC) is a chronic inflammatory condition predominantly affecting young patients (Ords et al., 2012). The prevalence is rising, especially in newly industrialised nations(GBD, 2020). This will directly impact delivery of care across healthcare systems including resource poor settings.
Robust methods of monitoring disease activity aid physicians when planning treatment escalation. Patients achieving mucosal healing have reduced rates of colectomy, colorectal cancer (Flores et al., 2017); and improved quality of life (Knowles et al., 2018). A ?treat to target? (T2T) approach has been proposed with focus on achieving mucosal healing (mayo endoscopic score = 0/1) (Peyrin-Biroulet et al., 2015). There are challenges delivering this strategy using endoscopy. Highlighting the need for non-invasive markers of activity; existing methods include symptom indexes and faecal calprotectin (FC).
At best symptoms indexes differentiate patients in remission (score of 0 for stool frequency and rectal bleeding on PRO2, sensitivity = 36%, specificity = 96% for remission); and are weakly correlated with endoscopic activity (r = 0.44, p" ["project_specific_aims"]=> string(850) "1. Determining agreement between endoscopic and a novel histological definition of remission (Personal Communication; B. Hayee, 2020 - forthcoming peer reviewed consensus statement)
2. Identification of a endoscopically diagnosed (upper) threshold for relapse/flare based on faecal calprotectin results
3. Evaluating the increase in diagnostic accuracy from knowledge of an index calprotectin measurement (i.e. the role of longitudinal measurements in diagnosing response to treatment)
4. Identification of covariates that are associated with variation in the faecal calprotectin results for individuals with endoscopically confirmed remission.
5.Developing a prediction model for endoscopic remission based on features collected routinely in clinical practice
6.Rasch analysis [psychometric validation] of the Mayo Tool" ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(1) { [0]=> array(2) { ["value"]=> string(5) "Other" ["label"]=> string(5) "Other" } } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> array(2) { ["value"]=> string(1) "R" ["label"]=> string(1) "R" } ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(348) "Analyses will be performed using data from the therapeutic trials for vedolizumab (via the Vivli platform: NCT02497469 and NCT00783718) and golimumab (via the YODA platform: NCT00488631 and NCT00487539). All patients with confirmed ulcerative colitis enrolled in the mentioned therapeutic trials will be included in analyses for our proposed study." ["project_main_outcome_measure"]=> string(472) "Endoscopic Remission: Defined based on the mayo endoscopic score (MES). Two thresholds will be used: 0, and less than or equal to 1.
The MES is categorised as:
Mayo 0 - Normal mucosa / inactive disease
Mayo 1 - Mild erythema, decreased vascular pattern and friability
Mayo 2 - Marked erythema, lack of vascular pattern, friability and erosions
Mayo 3 - Spontaneous bleeding and ulceration
Histological remission: absence of neutrophils" ["project_main_predictor_indep"]=> string(124) "Faecal calprotectin - continuous outcome from assay (week 0, post-induction review alongside endoscopy, and final follow-up)" ["project_other_variables_interest"]=> string(786) "Gender - Binary category (Male/Female)
Age - continuous (years)
Disease History - Location; Montreal/Paris classification (Ordinal); duration (years/months)
Race - Categories defined in the original studies
Smoking status - Binary (yes/no)
Concurrent medical conditions - categorised by the presence or absence of the condition for each individual.
Medication history - presence or absence of a prescription (30 days prior to consent), or current prescription for each individual.
height - Continuous in cm
weight - Continuous in kg
Extraintestinal manifestations of disease ? presence/absence of ?accepted? extraintestinal features of IBD on physical examination at screening
Laboratory results - all as continuous variables" ["project_stat_analysis_plan"]=> string(2718) "A more extensive description of the statistical methods that we will employ have been detailed in the attached statistical analysis plan, which provides links to specific references which demonstrate that the applicants have previously applied these methods in other settings, and are both aware of and involved in the development of best practice guidelines for carrying out the described analyses.
This proposal is based on using three core sets of methods:
1) Agreement statistics (incl. Fleiss? and Cohen?s Kappa) to explore the concordance between endoscopic and histological definitions of remission. This will be based on the 94 individuals with paired histological sampling form the PURSUIT trial. Agreement will be tested at the 0-week time point, and the re-randomisation (post-induction) time-point. Given the sample size this will be explicitly framed as a pilot study to inform future prospective applications to generate a larger databank.
2) Prediction modelling ? we intend to explore both regression (i.e. prediction of the faecal calprotectin), and dichotomous classification tasks (i.e. prediction of remission, as defined by a mayo score cut-off). We intend to benchmark a series of classical statistical models and machine learning methods, using k-fold cross validation, to determine the optimal approach based on out-of-sample errors. Multiple imputation by chained equations will be used for missing data handling. Fractional polynomials will be sued to transform potentially useful non-linear relationships identified from a random 10% hold-out sample. We believe that the sample sizes of the studies in question satisfy current thinking around minimum requirements (see Riley et al., 2020, BMJ). A full description of the proposed computational experiments is outline the attached statistical analysis plan document, including how we intend to handle the issue of variable selection.
3) Rasch Analysis ? we will use pre-existing packages in R (e.g. eRM) to fit a Rasch model to the Mayo scale data. The purpose will be to determine whether the ordinal presentation of the Mayo has a corresponding interval scale based on the hypothesis that the score relates to a latent trait of ?remission/disease activity?. Confirmation to the assumptions of the Rasch model will be checked using a chi-squared test, and post-hoc changes to the Rasch-andrich thresholds will be justified based on domain expertise and carried out in sequence to determine their impact on the fit statistics. Alongside these noveler Rasch-specific measures, we will also report the cronbach?s alpha as a measure on reliability in both the original format, and following post-hoc correction of misfit." ["project_timeline"]=> string(250) "Data Access = January - March 2021
Analysis completion date = September 2021
Dissemination (manuscript preparation and submission of draft for publication = October-November 2021
Results Reported back to YODA project = December 2021" ["project_dissemination_plan"]=> string(556) "Each of the above objectives represents a unique manuscript that we intend to publish in a gastroenterology or general medical journal as appropriate. Whilst working towards publication in a peer-reviewed journal, we may submit abridged versions of the results to relevant conferences. Moreover, where appropriate our results will be submitted to members of the British Society for Gastroenterology IBD sub-committee for consideration in circumstances where we feel they might consider an interim update to their recently published IBD clinical guidelines." ["project_bibliography"]=> string(6041) "

Dulai, P. S., Singh, S., Jairath, V., Ma, C., Narula, N., Vande Casteele, N., Peyrin-Biroulet, L., Vermeire, S., D?Haens, G., Feagan, B. G., & Sandborn, W. J. (2020). Prevalence of endoscopic improvement and remission according to patient-reported outcomes in ulcerative colitis. Alimentary Pharmacology and Therapeutics, 51(4), 435?445. https://doi.org/10.1111/apt.15577
Falvey, J. D., Hoskin, T., Meijer, B., Ashcroft, A., Walmsley, R., Day, A. S., & Gearry, R. B. (2015). Disease activity assessment in IBD: Clinical indices and biomarkers fail to predict endoscopic remission. Inflammatory Bowel Diseases, 21(4), 824?831. https://doi.org/10.1097/MIB.0000000000000341
Flores, B. M., O?Connor, A., & Moss, A. C. (2017). Impact of mucosal inflammation on risk of colorectal neoplasia in patients with ulcerative colitis: a systematic review and meta-analysis. Gastrointestinal Endoscopy, 86(6), 1006-1011.e8. https://doi.org/10.1016/j.gie.2017.07.028
GBD. (2020). The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990?2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterology Hepatology, 5, 17?30. https://doi.org/10.1016/ S2468-1253(19)30333-4 See
Harpaz, N., Ballentine, S., Colombel, J. F., E Sands, B., & Ko, H. M. (2020). Microscopic heterogeneity in ulcerative colitis: Implications for microscopic measurement of disease activity. Gut, 69(2), 401?402. https://doi.org/10.1136/gutjnl-2018-318137
Heida, A., Park, K. T., & Van Rheenen, P. F. (2017). Clinical Utility of Fecal Calprotectin Monitoring in Asymptomatic Patients with Inflammatory Bowel Disease: A Systematic Review and Practical Guide. Inflammatory Bowel Diseases, 23(6), 894?902. https://doi.org/10.1097/MIB.0000000000001082
Knowles, S. R., Graff, L. A., Wilding, H., Hewitt, C., Keefer, L., & Mikocka-Walus, A. (2018). Quality of Life in Inflammatory Bowel Disease: A Systematic Review and Meta-analyses – Part i. Inflammatory Bowel Diseases, 24(4), 742?751. https://doi.org/10.1093/ibd/izx100
Lamb, C. A., Kennedy, N. A., Raine, T., Hendy, P. A., Smith, P. J., Limdi, J. K., Hayee, B., Lomer, M. C. E., Parkes, G. C., Selinger, C., Barrett, K. J., Davies, R. J., Bennett, C., Gittens, S., Dunlop, M. G., Faiz, O., Fraser, A., Garrick, V., Johnston, P. D., ? Hawthorne, A. B. (2019). British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut, 68, s1?s106. https://doi.org/10.1136/gutjnl-2019-318484
Maaser, C., Sturm, A., Vavricka, S. R., Kucharzik, T., Fiorino, G., Annese, V., Calabrese, E., Baumgart, D. C., Bettenworth, D., Borralho Nunes, P., Burisch, J., Castiglione, F., Eliakim, R., Ellul, P., Gonzlez-Lama, Y., Gordon, H., Halligan, S., Katsanos, K., Kopylov, U., ? Stoker, J. (2019). ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. Journal of Crohn?s and Colitis, 13(2), 144?164. https://doi.org/10.1093/ecco-jcc/jjy113
Mosli, M., Bhandari, A., Nelson, S. A., D?Haens, G., Feagan, B. G., Baker, K. A., Sandborn, W. J., Zou, G., Macdonald, J. K., & Levesque, B. G. (2017). Histologic scoring indices for evaluation of disease activity in ulcerative colitis. Cochrane Database of Systematic Reviews, 5. https://doi.org/10.1002/14651858.CD011256.pub2.
Mosli, M. H., Zou, G., Garg, S. K., Feagan, S. G., MacDonald, J. K., Chande, N., Sandborn, W. J., & Feagan, B. G. (2015). C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: A systematic review and meta-analysis. American Journal of Gastroenterology, 110(6), 802?819. https://doi.org/10.1038/ajg.2015.120
Narula, N., Alshahrani, A. A., Yuan, Y., Reinisch, W., & Colombel, J. F. (2019). Patient-Reported Outcomes and Endoscopic Appearance of Ulcerative Colitis: A Systematic Review and Meta-analysis. Clinical Gastroenterology and Hepatology, 17(3), 411-418.e3. https://doi.org/10.1016/j.cgh.2018.06.015
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Peyrin-Biroulet, L., Sandborn, W., Sands, B. E., Reinisch, W., Bemelman, W., Bryant, R. V., D?Haens, G., Dotan, I., Dubinsky, M., Feagan, B., Fiorino, G., Gearry, R., Krishnareddy, S., Lakatos, P. L., Loftus, E. V., Marteau, P., Munkholm, P., Murdoch, T. B., Ords, I., ? Colombel, J. F. (2015). Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target. American Journal of Gastroenterology, 110(9), 1324?1338. https://doi.org/10.1038/ajg.2015.233
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Takeuchi, Y., Hanafusa, M., Kanzaki, H., Ohta, T., Hanaoka, N., Yamamoto, S., Higashino, K., Tomita, Y., Uedo, N., Ishihara, R., & Iishi, H. (2015). An alternative option for ?resect and discard? strategy, using magnifying narrow-band imaging: a prospective ?proof-of-principle? study. Journal of Gastroenterology, 50(10), 1017?1026. https://doi.org/10.1007/s00535-015-1048-1

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2020-4397

Research Proposal

Project Title: Methods for Staging disease activity In ulcerative colitis; A comparison of endoscopy and Histology (MESIAH)

Scientific Abstract: Background: Endoscopic and histological remission for ulcerative colitis (UC) is associated with successful steroid tapering; reduced hospitalisation, surgery and cancer. This highlights the need for robust makers to stage inflammation in response to treatment. Endoscopy is the gold standard, but is invasive, expensive and can delay treatment decisions due to availability. Objective: To identify the utility of non-invasive markers of disease activity of UC. Specifically: thresholds of calprotectin for endoscopic activity; serial calprotectin results to determine treatment response; and ultimately, create a model that combines markers (symptom, serum markers, calprotectin) to predict endoscopic activity. Study Design: This study will use prospectively collected data from therapeutic clinical trials available on the YODA and Vivli platforms to address the objectives and validate findings. Participants: patients enrolled in therapeutic clinical trials with established UC. Main Outcome: endoscopic remission (mayo endoscopic subscore = 0/1) and histological remission (absence of neutrophils). Statistical analysis: agreement statistics (Fleiss? and Cohen?s Kappa), statistics for diagnostic accuracy (sensitivity, specificity, positive predictive value, negative predictive value, receiver operator curve analysis), regression analysis, decision curve analysis and predictive modelling experiments.

Brief Project Background and Statement of Project Significance: Ulcerative colitis (UC) is a chronic inflammatory condition predominantly affecting young patients (Ords et al., 2012). The prevalence is rising, especially in newly industrialised nations(GBD, 2020). This will directly impact delivery of care across healthcare systems including resource poor settings.
Robust methods of monitoring disease activity aid physicians when planning treatment escalation. Patients achieving mucosal healing have reduced rates of colectomy, colorectal cancer (Flores et al., 2017); and improved quality of life (Knowles et al., 2018). A ?treat to target? (T2T) approach has been proposed with focus on achieving mucosal healing (mayo endoscopic score = 0/1) (Peyrin-Biroulet et al., 2015). There are challenges delivering this strategy using endoscopy. Highlighting the need for non-invasive markers of activity; existing methods include symptom indexes and faecal calprotectin (FC).
At best symptoms indexes differentiate patients in remission (score of 0 for stool frequency and rectal bleeding on PRO2, sensitivity = 36%, specificity = 96% for remission); and are weakly correlated with endoscopic activity (r = 0.44, p

Specific Aims of the Project: 1. Determining agreement between endoscopic and a novel histological definition of remission (Personal Communication; B. Hayee, 2020 - forthcoming peer reviewed consensus statement)
2. Identification of a endoscopically diagnosed (upper) threshold for relapse/flare based on faecal calprotectin results
3. Evaluating the increase in diagnostic accuracy from knowledge of an index calprotectin measurement (i.e. the role of longitudinal measurements in diagnosing response to treatment)
4. Identification of covariates that are associated with variation in the faecal calprotectin results for individuals with endoscopically confirmed remission.
5.Developing a prediction model for endoscopic remission based on features collected routinely in clinical practice
6.Rasch analysis [psychometric validation] of the Mayo Tool

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: Other

Software Used: R

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Analyses will be performed using data from the therapeutic trials for vedolizumab (via the Vivli platform: NCT02497469 and NCT00783718) and golimumab (via the YODA platform: NCT00488631 and NCT00487539). All patients with confirmed ulcerative colitis enrolled in the mentioned therapeutic trials will be included in analyses for our proposed study.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Endoscopic Remission: Defined based on the mayo endoscopic score (MES). Two thresholds will be used: 0, and less than or equal to 1.
The MES is categorised as:
Mayo 0 - Normal mucosa / inactive disease
Mayo 1 - Mild erythema, decreased vascular pattern and friability
Mayo 2 - Marked erythema, lack of vascular pattern, friability and erosions
Mayo 3 - Spontaneous bleeding and ulceration
Histological remission: absence of neutrophils

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Faecal calprotectin - continuous outcome from assay (week 0, post-induction review alongside endoscopy, and final follow-up)

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Gender - Binary category (Male/Female)
Age - continuous (years)
Disease History - Location; Montreal/Paris classification (Ordinal); duration (years/months)
Race - Categories defined in the original studies
Smoking status - Binary (yes/no)
Concurrent medical conditions - categorised by the presence or absence of the condition for each individual.
Medication history - presence or absence of a prescription (30 days prior to consent), or current prescription for each individual.
height - Continuous in cm
weight - Continuous in kg
Extraintestinal manifestations of disease ? presence/absence of ?accepted? extraintestinal features of IBD on physical examination at screening
Laboratory results - all as continuous variables

Statistical Analysis Plan: A more extensive description of the statistical methods that we will employ have been detailed in the attached statistical analysis plan, which provides links to specific references which demonstrate that the applicants have previously applied these methods in other settings, and are both aware of and involved in the development of best practice guidelines for carrying out the described analyses.
This proposal is based on using three core sets of methods:
1) Agreement statistics (incl. Fleiss? and Cohen?s Kappa) to explore the concordance between endoscopic and histological definitions of remission. This will be based on the 94 individuals with paired histological sampling form the PURSUIT trial. Agreement will be tested at the 0-week time point, and the re-randomisation (post-induction) time-point. Given the sample size this will be explicitly framed as a pilot study to inform future prospective applications to generate a larger databank.
2) Prediction modelling ? we intend to explore both regression (i.e. prediction of the faecal calprotectin), and dichotomous classification tasks (i.e. prediction of remission, as defined by a mayo score cut-off). We intend to benchmark a series of classical statistical models and machine learning methods, using k-fold cross validation, to determine the optimal approach based on out-of-sample errors. Multiple imputation by chained equations will be used for missing data handling. Fractional polynomials will be sued to transform potentially useful non-linear relationships identified from a random 10% hold-out sample. We believe that the sample sizes of the studies in question satisfy current thinking around minimum requirements (see Riley et al., 2020, BMJ). A full description of the proposed computational experiments is outline the attached statistical analysis plan document, including how we intend to handle the issue of variable selection.
3) Rasch Analysis ? we will use pre-existing packages in R (e.g. eRM) to fit a Rasch model to the Mayo scale data. The purpose will be to determine whether the ordinal presentation of the Mayo has a corresponding interval scale based on the hypothesis that the score relates to a latent trait of ?remission/disease activity?. Confirmation to the assumptions of the Rasch model will be checked using a chi-squared test, and post-hoc changes to the Rasch-andrich thresholds will be justified based on domain expertise and carried out in sequence to determine their impact on the fit statistics. Alongside these noveler Rasch-specific measures, we will also report the cronbach?s alpha as a measure on reliability in both the original format, and following post-hoc correction of misfit.

Narrative Summary: It is essential tests accurately gauge inflammation for ulcerative colitis. Endoscopy is the best test, but calprotectin (stool test) is an alternative. This study will use data from clinical trials to identify:
-calprotectin thresholds for endoscopic inflammation
-if calprotectin can monitor response to medication
-factors influencing calprotectin results
- Combine symptoms, blood and calprotectin to create a model to predict endoscopic inflammation.
Calprotectin and the proposed model are inexpensive, less invasive and more accessible than endoscopy; potentially improving patient outcomes. Findings will inform design and interpretation of therapeutic drug trials.

Project Timeline: Data Access = January - March 2021
Analysis completion date = September 2021
Dissemination (manuscript preparation and submission of draft for publication = October-November 2021
Results Reported back to YODA project = December 2021

Dissemination Plan: Each of the above objectives represents a unique manuscript that we intend to publish in a gastroenterology or general medical journal as appropriate. Whilst working towards publication in a peer-reviewed journal, we may submit abridged versions of the results to relevant conferences. Moreover, where appropriate our results will be submitted to members of the British Society for Gastroenterology IBD sub-committee for consideration in circumstances where we feel they might consider an interim update to their recently published IBD clinical guidelines.

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