Natural History Of Disease Research Articles

Otorhinologic Disorders in 22q11.2 Deletion Syndrome.

Investigate incidence and natural history of otologic and sinonasal disease associated with 22q11.2 deletion syndrome. Case series. Tertiary care children's hospital. Charts from consecutive children born 2000 to 2018 with a diagnosis of 22q11.2 deletion, DiGeorge, or velocardiofacial syndrome based on the International Classification of Diseases (ICD)-9 and ICD-10 codes were reviewed. Otologic and rhinologic diagnoses and surgeries and immune and microbiologic laboratory findings were collected from the medical record. After the exclusion of patients with no 22q11.2 deletion (n = 101), otologic care at an outside hospital (n = 59), and loss to follow-up prior to 3 years of age (n = 22), 128 were included. Males comprised 80 (62.5%) patients, 115 (89.8%) were white, and the median age at genetic confirmation of 22q11.2 deletion was 119 days (range 0 days to 14.6years). Recurrent acute otitis media (RAOM), chronic otitis media with effusion, chronic rhinosinusitis, and recurrent acute sinusitis were diagnosed in 54 (42.2%), 37 (28.9%), 10 (7.8%), and 8 (6.3%), respectively. Tympanostomy tubes were placed in 49 (38.3%). Adenoidectomy and sinus surgery were performed in 38 (29.7%) and 4 (3.1%), respectively. Neither immunoglobulin nor cluster of differentiation deficiency increased the odds of RAOM diagnosis, tympanostomy tube placement, or chronic/recurrent sinusitis. Methicillin-resistant Staphylococcus aureus was the most common organism in sinus cultures (4/13, 30.8%). Streptococcus pneumonia dominated otorrhea cultures (11/21, 52.4%). Approximately half of children with 22q11.2 deletion may experience otologic disease that often requires surgical management. Future studies will utilize a larger cohort to examine the role of immunodeficiency in otologic and rhinologic disease in this population.

Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci.

Canine RPGRIP1-cone-rod dystrophy (CRD), a model for human inherited retinal diseases (IRDs), was originally identified as autosomal recessive early-onset blindness. However, later studies revealed extensive phenotypic variability among RPGRIP1 mutants. This led to the identification of a homozygous MAP9 variant as a modifier associated with early-onset disease. Based on further phenotypic variation affecting cone photoreceptor function, we report mapping of L3 as an additional modifier locus, within a 4.1-Mb locus on canine chromosome 30. We establish the natural disease history of RPGRIP1-CRD based on up to 9-year long-term functional and structural retinal data from 58 dogs including 44 RPGRIP1 mutants grouped according to the modifier status. RPGRIP1 mutants affected by both MAP9 and L3 modifiers exhibited the most severe phenotypes with rapid disease progression. MAP9 alone was found to act as an overall accelerator of rod and cone diseases, while L3 had a cone-specific effect. Ultrastructural analysis of photoreceptors revealed varying degrees of rod and cone damage, while the connecting cilia appeared structurally preserved in all groups. We conclude that RPGRIP1-CRD is an oligogenic disease with at least three loci contributing to the pathogenesis. While the RPGRIP1 variant is required for developing the disease, MAP9 and L3 modifiers exacerbate the phenotype, individually and cumulatively. Oligogenic canine RPGRIP1-CRD illustrates the impact of multiple genetic modifiers on disease phenotype and thus has the potential to reveal new targets for broad-spectrum therapies for oligogenic or polygenic forms of human IRDs.

Opportunities and Challenges of Disease Progression Modeling in Drug Development - An IQ Perspective.

Disease progression modeling (DPM) represents an important model-informed drug development framework. The scientific communities support the use of DPM to accelerate and increase efficiency in drug development. This article summarizes International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development mediated survey conducted across multiple biopharmaceutical companies on challenges and opportunities for DPM. Additionally, this summary highlights the viewpoints of IQ from the 2021 workshop hosted by the US Food and Drug Administration (FDA). Sixteen pharmaceutical companies participated in the IQ survey with 36 main questions. The types of questions included single/multiple choice, dichotomous, rank questions, and open-ended or free text. The key results show that DPM has different representation, it encompasses natural disease history, placebo response, standard of care as background therapy, and can even be interpreted as pharmacokinetic/pharmacodynamic modeling. The most common reasons for not implementing DPM as frequently seem to be difficulties in internal cross-functional alignment, lack of knowledge of disease/data, and time constraints. If successfully implemented, DPM can have an impact on dose selection, reduction of sample size, trial read-out support, patient selection/stratification, and supportive evidence for regulatory interactions. The key success factors and key challenges of disease progression models were highlighted in the survey and about 24 case studies across different therapeutic areas were submitted from various survey sponsors. Although DPM is still evolving, its current impact is limited but promising. The success of such models in the future will depend on collaboration, advanced analytics, availability of and access to relevant and adequate-quality data, collaborative regulatory guidance, and published examples of impact.

Brazilian registry of patients with porphyria: REBRAPPO study

BackgroundPorphyrias are a rare group of disease due to inherited defects of heme synthesis with important systemic manifestations and great burden of disease for patients and families due to the exceptional course of disease with disabling chronic symptoms interposed by life-threatening acute attacks. Unfortunately, the porphyrias are usually underrecognized reflecting a lack of medical and disease awareness as well as few studies about natural history in large cohorts of patients. The main aim of this article is present consistent data about natural history and burden of disease in a large Brazilian cohort.MethodsWe conducted a national cross-sectional registry with retrospective clinical data of Brazilian patients with porphyria collected with Brazilian patients Association with Porphyria in collaboration with a tertiary care center for rare diseases.ResultsA cohort of 172 patients was analyzed in which 148 (86%) patients had the diagnosis of acute hepatic porphyria [AHP] that needed a mean of 62.04 medical visits and 9.6 years to achieve a definitive diagnosis. About AHP cohort, the most common first clinical manifestation were abdominal pain in 77 (52%) patients and acute muscle weakness in 23 (15.5%) with 73 (49.3%) patients presenting only one attack during disease course and 37 (25%) exhibiting 4 or more attacks in the last year. Of note, 105 patients with AHP reported chronic manifestations and the scores for quality of life are lower when compared with general healthy population.ConclusionsBrazilian patients with AHP had a higher prevalence of chronic disabling manifestations and a poor quality of life like other cohorts and a higher proportion of patients with recurrent attacks than previously reported.

Demonstrating multi-country calibration of a tuberculosis model using new history matching and emulation package - hmer

Infectious disease models are widely used by epidemiologists to improve the understanding of transmission dynamics and disease natural history, and to predict the possible effects of interventions. As the complexity of such models increases, however, it becomes increasingly challenging to robustly calibrate them to empirical data. History matching with emulation is a calibration method that has been successfully applied to such models, but has not been widely used in epidemiology partly due to the lack of available software. To address this issue, we developed a new, user-friendly R package hmer to simply and efficiently perform history matching with emulation. In this paper, we demonstrate the first use of hmer for calibrating a complex deterministic model for the country-level implementation of tuberculosis vaccines to 115 low- and middle-income countries. The model was fit to 9–13 target measures, by varying 19–22 input parameters. Overall, 105 countries were successfully calibrated. Among the remaining countries, hmer visualisation tools, combined with derivative emulation methods, provided strong evidence that the models were misspecified and could not be calibrated to the target ranges. This work shows that hmer can be used to simply and rapidly calibrate a complex model to data from over 100 countries, making it a useful addition to the epidemiologist’s calibration tool-kit.

Identifying type 1 / type 2 diabetes in medico-administrative database to improve health surveillance, medical research and prevention in diabetes: Algorithm development and application

IntroductionBig data sources represent an opportunity for diabetes research. One example is the French national health data system (SNDS), gathering information on medical claims of out-of-hospital health care and hospitalizations for the entire French population (66 million). Currently, a validated algorithm based on antidiabetic drug reimbursement is able to identify people with pharmacologically-treated diabetes in the SNDS. But it cannot distinguish type 1 from type 2 diabetes. Differentiating type 1 and type 2 diabetes is crucial in diabetes surveillance, because they carry differences in their prevention, populations at risk, disease natural history, pathophysiology, management and risk of complications.This article investigates the development of a type 1/type 2 diabetes classification algorithm using artificial intelligence and its application to estimate the prevalence of type 1 and type 2 diabetes in France. MethodsThe final data set comprised all diabetes cases from the CONSTANCES cohort (n = 951). A supervised machine learning method based on eight steps was used: final data set selection, target definition (type 1), coding features, final data set splitting into training and testing data sets, feature selection and training and validation and selection of algorithms. The selected algorithm was applied to SNDS data to estimate the type 1 and type 2 diabetes prevalence among adults 18–70 years of age. ResultsAmong the 3481 SNDS features, 14 were selected to train the different algorithms. The final algorithm was a linear discriminant analysis model based on the number of reimbursements for fast-acting insulin, long-acting insulin and biguanides over the previous year (specificity 97% and sensitivity 100%). In 2016, after adjusting for algorithm performance, type 1 and type 2 diabetes prevalence in France was estimated to be 0.3% and 4.4%, respectively. ConclusionOur type 1/type 2 classification algorithm was found to perform well and to be applicable to any prescription or medical claims database from other countries. Artificial intelligence opens new possibilities for research and diabetes prevention.

Lung cancer surgery in women: focus on gender-related outcomes—a narrative review

Background and Objective: The cases of lung neoplasm in women have been raised over the years. Genetic, molecular and hormonal factors play an important role and biologically differentiate the disease of female patients from males. Gender differences were also observed in the evaluation of post-operative results of lung cancer patients. Aim of this study is the analysis of gender-related outcomes after surgery for lung cancer, with the individuation of possible factors influencing the natural history of lung cancer disease in women. The authors evaluated literature and their single centre experience in robotic surgery, considering the lack of data in this field.

Abstract P3-01-13: Palbociclib, ribociclib and abemaciclib in real-world data: risk of disease progression on first-line treatment of metastatic breast cancer

Abstract Introduction and objectives: Cyclin dependent kinase (CDK) 4/6 inhibitors along with endocrine therapy (ET) is the standard first-line for endocrine receptor (ER)-positive HER2-negative metastatic breast cancer. Three CDK 4/6 inhibitors have the FDA and EMA approval: abemaciclib, palbociclib and ribociclib. They appear to have notable differences in their pharmacokinetic characteristics and ability to inhibit every cyclin. Nevertheless, the natural history of disease associated with each CDK 4/6 inhibitor remains unclear. The aim of this study is to establish a risk prediction model for disease progression under the different therapeutic regimes and assess whether there are differences in terms of efficacy between them. Methods: This is a retrospective observational study in which patients treated with ET plus abemaciclib, palbociclib or ribociclib as front line for metastatic breast cancer in Virgen del Rocio Hospital between April 2014 and April 2021 were selected. Patients in this population were followed for a period of 36 months. They were studied according to their clinical characteristics and disease outcome using descriptive analysis. The risk of progression was studied by a transversal method using a univariate logistic regression model. Moreover, Kaplan Meier curves were used to estimate progression-free survival (PFS) and the Breslow test to estimate the p value. All statistical analyses were performed with SPSS 28.0 (Statistical Package for the Social Sciences). Results: A total of 189 patients were selected. 55(29.1%) of them received abemaciclib, 83(44%) palbociclib and 51(27%) ribociclib. 50(27%) patients had de novo metastatic disease, while 139(73%) were recurrences of previous disease. Almost half of the patients (45%) received fulvestrant and 104 (55%) patients received aromatase inhibitors. Table 1 represents the proportion of patients with visceral involvement and endocrine resistance in each arm. The univariate logistic regression model showed that patients treated with palbociclib had 2.36(CI95% 1.165-4.765) times the risk of progression compared to abemaciclib, while patients treated with ribociclib had 2.50(CI95% 1.139-5. 475) times the risk of progression compared to abemaciclib. Overall PFS was 30.03 months. A tendency towards best PFS with abemaciclib in comparison with the other CDK 4/6 inhibitors was appreciated, but it did not reach statistical significance (abemaciclib-palbociclib p=0.289; abemaciclib-ribociclib; p= 0.293; palbociclib-ribociclib p=0.979). Conclusions: In our sample of patients with ER-positive HER2-negative metastatic breast cancer treated with the different CDK 4/6 inhibitors as front line therapy, patients with abemaciclib achieved a lower risk of progression and a trend toward longer PFS. Further follow-up will be necessary to determine whether abemaciclib provides greater benefit in PFS. Table 1. Proportion of patients with visceral involvement and endocrine resistance in each arm. Visceral metastases: Liver, Lung, central nervous System; Non-Visceral: Bone, skin, Lymph node. Citation Format: Mónica Cejuela, M. ángeles Castilla, Marta Benavent, Sonia Molina-Pinelo, Maria A Dominguez-Cejudo, Ana Gil, Alejandro Falcon, Francisco Javier Salvador Bofill. Palbociclib, ribociclib and abemaciclib in real-world data: risk of disease progression on first-line treatment of metastatic breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-13.

Abstract P539A: Advanced Chronic Kidney Disease Does Not Significantly Affect All-Cause Mortality and Rate of Hemodynamic Complications in Acute Pericarditis

Background: Advanced chronic kidney disease (advanced CKD) patients have several metabolic, immunologic, and hemodynamic derangements that can negatively impact the natural history of cardiac disease. Some efficacious treatments for acute pericarditis such as colchicine and NSAIDS may not be well tolerated by advanced CKD patients. Hypothesis: Advanced CKD may portend worse outcomes based on clinical severity and likely higher side effect of treatments among patients hospitalized with acute pericarditis. Method: A retrospective cohort study with data from the 2016 to 2018 combined National Inpatient Sample (NIS) database was employed. ICD-10 codes were used to sample all adult admissions for acute pericarditis who were dichotomized based on the presence of a secondary diagnosis of advanced CKD including CKD stage 4, stage 5 and dialysis dependent patients. Primary outcomes of study were Mortality rate, length of stay and total hospital charge. Secondary outcomes were cardiac tamponade, cardiogenic shock, pericardial window rate, supraventricular tachycardia (SVT), ventricular tachycardia (VT) and gastrointestinal (GI) bleeding rate. Multivariate linear and logistic regressions were used to adjust for confounders. Results: We identified a total of 36570 admissions for acute pericarditis and among these, 4139.99 representing 5.96% had associated advanced CKD diagnosis. These patients were averagely 5 years older (57.14 vs 52.35, adjusted difference of 4.80 years, 95%CI: 3.11 - 6.48, p-value <0.001) and predominantly female (44.5% vs 39.12%, AOR 1.25, 95%CI: 1.02 - 1.52, p value: 0.029) compared to the counterpart cohort group. Details of study outcomes are summarized in table 1 below. Conclusion: Among patients hospitalized with acute pericarditis, the presence of advanced CKD as a secondary diagnosis was associated with increase length of stay and total charge but without statistical significance effect on odds of mortality and odds of relevant hemodynamic complications.

Areas of improvement in the medical care of SMA: evidence from a nationwide patient registry in Germany

BackgroundManagement and treatment of spinal muscular atrophy (SMA) has changed in recent years due to the introduction of novel transformative and potentially curative therapies resulting in the emergence of new disease phenotypes. Yet, little is known about the uptake and impact of these therapies in real-world clinical practice. The objective of this study was to describe current motor function, need of assistive devices, and therapeutic and supportive interventions provided by the healthcare system, as well as the socioeconomic situation of children and adults with different SMA phenotypes in Germany. We conducted a cross-sectional, observational study of German patients with genetically confirmed SMA identified and recruited via a nationwide SMA patient registry (www.sma-register.de) within the TREAT-NMD network. Study data was recorded directly from patient-caregiver pairs through a study questionnaire administered online via a dedicated study website.ResultsThe final study cohort consisted of 107 patients with SMA. Of these, 24 were children and 83 adults. In total, about 78% of all participants were taking medication for SMA (predominantly nusinersen and risdiplam). All children with SMA1 were able to sit and 27% of children with SMA2 were able to stand or walk. Impaired upper limb function, scoliosis and bulbar dysfunction were observed more frequently in patients with reduced lower limb performance. Physiotherapy, occupational therapy, and speech therapy, as well as the use of cough assists were less common than indicated by care guidelines. Family planning and educational and employment status appear to be related to motor skill impairment.ConclusionsWe show that the natural history of disease has changed in Germany following improvements in SMA care and the introduction of novel therapies. Yet, a non-trivial proportion of patients remain untreated. We also identified considerable limitations in rehabilitation and respiratory care, as well as low labour-market participation among adults with SMA, calling for action to improve the current situation.

Prognostic impact of circulating tumor cells in oligometastatic hormone-sensitive prostate cancer following metastasis-directed therapy.

199 Background: Contained within the spectrum of metastatic cancer is an oligometastatic state where metastases are limited in number. Recent prospective data have shown that metastasis directed therapy (MDT) can alter the natural history of oligometastatic disease. In hormone-sensitive prostate cancer (HSPC), the positive clinical effect of MDT has been observed by the phase II STOMP and ORIOLE trials. Circulating tumor cells (CTCs) are a likely origin of the formation of macroscopic metastases. CTCs thus may provide an approach for identifying subgroups of patients with oligometastatic HSPC (oligoHSPC) that would benefit most from MDT. Our main goal was to evaluate the association between presence of CTCs at baseline or day 180 with clinical outcomes in the ORIOLE trial. Methods: ORIOLE was a phase II trial randomizing men with recurrent oligoHSPC with 1-3 metastases to observation (Obs) versus stereotactic ablative radiotherapy (SABR) MDT. Blood samples were prospectively collected at baseline and day 180. Progression-free survival (PFS) was a composite endpoint including any of the following: a PSA rise of at least 2 ng/dL and 25% above nadir; radiologic progression by CT, MRI or bone scan (RECIST v1.1); symptomatic progression of disease; initiation of ADT; or death. Patient blood samples were shipped for analysis on Epic Sciences liquid biopsy platform (Epic Sciences, San Diego, CA). Machine learning algorithms identified CTCs and characterized androgen receptor (AR) expression. Comparisons of patient and tumor characteristics between the groups were performed by two-sample t-tests. Survival curves were generated using the Kaplan-Meier method and p-values were calculated using log-rank test. Analysis was performed using SPSS version 28. Results: A total of 82 samples were collected: 70 from the SABR arm (35 baseline and 35 on day 180) and 12 Obs (7 baseline and 5 on day 180). CTCs were detected in 30/42 samples at baseline (71%, AR+= 7) and in 26/40 samples on day 180 (65%, AR+= 9). In the SABR group there was no difference between CTC+ versus CTC- and AR + versus AR- groups for PSA evaluated at baseline, day 90 or day 180 or Gleason score. With a median follow-up of 41.7 months, PFS was significantly lower in the patients with AR+ versus AR- CTCs at baseline in the SABR arm (p = 0.011, mean PFS: AR+ = 9.3 months, AR- = 27.1 months). The mean biochemical failure-free survival was AR+= 12.9 versus AR-= 29.2 months (p = 0.058). Conclusions: Our preliminary results demonstrate an association between AR+ CTCs at baseline and Day 180 with clinical outcomes following SABR MDT in oligoHSPC. This is the first report examining baseline and dynamic presence of CTCs in oligoHSPC treated from a prospective randomized trial of SABR. Longer follow-up, further analysis and a greater number of patients are needed for a more comprehensive conclusion.

ABCA3-related interstitial lung disease beyond infancy

BackgroundThe majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first...

Insight into the Epidemiology Knowledge Transfer

knowledge is a fluid mixed of experiences, existing information, values, and expert insight, which is acquired by education and experience. Knowledge is classified into two major types, namely explicit and tacit. Unlike explicit knowledge, the tacit knowledge is intuitive and exists in the human brain, and cannot be simply codified and transferred.1Epidemiology is the scientific and systematic study of the occurrence, dispersion, and determinants of health-related conditions in a specific population at a point or period of time in order to manage health issues. The most important goals of epidemiology are: 1. planning for health services, 2. reducing the rate of morbidity and mortality, 3. determining the natural history of diseases, 4. applying different types of prevention, and 5. evaluating health programs. 2 Knowledge is useful when its results are used for decisions-making. Knowledge transfer mediates between knowledge production and its utilization. Indeed, a successful transfer is an essential factor contributing to the conversion of knowledge into practice.3 Knowledge transfer is defined as the process of conveyance of knowledge to individuals, groups, and organizations to facilitate decision-making and activities. Effective knowledge transfer of epidemiology means changing the information, attitude, and behavior of health service providers, individuals, patients, and managers. 4 Knowledge transfer consists of two key components, including sender and receiver. Performing an efficient knowledge transfer requires producing standardized information based on the target group's demands. Knowledge translation is often confused with knowledge transfer. The field of knowledge translation was created to ensure the optimal communication between people using knowledge and those producing it. Advanced epidemiological methods such as structural equation modeling and social network analysis are used for effective knowledge transfer. Analysis of Social Networks Social networks refer to a group of organizations or people who are tied through social relationships such as friendship, cooperation, or information exchange. Social network analysis such as graph analysis methods is a powerful diagnostic method for investigating the pattern of relationship linking members of a group.5 In this method, transferring certain knowledge is possible by identifying influential people. Influential person is someone who is skilled to persuade other individuals in socio network. Social network analysis can be used in decision-making and policy-making, and it plays a significant role in knowledge transfer and improves the novelty of knowledge. For example, sharing knowledge between individual leads to the creation of a new knowledge that is greater than the total knowledge of each person. Relationship among individuals in the social network can be facilitate knowledge transference. Given that knowledge is embedded in the relationship, stronger relationships not only improve knowledge transference but also generate considerable knowledge. Structural Equation Modeling Structural equation modeling (SEM) is a comprehensive statistical model for exploring the correlation between latent and observed variables. SEM has several analytic techniques including analysis of variance, regression analysis, and factor analysis. Factor analysis is used to estimate latent variables based on the observed variables. The data extracted from observational, nonexperimental, and experimental studies can be analyzed by SEM. Although SEM is employed in many fields, it has not been extensively used in epidemiology yet.6Given the above discussion, effective knowledge transfer of epidemiology means changing the information, attitude, and behavior of health service providers, individuals, patients, and managers. Generating standardized information based on the target group's demands is essential to perform efficient knowledge transfer. Advanced epidemiological methods such as structural equation modeling and social network analysis are used for effective knowledge transfer.

Reply.

We thank Drs Singh and Mondia for their interest in our work and their comments regarding our article titled “Natural history of liver disease in a large international Cohort of children with Alagille syndrome: results from The GALA Study.” We acknowledge the absence of detailed analyses of extrahepatic manifestations in our paper. Since Alagille syndrome (ALGS) is dominated by cholestatic liver disease, the focus of our first manuscript was to describe the natural history of liver disease in the largest real-world cohort of ALGS. Additional analyses into other organ systems were simply beyond the scope of this paper. However, we absolutely agree that as Hepatologists/Gastroenterologists, we must think beyond the liver, and through the rich and robust Global Alagille Alliance (GALA) data set, these analyses are finally possible. The suggested analyses are currently planned or in progress and will allow us to coordinate subspecialist care and provide evidenced-based holistic care. We look forward to sharing these results in upcoming publications. CONFLICT OF INTEREST Binita M. Kamath consults for and received grants from Mirum and Albireo. She consults for Audentes. Shannon M. Vandriel has no conflicts to report.

Natural history and prognosis of pediatric PSC with updates on management.

Natural history and prognosis of pediatric PSC with updates on management.

Incidence, and natural history of inflammatory bowel disease in Castilla y León:Prospective and multicenter epidemiological study

Incidence, and natural history of inflammatory bowel disease in Castilla y León:Prospective and multicenter epidemiological study

Identifying and Overcoming Challenges in Developing Effective Treatments for Usher 1B: A Workshop Report

To identify challenges and opportunities for the development of treatments for Usher syndrome (USH) type 1B. In September 2021, the Foundation Fighting Blindness hosted a virtual workshop of clinicians, academic and industry researchers, advocates, and affected individuals and their families to discuss the challenges and opportunities for USH1B treatment development. The workshop began with insights from individuals affected by USH1B. Presentation topics included myosin VIIA protein function in the ear and eye and its role in disease pathology; challenges with the USH1B mouse model most used in disease research to date; new investigations into alternative disease models that may provide closer analogues to USH1B in the human retina, including retinal organoids and large animal models; and learnings from and limitations of available disease natural history data. Participants discussed the need for an open dialogue between researchers and regulators to design USH1B clinical trials with appropriate outcome measures of vision improvement, along with multimodal imaging of the retina and other testing approaches that can help inform trial designs. The workshop concluded with presentations and a roundtable reviewing emerging treatments, including USH1B-targeted genetic augmentation therapy and gene-agnostic approaches. Initiatives like this workshop are important to foster all stakeholders in support of achieving the shared goal of treating and curing USH1B. Presentations and discussions focused on overcoming disease modeling and clinical trial design challenges to facilitate development, testing, and implementation of effective USH1B treatments.

The Frequency of Major and Minor Amputations in Patients with Diabetic Foot

Introduction: Diabetic foot (DF) is the main cause of non-traumatic lower extremity amputations. Major and minor amputations in diabetic foot disease are benchmark indicators of natural history and prognosis of disease. This study will help to prevent DF complications and improve care of diabetes foot. Objectives: To determine the frequency of major and minor amputations and the factors responsible for patients with diabetic foot coming in surgical OPD. Methods: All the patients who presented in hospital with diabetic foot ulcer were included in this study from 01-11-2019 to 30-10-2020. One hundred and forty patients of either gender with age between 20 to 80 years with diabetic foot ulcers of any grade were enrolled in the study. Frequency of minor and major amputations was measured. Results: Out of three hundred and twenty patients, 16.4% (n=69/320) patients underwent lower limb amputations. Minor amputations were made in 12.1% (n=51/320) and major were made in 4.3% (n=18) of patients. Frequency of amputations was significantly higher in older age groups (61-80 years), patients with longer disease duration (>10 years), with poor glycemic control (HBA1-C>8.0) and patients with higher grades of ulcers (grades III and IV) (P<0.05). No significant difference was observed among gender, different education and occupation groups (P>0.05). Conclusions: A significant percentage of patients with diabetic foot ulcers underwent lower limb amputations, which was significantly associated with older age, longer disease duration, poor glycemic control and higher grades of ulcers. Keywords: Diabetic foot, Lower limb amputation, diabetic ulcers.

P121 Clinicomic profiles new feature patterns based on a simplified location classification for Crohn’s disease

Abstract Background Crohn’s disease (CD) is a heterogeneous and complicated condition that often has delayed diagnoses and poor outcomes. Disease location and site-specific mechanisms have received increasing attention in recent studies. Suboptimal classification adds complexity to clinical management for CD and the interpretation of its characteristics. This study aims to clarify the clinicopathological characteristics of CD patients through a prospective cohort. Methods The clinical data from 1173 patients with definite CD diagnoses and a simplified location classification based on anatomical traits (G1: esophagus+stomach+duodenum; G2: jejunum+ileum; G3: ileocecum; G4: colon+rectum) were used to clarify the feature patterns (Figure 1). Results Of the enrolled patients, 437 were newly diagnosed, and 736 were prevalent patients. A higher proportion of L4 involvement (45.8%) and a lower proportion of L2 (6.8%) patients were observed under the Montreal location classification. Single G2 (17.8%), G2+G3 (22.2%), G3+G4 (12.5%) and G2+G3+G4 (27.8%) were the four major types in the simplified location classification (Figure 2A-2B). The patients with G4 presented with higher C-reactive protein, G2 patients had more stricturing/penetrating behavior, and single G2 patients had the oldest age at diagnosis (Table 1). A clinicomic study with machine learning methods including principal component analysis, cluster analysis and partial least squares discriminant analysis, identified hemoglobin, platelet count and C-reactive protein as the three key indicators. A decision tree based on the three indicators and disease behavior stratified all patients into six feature patterns (simply/complicatedly active, simply/complicatedly anemia and simply/complicatedly stable), which formed a two-twisted-cycle model for natural disease history (Figure 2C). Most patients started their cycles at the active phase, and the “simply” cycle was mainly advanced by medications, while most patients in the “complicatedly” cycle needed multidisciplinary care. Comparisons among the six subgroups showed that age at diagnosis had the same rise-and-fall pattern as the G2+G4- proportion, while the G2-G4+ proportion showed the opposite trend (Table 2, Figure 2D-2E). An external validation group (n=301) confirmed the above results. The role of disease location could be interpreted as an important factor determining its start point and site-specific trajectory in the two-twisted-cycle model. Conclusion Site-specific clinical characteristics clarified by the simplified location classification, the new feature patterns profiled by the clinicomic study may provide new insights into CD phenotyping, risk stratification and precision treatment.

Rising incidence, progression and changing patterns of liver disease in Wales 1999-2019.

Liver disease incidence and hence demand on hepatology services is increasing. To describe trends in incidence and natural history of liver diseases in Wales to inform effective provision of hepatology services. The registry is populated by International Classification of Diseases-10 (ICD-10) code diagnoses for residents derived from mortality data and inpatient/day case activity between 1999-2019. Pseudo-anonymised linkage of: (1) Causative diagnoses; (2) Cirrhosis; (3) Portal hypertension; (4) Decompensation; and (5) Liver cancer diagnoses enabled tracking liver disease progression. The population of Wales in 2019 was 3.1 million. Between 1999 and 2019 73054 individuals were diagnosed with a hepatic disorder, including 18633 diagnosed with cirrhosis, 10965 with liver decompensation and 2316 with hepatocellular carcinoma (HCC). Over 21 years the incidence of liver diseases increased 3.6 fold, predominantly driven by a 10 fold increase in non-alcoholic fatty liver disease (NAFLD); the leading cause of liver disease from 2014. The incidence of cirrhosis, decompensation, HCC, and all-cause mortality tripled. Liver-related mortality doubled. Alcohol-related liver disease (ArLD), autoimmune liver disease and congestive hepatopathy were associated with the highest rates of decompensation and all-cause mortality. A 10 fold increase in NAFLD incidence is driving a 3.6 fold increase in liver disease in Wales over 21 years. Liver-related morbidity and mortality rose more slowly reflecting the lower progression rate in NAFLD. Incidence of ArLD remained stable but was associated with the highest rates of liver-related and all-cause mortality.