Meta-analysis: High pooled positive predictive value of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition no-biopsy approach for coeliac disease testing in children.

BACKGROUND: The European Society of Paediatric Gastroenterology, Hepatology and Nutrition established guidelines in 2012 for a no-biopsy approach to diagnose coeliac disease in children. This guideline required symptoms suggestive of coeliac disease, positive human leukocyte antigen (HLA) DQ2/DQ8 haplotypes, tissue transglutaminase type-2 immunoglobulin A antibody titre at levels greater than 10 times the upper limit of normal, and positive endomysial immune-globulin A antibody test. An updated 2020 guideline excluded the need for symptoms and positive HLA. AIMS: To assess the pooled positive predictive value (PPV) of the no-biopsy approach with small bowel biopsy (SBB) data as the reference standard for comparison. METHODS: Database searches (October 2023) provided data that we combined using a random-effects meta-analysis to provide a pooled PPV, representing the probability that a positive test result means that an individual truly has the condition. RESULTS: We included 23 studies. Study sample sizes totalled 23,769 but only 3007 children had comparative SBB. The proportion of coeliac disease confirmed by the no-biopsy approach and SBB ranged from 79.2% to 100%, with an overall pooled PPV of 97.4% (95% confidence interval 96.0, 98.6). Sensitivity analysis showed higher PPV for the criteria that included HLA (98.5% vs. 96.8%; p = 0.017). CONCLUSION: Both no-biopsy criteria exhibit high PPV when compared to the reference standard. These results provide a consistent message of accuracy and feasibility to inform change and improve outcomes.

A Systematic Review of Tools to Assess Coeliac Disease-Related Knowledge.

Background: Coeliac disease (CD) is an immune-mediated disorder, with dietary exclusion of gluten the only current treatment. A good knowledge of CD and gluten-free diet (GFD) is essential for those with CD to support effective self-management. Knowledge assessment with a validated tool helps evaluate understanding and knowledge gaps to better tailor educational resources. This study's aim was to perform a systematic review to identify validated CD knowledge assessment tools. Methods: PRISMA guidelines were followed, and searches were carried out in five literature databases. Papers were reviewed for tool development and testing process and assessed against pre-defined criteria for feasibility, validity, and reliability. Results: Twenty-five papers were included in the final analysis. Studies were from 16 countries, with a range of target populations, study designs, and development processes. Eleven reported pilot testing, and five assessed readability. Content validity was assessed in ten papers and formal content validity testing in one. Many tools contained items affecting generalisability outside the region developed. Conclusions: For a CD knowledge assessment tool to be suitable for use, it needs to be well designed, tested, and generalisable. No papers identified satisfied all requirements, thus highlighting a need to develop an appropriate tool.

Pediatric to Adult Transition in Inflammatory Bowel Disease: Consensus Guidelines for Australia and New Zealand.

BACKGROUND: The incidence of pediatric inflammatory bowel disease (IBD) is rising, and there is an increasing need to support adolescents when they transition to adult care. Evidence supports the use of a structured transition process but there is great variation across Australasia. The study aim was to develop evidence and expert opinion-based consensus statements to guide transitional care services in IBD. METHODS: A modified UCLA-RAND methodology was employed to develop consensus statements. An IBD expert steering committee was formed and a systematic literature review was conducted to guide the drafting of consensus statements. A multidisciplinary group was formed comprising 16 participants (clinicians, nurses, surgeons, psychologists), who anonymously voted on the appropriateness and necessity of the consensus statements using Likert scales (1 = lowest, 9 = highest) with a median ≥7 required for inclusion. Patient support groups, including direct input from young people with IBD, informed the final recommendations. RESULTS: Fourteen consensus statements were devised with key recommendations including use of a structured transition program and transition coordinator, mental health and transition readiness assessment, key adolescent discussion topics, allied health involvement, age for transition, and recommendations for clinical communication and handover, with individualized patient considerations. Each statement reached median ≥8 for appropriateness, and ≥7 for necessity, in the first voting round, and the results were discussed in an online meeting to refine statements. CONCLUSIONS: A multidisciplinary group devised consensus statements to optimize pediatric to adult transitional care for adolescents with IBD. These guidelines should support improved and standardized delivery of IBD transitional care within Australasia.

Transitional care practices for adolescents with inflammatory bowel disease vary across Australasia, and a need for standardized care has been identified. A multidisciplinary team developed Consensus Guidelines to facilitate standardized transition from the pediatric to adult healthcare setting across Australasia.

Association between Paediatric Complementary and Alternative Medicine Use and Parental Health Literacy, Child Health, and Socio-Economic Variables: A Prospective Study.

Complementary and Alternative Medicines (CAMs) constitute products and practices not considered allopathic medicine. CAM use is high in children, but little is known about factors that may influence parents using CAM with their child. This study aimed to determine the variables associated with CAM use in children with a prospective study among children and their parents attending a tertiary care hospital in New Zealand (NZ). Outcomes included current CAM use, parental opinions on CAM, parental health literacy and child well-being. This study was completed by 130 parents (85% female), and the mean child age was 6.7 years. CAM use was reported for 59 (45%) children, the most common being oral supplements and body manipulation. Children were more likely to use CAM if their parent had higher health literacy (p = 0.001), and if they had previously attended the emergency department within 12 months (p = 0.03). There was no association between child well-being and CAM use. Parental opinion of using CAM only if a doctor recommended it was associated with CAM use for their child (p = 0.01). Only 40% of parents disclosed their child's CAM use to the medical team. This study highlights that parental health literacy influences the use of CAM for children in NZ, providing insight for translational research to improve CAM safety and disclosure rates in NZ.

Exploring the Diagnostic Spectrum of Children with Raised Faecal Calprotectin Levels.

Faecal calprotectin (FC) is a marker of gut inflammation. The cause and relevance of raised FC in children outside the context of established inflammatory bowel disease (IBD) have had minimal attention. This study aimed to address this by carrying out a retrospective study on children with abnormal FC tests aged 4-17 years without established IBD in the South Island, New Zealand. Abnormal FC results were stratified: 51-249 µg/g, 250-499 µg/g, and 500+ µg/g, and participants were categorised into diagnostic groups. Data were collected on symptoms and diagnostic tests. Three-hundred and ten children had abnormal index FC results, with a mean age of 12.9 years, and a 55% proportion of females. The median FC was 125 µg/g; 71% had levels 51-249 µg/g and 21% had levels 500+ µg/g. Of those with FC 500+ µg/g, 89% either had infectious diarrhoea or were diagnosed with IBD at the time of, or subsequent to, the index FC. Alarm symptoms did not delineate between groups with FC 500+ µg/g. Abnormalities in platelet levels, abdominal ultrasound, and colonoscopy were more frequent for children diagnosed with IBD. Repeat FC test levels were significantly reduced except for those subsequently diagnosed with IBD. Abnormal FC levels for the majority were below the level indicative of mucosal inflammation. Repeat FC testing could play an important role in distinguishing between diagnoses.

Patterns of vitamin D testing and supplementation for children with inflammatory bowel disease in Australasia.

Background and Aim: For children with inflammatory bowel disease (IBD), optimal levels of vitamin D are ascribed anti-inflammatory and essential immune system roles that are associated with reduced disease activity, lower postoperative recurrence, and higher quality of life. International guidelines for vitamin D testing and supplementation provide inconsistent recommendations. The aim of this study was to survey Australasian pediatric gastroenterologists to ascertain current practices of vitamin D testing and supplementation for children with IBD. Methods: Members of the Australian Society of Pediatric Gastroenterology, Hepatology and Nutrition were invited to complete an online survey. Respondents were asked to provide information on frequency of vitamin D testing and supplementation, adherence, and benefits of vitamin D to children with IBD. Results: Thirty-two (54%) pediatric gastroenterologists completed the survey: 27 (84%) from Australia and 5 (16%) from New Zealand. The majority (90%) tested vitamin D levels at diagnosis and follow up, although testing frequency varied (1-3 times/year) and only 8 (28%) tested seasonally. While 28 (88%) recommended supplementation based on serum levels, inconsistent cutoff values were used. Most respondents (n = 27) recommended Stoss (single dose) or vitamin D3 (daily for 8-12 weeks). The majority (84%) rated the overall benefit of optimal vitamin D levels at ≥6/10, although fewer (54%) rated the benefit to disease activity at ≥6/10. Conclusions: The results indicate that standardized guidelines for vitamin D testing and supplementation for clinicians caring for children with IBD throughout Australasia are required. Consensus statements may optimize the care of children with IBD in this diverse geographical region.

Transitional care of adolescents with inflammatory bowel disease to adult services varies widely across Australia and New Zealand.

Background and Aim: Children and adolescents account for approximately 14% of inflammatory bowel disease (IBD) diagnoses. At an appropriate age and level of development adolescents with IBD have their care transferred from the pediatric to adult clinical team during a process termed "transition". The study aim was to survey pediatric gastroenterologists throughout Australasia to identify commonality in the transition process to contribute to standardized guideline development. Methods: A descriptive survey captured key variables: transition clinic format, process and infrastructure, transition assessments, and guidelines. The survey was distributed electronically to 59 Pediatric Gastroenterologists throughout Australasia in January 2023. Results: Seventeen (29%) clinicians completed the survey: Australia 13 (76%). New Zealand 4 (24%). Thirteen (76%) respondents had access to a dedicated IBD transition clinic. Adolescents attended transition clinics 1-7 times, and the main processes transferred were: prescription provision, biologic appointments, and adult team contacts. Transition was first discussed age 13-15 years (53%), or 16-18 years (47%), with the main discussion topics including: continuing adherence (88%), smoking (59%), alcohol use (59%), recreational drug use (59%). Transition readiness assessments were done infrequently (24%). The minority (24%) used formal guidelines to inform the transition process, but 15 (88%) considered the development of a standardized Australasian guideline as beneficial/extremely beneficial. Conclusions: This survey highlighted that transition care for adolescents with IBD is variable across Australasia. Australasian guideline development may optimize the transition process for adolescents with IBD and improve their longitudinal outcomes.

Knowledge Levels About Inflammatory Bowel Disease Vary Between Healthcare Professional Groups.

BACKGROUND: Inflammatory Bowel Disease (IBD) is one of the most serious chronic diseases affecting the global population. Clinical team members involved in the care of individuals with IBD should have sufficient knowledge about IBD. AIMS: The study aim was to assess IBD knowledge among four health care professional groups in New Zealand: nurses, medical students, dietitians, and pharmacists. METHODS: All four groups completed surveys on demographics, work experience, and contact with patients with IBD. All completed a validated IBD knowledge assessment questionnaire (IBD-KID2), and percentage scores with standard deviation (SD) for each group calculated and compared. RESULTS: Participants included 200 nurses, 196 medical students, 45 dietitians, and 28 pharmacists. Mean IBD-KID2 percentage scores were nurses 69.7% (SD 14.7), medical students 77.6% (SD 14.5), dietitians 87.4% (SD 8.3), and pharmacists 83.4% (SD 10.1). Nurses scored lower than other HCP (P < 0.001). Independent variables were associated (P < 0.05) with higher scores for nurses having first degree relative with IBD, access to IBD guidelines, worked with children with IBD; medical students in their clinical years of study; and dietitians with IBD-specific education. Specific items scored poorly: growth, food triggers, heritability of IBD, and nutrient absorption. CONCLUSIONS: Knowledge gaps exist among HCP that may be addressed with targeted education. Improvements in the knowledge of those caring for people with IBD may optimize patient outcomes.

Profile of Helicobacter pylori infections among children in the South Island of New Zealand (2010-2021).

BACKGROUND: Helicobacter pylori is a gram-negative gut bacterium most often acquired during childhood. International guidelines state that children with suspected H. pylori infection should be referred to a gastroenterologist for investigation via gastroscopy and biopsy. Eradication therapy should be prescribed for children with peptic ulcer disease or following a treatment risk/benefit discussion for those with an incidental gastroscopy finding. Guidelines state that for children a "test-and-treat" approach is not warranted, contrasting recommendations for adults. The aim of this study was to profile pediatric H. pylori infections in the South Island of New Zealand (NZ) to determine diagnostic and management strategies, and adherence to international guidelines. MATERIALS AND METHODS: Retrospective data for positive H. pylori tests between 2010 and 2021 were retrieved from hospitals and regional testing laboratories throughout the South Island (NZ) for children ≤18 years. Outcome data were retrieved from tertiary care hospital records; sociodemographic, testing methods, eradication therapy, and symptoms. RESULTS: Two-hundred and forty children were identified: 105 (44%) male, mean age 13.2 years (SD 4.3). Participants of Pasifika, Asian, and Middle Eastern/Latin American/African heritage were overrepresented compared to the NZ census data. Overall, 138 (58%) children were diagnosed via stool antigen tests, 78 (32%) serum, and only 24 (10%) adhered to international guidelines in being confirmed via gastroscopy. Only 59 (25%) had a record of eradication therapy, and 39/59 (66%) were retested to determine eradication success, with 32 (82%) negative tests and seven (18%) remaining positive. Of the 181 (75%) that had eradication status unknown, 66 (28%) had a retest result available with 48 (73%) testing negative and 18 (27%) positive, suggesting a substantial proportion had received eradication therapy without adhering to international guidelines. CONCLUSIONS: International guidelines were not adhered to for most children in the study cohort. Implications of this include cost, unnecessary venipuncture, and unjustified antibiotic exposure.

Sex Differences in the Clinical Presentation and Natural History of Dilated Cardiomyopathy.

BACKGROUND: Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved. OBJECTIVES: This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors. METHODS: The authors conducted a prospective observational cohort study of DCM patients assessing baseline characteristics, cardiac magnetic resonance imaging, biomarkers, and genotype. The composite outcome was cardiovascular mortality or major heart failure (HF) events. RESULTS: Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline, female patients had higher left ventricular ejection fraction, smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%), and lower high-sensitivity cardiac troponin I than males (all P < 0.05) with no difference in time from diagnosis, age at enrollment, N-terminal pro-B-type natriuretic peptide levels, pathogenic DCM genetic variants, myocardial fibrosis extent, or medications used for HF. Despite a more favorable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted HR: 3.14; 95% CI: 1.55-6.35; P = 0.001). Between 2 and 5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, left ventricular ejection fraction, left atrial volume, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin I, left bundle branch block, and NYHA functional class were not sex-specific prognostic factors. CONCLUSIONS: The authors identified a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences.

Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms.

PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both Sequence Ontology (SO) and Human Phenotype Ontology (HPO) ontologies. Gene Curation Coalition member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

BACKGROUND: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. METHODS: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. RESULTS: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. CONCLUSIONS: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.

Co-design and Consultation Ensure Consumer Needs Are Met: Building an eHealth Platform for Children with Inflammatory Bowel Disease.

BACKGROUND: Crohn's Colitis Care is an adult inflammatory bowel disease eHealth system. Crohn's Colitis Care required additional pediatric functionality to enable life-long records and mitigate transition inadequacies. AIM: This study describes and evaluates a consensus method developed to ensure consumer needs were met. METHODS: Pediatric-specific functionality and associated resources considered important for inclusion were developed by a clinician consensus group. This group was divided into thematic subgroups and underwent two voting rounds. The content validity index was used to determine items reaching consensus. Children with inflammatory bowel disease and their parents were later shown a descriptive list of non-clinical inclusion topics proposed by the consensus group, and asked to vote on whether topic-related functionality and resources should be included. RESULTS: The consensus process consulted 189 people in total (38 clinicians, 32 children with inflammatory bowel disease and 119 parents). There was agreement across all groups to incorporate functionality and resources pertaining to quality of life, mental health, self-management, and transition readiness; however, divergence was seen for general inflammatory bowel disease facts, your inflammatory bowel disease history, and satisfaction. Cost saw the greatest disparity, being less supported by consumers compared to clinicians. Over 75% of consumers agreed it would be okay for appointments to take longer for survey completion, and > 90% thought Crohn's Colitis Care should allow consumers to ask their treating team questions. CONCLUSIONS: Widespread consumer co-design and consultation were important in unveiling differing perspectives to ensure Crohn's Colitis Care was built to support both consumer and clinician perspectives. Consumers collaborate to create a list of functionality and resources to be included in software (left), influencing the final product build (right).

Promoting early testing and appropriate referral to reduce diagnostic delay for children with suspected inflammatory bowel disease, a narrative review.

Background and Objective: When a child with chronic gastrointestinal (GI) symptoms presents to a primary care physician or general paediatrician, the clinician is challenged with differentiating between functional or organic disease. When there is a high suspicion of inflammatory bowel disease (IBD), rapid referral to a paediatric gastroenterologist for assessment and treatment will help protect against the sequelae of a delayed diagnosis for a child. However, this must be balanced against the need for ensuring appropriate referrals and avoiding invasive diagnostic testing for those with non-organic aetiology. The objective of this narrative review was to present evidence on specific presenting symptoms, testing, and risk factors of paediatric IBD that may aid the identification of children requiring timely referral for specialist care, thereby reducing the chance of a delayed diagnosis. Methods: Literature databases (Medline, Embase) were searched using terms specific to the population studied, and topic specific terms relating to each section of the review. Year limits were set for 2010-2022. Included papers were limited to original research, with meta-analyses considered where of benefit. Key Content and Findings: Children often present with non-specific GI symptoms that may be associated with a delayed diagnosis for those with subsequent IBD. Symptoms such as rectal bleeding or weight loss may indicate the need for rapid referral. However, non-specific symptoms necessitate testing strategies to differentiate between those with possible IBD and non-organic conditions. Definitive laboratory testing for IBD is not yet available. This review outlines those metrics that should be considered and monitored, then utilised to make a comprehensive referral to tertiary care for specialist paediatric gastroenterology review. Summaries are provided relating to presenting symptoms, extra-intestinal manifestations (EIMs), and alarm symptoms in order to highlight those reported most frequently. The diagnostic accuracy and importance of interpreting faecal calprotectin (FC) levels, in conjunction with additional measures, are also outlined. Conclusions: Diagnostic testing to effectively identify children with IBD without the need for endoscopy is not yet available. Primary care physicians and general paediatricians must, therefore, rely on interpreting a combination of symptoms, laboratory parameters, and risk factors to assess the need for specialist referral and diagnosis.

Descriptive Epidemiology of Pediatric Inflammatory Bowel Disease in Oceania: A Systematic Review and Meta-Analysis.

OBJECTIVES: Pediatric inflammatory bowel diseases (IBDs) are chronic, idiopathic illnesses of the digestive tract, which can impact adversely on children's quality of life and burden health systems. International studies have shown these diseases are increasing. The aim was to describe pediatric IBD epidemiology across Oceania by conducting a systematic review and meta-analysis of incidence and prevalence. METHODS: Medline, EMBASE and Web of Science databases were searched in October 2022 for studies reporting rates of IBD, Crohn disease (CD), or ulcerative colitis (UC) in children (≤19 years). Several data collection methodologies were included and pooled estimates of incidence and prevalence were calculated using a random effects model with I2 measures of heterogeneity. RESULTS: Nineteen articles provided 15 incidence and 7 prevalence studies. Fourteen studies were from Australia, 8 studies from New Zealand, and no studies were found from the Pacific Islands. Study dates ranged from 1950 to 2020 with 11 studies using population-based designs. Pooled estimates for annual incidence were IBD 4.1 (3.4-4.8, I2 = 98.7), CD 2.3 (1.9-2.7, I2 = 98.6), and UC 0.9 (0.6-1.1, I2 = 96.8) per 100,000 person-years. Prevalence rates were IBD 36.0 (23.5-48.5, I2 = 98.4), CD 23.2 (6.6-39.8, I2 = 97.8), and UC 7.6 (2.7-12.5, I2 = 99.6) per 100,000 persons. CONCLUSIONS: Pediatric IBD is prevalent in Oceania with high incidence rates, particularly for CD. Low rates of IBD were observed in indigenous Australian, Maori, and New Zealand Pacific children and there were no studies from the Pacific Islands highlighting this as an area in need of further research.

Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms.

PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

Background: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings. Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

Agreement Level of Inflammatory Bowel Disease Symptom Reports between Children and Their Parents.

Purpose: Children with inflammatory bowel disease (IBD) frequently undergo clinical assessments, involving triadic communication between clinician, parent, and child. During such encounters parents are traditionally the main communicator of information on their child's IBD, including subjective symptom reports. The level of agreement between children and their parents for IBD symptoms is poorly understood, and this study aimed to examine this factor. Methods: This was a cross-sectional study among children with IBD, and one parent. A validated paediatric IBD symptom report tool (IBDnow) enabled children and their parent to rate seven pain, well-being, and stool metrics, with dyads completing the tool concurrently. Results were assessed using: Individual agreement: proportion of identical symptom reports by each dyad (ideal score >0.7); Category agreement: percentage of identical reports for IBDnow metrics for the cohort; Inter-rater reliability: Gwet's AC1 coefficient with higher scores indicating better reliability (maximum=1). Results: Seventy-four parent/child dyads participated; child's mean age 12.2 years (standard deviation [SD] 2.9, range 6-16), mean time since diagnosis 2.8 years (SD 3), 54% female, 73% had Crohn's Disease. Mean individual agreement level was 0.6, with 27% of dyads agreeing on ≥6/7 IBDnow metrics. Category agreement was reported by 61% of dyads, 20% of parents overestimated, and 19% underestimated, their child's symptoms. Inter-rater reliability ranged from fair to good. Conclusion: These results should improve clinician awareness of how IBD symptom reports from parents may introduce bias. Children should be considered the most important source of symptom reports, and tools such as IBDnow utilised to enhance communication.

Systematic Review of Diagnostic Delay for Children With Inflammatory Bowel Disease.

OBJECTIVES: Pediatric inflammatory bowel disease (IBD) is a complex inflammatory condition of the gut. Diagnosing IBD involves distinct longitudinal periods from first symptoms to primary care assessment, tertiary care referral, and then endoscopic confirmation. The term diagnostic delay (DD) is used if these periods are prolonged. The aim of this review was to amalgamate DD data for children with IBD, and identify factors associated with prolonged DD. METHODS: Six health literature databases were searched (December 2020). Inclusion criteria for papers were children diagnosed with IBD before the age of 18 years, DD central tendency data, and to report a central tendency of their DD data, cohort >10 children. For analysis, all data were weighted by cohort sample size. RESULTS: Searches identified 236 papers, and 26 were included in the final analysis with a pooled cohort of 7030 children. The overall DD periods were IBD 4.5 months [Interquartile range (IQR) 3.6-8.7 months], Crohn disease (CD) 5 months (IQR 4-7.2 months), and ulcerative colitis/indeterminate colitis/IBD-unclassified (UC/IC/IBDU) 3 months (IQR 2.2-4.9 months). The difference between subtypes was significant ( P < 0.001), with shorter DD for UC/IC/IBDU than CD ( P < 0.001) and IBD ( P < 0.001). DD periods were longer for CD than IBD ( P < 0.001). DD decreased over time for IBD ( P < 0.001) and UC ( P < 0.001) but the trend suggested an increase for CD ( P 0.069). CONCLUSIONS: This data can be used to benchmark DD for children with IBD. Individual centers could determine whether improvements to awareness or infrastructure may reduce DD in order to minimize the risk of poor outcomes.

Fecal Calprotectin and Cow's Milk-Related-Symptoms Score in Children with Cow's Milk Protein Allergy.

Purpose: The cow's milk-related-symptom-score (CoMiSS) tool was developed as an awareness tool for the assessment of cow's milk-related symptoms in infants or children. Fecal calprotectin (FC) is a noninvasive biomarker of gut inflammation that can be measured in serum and stool. This study aimed to investigate the relationship between FC levels and CoMiSS scores in infants with cow's milk protein allergy. Methods: Infants (aged 6-12 months) who were allergic to cow's milk protein were enrolled prospectively. Following completion of the CoMiSS scoring, the infants were divided into group 1 (positive CoMiSS scores ≥12) and group 2 (negative CoMiSS scores <12). FC was measured using immunoassay. Results: Of the 120 infants enrolled in this study, 60 (50.0%) had positive CoMiSS scores (group 1), while 60 (50.0%) had negative scores (group 2). The mean FC level was higher in the infants in group 1 than those in group 2 (2,934.57 µg/g vs. 955.13 µg/g; p<0.001). In addition, there was a positive correlation between FC and CoMiSS scores (R=0.168, p<0.0001). A FC level of 1,700 µg/g provided a sensitivity of 98.3%, specificity of 93.3%, and accuracy of 95.8% for the diagnosis of cow's milk protein allergy (CMPA). Conclusion: FC measurement may have a role in the assessing infants with CMPA.