Health Innovation Challenge Fund Research Articles

Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland

BackgroundPediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits.MethodsWe conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis.ResultsA total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent–offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent–offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks’ gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78).ConclusionsAmong probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.)

Codesign of a digital health tool for suicide prevention: protocol for a scoping review

IntroductionThe role of digital health in providing psychological treatment and support for the prevention of suicide is well documented. Particular emphasis has been placed on digital health technologies during the...

Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial.

BackgroundMesenchymal stromal cells (MSCs) may be of benefit in acute respiratory distress syndrome (ARDS) due to immunomodulatory, reparative, and antimicrobial actions. ORBCEL-C is a population of CD362 enriched umbilical cord-derived MSCs. The REALIST phase 1 trial investigated the safety and feasibility of ORBCEL-C in patients with moderate to severe ARDS.MethodsREALIST phase 1 was an open label, dose escalation trial in which cohorts of mechanically ventilated patients with moderate to severe ARDS received increasing doses (100, 200 or 400 × 106 cells) of a single intravenous infusion of ORBCEL-C in a 3 + 3 design. The primary safety outcome was the incidence of serious adverse events. Dose limiting toxicity was defined as a serious adverse reaction within seven days. Trial registration clinicaltrials.gov NCT03042143.FindingsNine patients were recruited between the 7th January 2019 and 14th January 2020. Study drug administration was well tolerated and no dose limiting toxicity was reported in any of the three cohorts. Eight adverse events were reported for four patients. Pyrexia within 24 h of study drug administration was reported in two patients as pre-specified adverse events. A further two adverse events (non-sustained ventricular tachycardia and deranged liver enzymes), were reported as adverse reactions. Four serious adverse events were reported (colonic perforation, gastric perforation, bradycardia and myocarditis) but none were deemed related to administration of ORBCEL-C. At day 28 no patients had died in cohort one (100 × 106), three patients had died in cohort two (200 × 106) and one patient had died in cohort three (400 × 106). Overall day 28 mortality was 44% (n = 4/9).InterpretationA single intravenous infusion of ORBCEL-C was well tolerated in patients with moderate to severe ARDS. No dose limiting toxicity was reported up to 400 × 106 cells.

Eye Movement Patterns Can Distinguish Schizophrenia from the Major Affective Disorders and Healthy Control Subjects

Background: At present there are no objective tests or biomarkers in routine use that can help with the diagnosis of major mental disorders. This study aimed to determine the potential value of eye movement behaviour patterns for distinguishing individuals with schizophrenia compared to those with major affective disorders and control groups. Methods: Using a boosted decision tree multiclass classifier in a machine learning framework, we compared eye movement viewing patterns in a training set of UK subjects with Schizophrenia (SCZ) n=120, Bipolar affective disorder (BPAD) n=141, Major depressive disorder (MDD) n=136 and control (CON) n=142 group. A total of 133 individuals with group ratios similar to the training set acted as a hold-out test set for internal validation and a German cohort of SCZ (n=60) and a Scottish cohort of CON subjects (n=184) were used as a semi-independent test set for external validation. Findings: Based on internal validation, estimates of the area under the curve (AUC) for the one-versus-all comparisons for SCZ (0.85), BPAD (0.78), MDD (0.76) and CON (0.85) (with an overall estimate of 0.81) suggested high levels of discriminability between groups. The estimates of AUCs for the one-versus-one comparisons were also reasonably high; SCZ v CON 0.84, SCZ v BPAD 0.82, SCZ v MDD 0.76. The classifier showed good discrimination of BPAD and MDD from CON with AUCs 0.85 and 0.82, respectively; however, the performance was relatively lower between BPAD versus MDD with AUC 0.69. The estimates of AUC based on external validation were comparable: 0.89 for German SCZ and 0.65 for Scottish CON. The best individual discriminators included free viewing, fixation duration and smooth pursuit tasks. Our findings appear robust in the presence of potential confounders such as age, sex, medication or mental state at the time of testing. Interpretation: Eye movement behaviour patterns have good power to discriminate schizophrenia from both the major mood disorders and control subjects. The performance characteristics are within the range required of diagnostic biomarkers. Our findings are consistent with the Kraepelinian dichotomy of the functional psychoses. Funding: Royal Society of London, Chief Scientist Office Scotland (CZB/4/734), NHS Grampian,Tenovus Scotland (G12/31), Miller MacKenzie Trust, EU-FP6 (SGENE) and Health Innovation Challenge Fund, Wellcome Trust and Department of Health (WT-103911/Z/14/Z Declaration of Interest: Philip Benson and David St Clair are co-founders of SACCADE Diagnostics Ltd a spin out company tasked to develop eye movement technology to assist diagnosis of major mental health disorders. The University of Aberdeen has patents pending in Europe (PCT/GB2013/050016) and USA (14/370,611). The data reported in this paper arose solely from the acknowledged UK research bodies and charities none of whom have vested interests in the company. There are otherwise no competing interests. Ethical Approval: The Scottish and German studies obtained full multiregional ethics committee (MREC) and institutional review board (IRB) approvals respectively and were conducted in accordance with the Declaration of Helsinki.

A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis

BackgroundInfection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown.MethodsWe conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment.ResultsA total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval [CI], 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients [29.7%]) and the standard-care group (120 of 397 patients [30.2%]) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P=0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group.ConclusionsIn patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom. (Funded by the Health Innovation Challenge Fund; ATTIRE EudraCT number, 2014-002300-24; ISRCT number, N14174793.)

A Quantitative Evaluation of MIRU-VNTR Typing Against Whole-Genome Sequencing for Identifying Mycobacterium tuberculosis Transmission: A Prospective Observational Cohort Study.

BackgroundMycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR) typing is widely used in high-income countries to determine Mycobacterium tuberculosis relatedness. Whole-genome sequencing (WGS) is known to deliver greater specificity, but no quantitative prospective comparison has yet been undertaken.MethodsWe studied isolates from the English Midlands, sampled consecutively between 1 January 2012 and 31 December 2015. In addition to routinely performed MIRU-VNTR typing, DNA was extracted from liquid cultures and sequenced using Illumina technology. Demographic and epidemiological data for the relevant patients were extracted from the Enhanced Tuberculosis Surveillance system run by Public Health England. Closely related samples, defined using a threshold of five single nucleotide variants (SNVs), were compared to samples with identical MIRU-VNTR profiles, to samples from individuals with shared epidemiological risk factors, and to those with both characteristics.Findings1999 patients were identified for whom at least one M. tuberculosis isolate had been MIRU-VNTR typed and sequenced. Comparing epidemiological risk factors with close genetic relatedness, only co-residence had a positive predictive value of over 5%. Excluding co-resident individuals, 18.6% of patients with identical MIRU-VNTR profiles were within 5 SNVs. Where patients also shared social risk factors and ethnic group, this rose to 48%. Only 8% of MIRU-VNTR linked pairs in lineage 1 were within 5 SNV, compared to 31% in lineage 4.InterpretationIn the setting studied, this molecular epidemiological study shows MIRU-VNTR typing and epidemiological risk factors are poorly predictive of close genomic relatedness, assessed by SNV. MIRU-VNTR performance varies markedly by lineage.FundingPublic Health England, Health Innovation Challenge Fund, NIHR Health Protection Research Unit Oxford, NIHR Oxford Biomedical Research Centre.

Development of a novel application for visualising infectious diseases in hospital settings

BackgroundWhole-genome sequencing, and other molecular methods, can be used to identify potential chains of transmission of infections in hospitals. However, integrating this information with epidemiological data to guide control measures is challenging. We aimed to produce an interactive application for visualisation of hospital infections for use by infection control teams and researchers. MethodsWe developed this application using Shiny, the web application framework for R. The minimum data set required to run the application comprises admission and sample dates and the ward on which the sample was taken. Optional additional data are dates of patient ward transfers, descriptive patient characteristics including genetically defined clusters, and genetic distances between infections. We demonstrate this application with a case-study of 242 influenza samples from a UK hospital (September, 2012, to March, 2014), which were sequenced as part of the ICONIC project. FindingsThe application presents three data visualisations: one displays epidemic curves of the numbers of cases of the infection over time, both overall and separately for each ward. Interactive options allow the user to change graph scales and display subsets of the data. The second visualisation is a schematic representation of hospital wards that shows patient locations on a given date. It then highlights epidemiological and genetic links between patients. The third visualisation is an interactive timeline displaying the wards that patients were staying on and on which dates they were likely to be exposed to, or transmitting, an infection. InterpretationThis novel application produces visual displays to aid interpretation of complex epidemiological and genomic data in hospital settings. It can be used to highlight areas in a hospital in which infections may have been transmitted, and to trace possible chains of transmission by highlighting patients who share epidemiological or genetic links. Advantages include its user-friendly interface and flexibility for use in any setting with similar data on any pathogen. A challenge is integration with existing hospital systems to facilitate data import, since some expertise is needed to extract appropriately formatted data from hospital systems. FundingSupported by the Health Innovation Challenge Fund (T5-355) (ICONIC), a parallel funding partnership between the Department of Health and the Wellcome Trust.

Effects of control interventions on Clostridium difficile infection in England: an observational study

SummaryBackgroundThe control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility.MethodsRegional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998–2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses.FindingsNational fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations <0·59). Regionally, C difficile decline was driven by elimination of fluoroquinolone-resistant isolates (approximately 67% of Oxfordshire infections in September, 2006, falling to approximately 3% in February, 2013; annual incidence rate ratio 0·52, 95% CI 0·48–0·56 vs fluoroquinolone-susceptible isolates: 1·02, 0·97–1·08). C difficile infections caused by fluoroquinolone-resistant isolates declined in four distinct genotypes (p<0·01). The regions of phylogenies containing fluoroquinolone-resistant isolates were short-branched and geographically structured, consistent with selection and rapid transmission. The importance of fluoroquinolone restriction over infection control was shown by significant declines in inferred secondary (transmitted) cases caused by fluoroquinolone-resistant isolates with or without hospital contact (p<0·0001) versus no change in either group of cases caused by fluoroquinolone-susceptible isolates (p>0·2).InterpretationRestricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes.FundingUK Clinical Research Collaboration (Medical Research Council, Wellcome Trust, National Institute for Health Research); NIHR Oxford Biomedical Research Centre; NIHR Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (Oxford University in partnership with Public Health England [PHE]), and on Modelling Methodology (Imperial College, London in partnership with PHE); and the Health Innovation Challenge Fund.

Cost analysis of standard Sanger sequencing versus next generation sequencing in the ICONIC study

BackgroundHIV and hepatitis C virus (HCV) are a major cause of morbidity and mortality, and both viruses contain high genomic variation. To date, viral gene sequencing has been handled by standard Sanger sequencing (SSS) for the detection of specific drug-resistance determinants for HIV and HCV. However, SSS-derived information is very limited. By contrast, full-length viral gene sequences when linked to clinical data might influence the monitoring of drug resistance to optimally guide treatment, identify sources of viral transmissions within health-care settings, and track emerging epidemics. The ICONIC (Infection Response through Virus Genomics) study aims to introduce a novel method called next generation sequencing (NGS) within UK health-care settings, testing potential implementation in routine practice. With use of samples within established diagnostic laboratory workflows, NGS has the potential to produce higher informational content than SSS and report in a timely fashion. However, economic evidence for this emerging method is scarce. We aimed to use the examples of HIV and HCV to compare the cost of NGS versus SSS. MethodsWe performed a bottom-up cost analysis using published, genomic-testing, costing templates to estimate the mean cost per sample for SSS and NGS methods over a 1 year period at a major London hospital. Data on resource use associated with genomic testing were based on estimates from individual sample data, routinely collected from a UK population. FindingsWith SSS, mean cost per sample, including operating costs, was £178 for HCV (2080 samples) and £79 for HIV (520). Mean cost per sample with NGS was £119 (2207 samples), including operating costs, generating a cost saving of £59 for HCV and a surplus of £40 for HIV. Although this method is still research based and prices vary widely, our results demonstrated a broad NGS and SSS cost equivalence. InterpretationNGS is data rich and could be integrated in emerging stratified patient treatments. The mean cost per sample for the two methods should be similar and provide added-value information. A number of costing toolkits should be designed to address the appropriate pricing, including health-care consultation and operating costs when considering NGS efficiency and cost-effectiveness. The mean cost per sample for NGS as part of routine health care requires further exploration. FundingThis project is funded by the Health Innovation Challenge Fund, a parallel partnership between the Wellcome Trust and the Department of Health (ref HICF-T5-344). FRB received funding for this study from the National Institute for Health Research (NIHR) Biomedical Research Centre, and the UCLH/UCL Biomedical Research Centre funded this NIHR Health Informatics Collaborative study.

Abstract 333: Development and validation of a LC-MS/MS method for the quantification of the tropomyosin receptor kinase (Trk) inhibitor pegcantratinib in human skin tumors

Abstract Background: Pegcantratinib is the first topically applied tropomyosin receptor kinase inhibitor allowing retention in the skin to exert its effects at nanomolar concentrations. Pegcantratinib is now under early clinical evaluation as an anti-tumour agent in patients with germline mutations in the tumour suppressor gene CYLD, which include multiple clinical presentations of rare, skin appendage tumours. No pharmacological treatment is currently available and patients face repeated and disfiguring surgery to control tumour burden. We report on the development and validation of an analytical method to quantify pegcantratinib in skin tumour biopsies of patients to determine tumour penetration. Methods: A sensitive and specific HPLC-MS/MS (API 4000) assay coupled with in-source CID was developed and validated according to EMA guidelines, for direct quantitative measurement of pegcantratinib in biopsies of human skin tumours. The sample preparation procedure required a 10 mg sample volume and involved protein precipitation with acetonitrile following tissue homogenization and addition of internal standard. Reversed-phase chromatography under gradient conditions (MP A - 1% formic acid; MP B - 1% formic acid in acetonitrile) was applied with separation on a Kinetex 2.6 μm C18 column (100 Å, 50 × 4.6 mm). Detection was obtained by SRM, following the transitions m/z 419.0 → 376.4. The method is rapid and selective, allowing good resolution of peaks in 2.4 min. Results: The assay was fully validated and the method exhibited good sensitivity, precision, and accuracy, with overall precision expressed as CV ≤8.5% and accuracy in the range 96-99%. Recovery was high (≥85%) and consistent with CV ≤13%. No matrix effect was observed in four independent matrix sources including 3 different tumours and normal skin, the calculated CV was 5%. The limit of quantitation was 2.5 ng/ml, with precision and accuracy of 6% and 99%, respectively. The assay developed was linear in the range 1.0-500 ng/ml, with mean precision &amp;lt;8% and accuracy within the range 96-105%. Inter/intra-day precision and accuracy were always &amp;lt;8.5% and within the range 95-99%, respectively. Pegcantratinib is stable in tumour homogenate for at least 4 hours at room temperature, for 10 days at 4°C, before and after extraction, and over 3 freeze-thaw cycles. Preliminary data of an ex-vivo incubation of skin tumours biopsies, from two patients, at 5μM pegcantratinib for 1, 3 and 6h, showed that drug achieved concentrations of 1.5-2.5 μM in the tumours analysed. Conclusion: We have successfully developed a LC-MS/MS method to measure the anti-tumour agent pegcantratinib in human skin tumour samples. Analysis of samples obtained from the Phase 1b/2a clinical trial is now underway. Acknowledgements: Work supported by the Department of Health and Wellcome Trust through the Health Innovation Challenge Fund and Cancer Research UK. Citation Format: Monique Zangarini, Neil Rajan, Marina Danilenko, Philip Berry, Gareth J. Veal. Development and validation of a LC-MS/MS method for the quantification of the tropomyosin receptor kinase (Trk) inhibitor pegcantratinib in human skin tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 333.

PTH-103 Evaluation of a novel system for image guided laparoscopic liver surgery in an animal model and first clinical experience

PTH-103 Evaluation of a novel system for image guided laparoscopic liver surgery in an animal model and first clinical experience

Drug-resistance mechanisms and tuberculosis drugs

The Health Innovation Challenge Fund (HICF-T5-342 and WT098600), a parallel funding partnership between the UK Department of Health and Wellcome Trust.

PMO-182 HCV research UK: a UK national resource to support research into HCV infection

IntroductionBackground: Hepatitis C virus (HCV) infection has been identified by the MRC and Department of Health MRC as a priority area for research and development to meet the clinical challenges...