Standard Diagnostic Pathway Research Articles

Effect of a Point-of-Care Ultrasound-Driven vs Standard Diagnostic Pathway on 24-Hour Hospital Stay in Emergency Department Patients with Dyspnea-Protocol for A Randomized Controlled Trial.

Point-of-care ultrasound (POCUS) helps emergency department (ED) physicians make prompt and appropriate decisions, but the optimal diagnostic integration and potential clinical benefits remain unclear. We describe the protocol and statistical analysis plan for a randomized controlled trial. The objective is to determine the effect of a POCUS-driven diagnostic pathway in adult dyspneic ED patients on the proportion of patients having a hospital stay of less than 24 hours when compared to the standard diagnostic pathway. This is a multicenter, randomized, investigator-initiated, open-labeled, pragmatic, controlled trial. Adult ED patients with chief complaint dyspnea are eligible. Patients are randomized (1:1) to the POCUS-driven diagnostic pathway or standard diagnostic pathway, with 337 patients in each group. The primary outcome is the proportion of patients having a hospital stay (from ED arrival to hospital discharge) of less than 24 hours. Key secondary outcomes include hospital length-of-stay, 72-hour revisits, and 30-day hospital-free days. Sparse evidence exists for any clinical benefit from a POCUS-integrated diagnostic pathway. The results from this trial will help clarify the promising signals for POCUS to influence patient care among ED patients with dyspnea.

Best Practices in Nuclear Imaging for the Diagnosis of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in KSA: The Eagle Eyes of Local Experts.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a complex and serious form of heart failure caused by the accumulation of transthyretin amyloid protein in the heart muscle. Variable symptoms of ATTR-CM can lead to a delayed diagnosis. Recognizing the diagnostic indicators is crucial to promptly detect this condition. A targeted literature review was conducted to examine the latest international consensus recommendations on a comprehensive diagnosis of ATTR-CM. Additionally, a panel consisting of nuclear medicine expert consultants (n = 10) and nuclear imaging technicians (n = 2) convened virtually from the Kingdom of Saudi Arabia (KSA) to formulate best practices for ATTR-CM diagnosis. The panel reached a consensus on a standard diagnostic pathway for ATTR-CM, which commences by evaluating the presence of clinical red flags and initiating a cardiac workup to assess the patient's echocardiogram. Cardiac magnetic resonance imaging may be needed, in uncertain cases. When there is a high suspicion of ATTR-CM, patients undergo nuclear scintigraphy and hematologic tests to rule out primary or light-chain amyloidosis. The expert panel emphasized that implementing best practices will support healthcare professionals in KSA to improve their ability to detect and diagnose ATTR-CM more accurately and promptly. Diagnosing ATTR-CM accurately and early can reduce morbidity and mortality rates through appropriate treatment.

P20 Clinical metagenomics from cell-free DNA: overview and lessons learned from 4 years as a clinical metagenomics provider

Abstract Background Clinical metagenomics emerges more and more from academic research to clinical practice. Here, we share an overview of the field of clinical metagenomics on cell-free DNA found in the blood of patients with severe infections and share a few learning points regarding the implementation as a routine lab service and CE-IVD marked software running in the cloud. Methods We use next-generation sequencing of cell-free DNA to digitally determine relevant pathogens from patients with systemic infections in blood and other bodily fluids using our CE-IVD marked DISQVER diagnostic platform. Until now we have collected microbial data from several thousand samples within 4 years of routine service. Results The set up of the DISQVER test is within the regulatory framework of CE-IVD marking of software as a service (SaaS) and ISO 13485 accreditation. This brings practical implications on database quality, software lock-in/development/testing, change and risk management, technical documentation, requiring substantial resources. Also the wetlab process runs within tightly defined and controlled QM boundaries, pre-set by extensive analytical validations. We clinically validated our test for pathogen identification from blood within 8 clinical trials for intensive care medicine, haematology and coinfection in COVID-19, showing 2- to 3-fold higher identification rates for pathogens in comparison to standard of care blood culture. Furthermore, several case reports/ case series from different clinical backgrounds, frequently with difficult to diagnose pathogens, have been published. From the analysis of our routine processes with several thousand samples, we could show that the turn-around time of our mNGS process is very fast and can detect more species than blood culture. In particular, the relatively high proportion of fungi and dsDNA viruses indicates superiority of the method compared with the standard diagnostic pathway. Conclusions To bridge the gap between academic research and clinical implementation, many aspects of regulatory, technical and data protection requirements need to be addressed. Within the timeframe of commercial availability DISQVER from cell-free DNA found in the blood of infected patients is increasingly becoming a useful tool for infection diagnostics.

Accuracy and usability of AcuPebble SA100 for automated diagnosis of obstructive sleep apnoea in the home environment setting: an evaluation study

ObjectivesObstructive sleep apnoea (OSA) is a heavily underdiagnosed condition, which can lead to significant multimorbidity. Underdiagnosis is often secondary to limitations in existing diagnostic methods. We conducted a diagnostic accuracy...

Clinical risk score for individualized risk stratification of patients with clinically suspected myocardial inflammation

Abstract Objective To develop a clinical risk score for individualized risk stratification of patients with clinically suspected myocardial inflammation. Background Myocardial inflammation is a prominent cause of non-ischaemic dilated cardiomyopathy, heart failure (HF) and sudden cardiac death. Methods This is a prospective multicentre longitudinal study of consecutive patients referred to cardiac magnetic resonance (CMR) with clinically suspected myocardial inflammation between October 2011 and December 2019 as a part of standard diagnostic pathway. Patients were followed up from the date of CMR. The outcome endpoints included major adverse cardiovascular event (MACE, cardiovascular mortality, sudden cardiac death, appropriate device discharge); or death or hospitalisation due to HF). A prognostic model was developed using Cox proportional hazards analysis and validated internally and externally. Results The final dataset included 722 subjects (50 years (40–61); males 422 (58%)). During a follow-up period of median 19 (15–23) months, there were 64 (9%) MACE and 130 (18%) HF events. Ten predictor variables qualified for entry into the prognostic model: age, sex, hematocrit, C-reactive protein, high-sensitive troponin-T (TNT), left and right ventricular ejection fraction, native T1 and T2, and late gadolinium enhancement (LGE). The final multivariable Cox regression model included native T2 (Figure 1A), TNT and LGE (Figure 1B) for the primary (Chi-square: 102.0, p<0.001) and secondary endpoint (Chi-square: 166.9, p<0.001), respectively. Cross-validation as well as external validation of the secondary models revealed good performance and no healthcare system effect. Based on the MyoRISK Score, patients were classified into three risk groups with respective event rates for MACE of 0%, 6.3% and 25.1%, and HF endpoint of 1.8%, 17.3% and 44.2%. TNT≥7 pg/ml allowed to efficiently preselect patients prior to CMR. Conclusions This is the first systematic assessment of outcomes in patients with clinically suspected myocardial inflammation, providing a non-invasive estimation of the probability of adverse events based on a score using readily available clinical parameters. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): DZHK

ROLE OF NEXT GENERATION SEQUENCING WITH PERCEPTA BRUSHING IN RECLAFFYING LUNG NODULE RISK AFTER A NON-DIAGNSOTIC BRONCHOSCOPY

TOPIC: Lung Cancer TYPE: Original Investigations PURPOSE: Lung cancer is most common cancer in the world and the most common cause of death from cancer in the United States. With the recent expansion of eligibility for lung cancer screening and expanded acceptance of screening, we are likely to see a growing number of patients with pulmonary nodules. Current ACCP Guidelines recommend non-surgical biopsy for nodule with a risk of malignancy between 5% and 65%, however up to 60% of lung cancer bronchoscopy results are inconclusive. Percepta Genomic Sequencing Classifier (GSC) is an RNA-seq based genomic classifier using cells from a bronchial brushing of benign mucosa to assess risk of lung cancer in a lung nodule in a patient with a history of smoking when the bronchoscopy is inconclusive. The test can reclassify risk. From a pre-bronch intermediate risk, GSC can up-classify to high risk with a 65% PPV or down-classify to low risk with a 91% NPV. We sought to identify the frequency with which Percepta GSC helps to reclassify malignancy risk in intermediate risk nodules to guide further decision-making. METHODS: This was a retrospective review of all inconclusive bronchoscopies in ever smokers with a lung nodule from January 2019 to October 2020 . All nodules were intermediate risk determined by physician-assessed risk (PAR). Right mainstem bronchial brushings for Percepta GSC had been performed in all cases, with the genomic classifier analysis initiated at the time of the non-diagnostic result. The frequency of up and down classification was analyzed. RESULTS: Out of 30 patients classified as intermediate per PAR, 13 (43.3%) patients had an Intermediate GSC result. 8 (26.6%) patients were re-classified with a High GSC result. 9 (30.0%) patients were re-classified with a Low GSC result. In total, in 17 of 30 (56.6%) of patients with a non-diagnostic bronchoscopy, the classifier provided new information to guide further decision-making. For the patients with a Low GSC result, we observed a significant reduction in additional invasive procedures compared to the pre-test management plan. It is interesting to note that out of 9 patient that got reclassified in low category, 1 patient lost to follow up. Seven patients had at least 12 months follow up on their ct chest with nodule size remaining stable. Interestingly one patient on biopsy showed granulomas with culture growing aspergillus and patient treated with voriconazole which resulted in resolution of nodule. CONCLUSIONS: Within this group of patients with a PAR of Intermediate, Percepta GSC provided additional information in the majority of cases where bronchoscopy was non-diagnostic and has helped our lung nodule work up algorithm. Down classification allowed for consideration of deferring CT-guided fine needle aspiration or surgical lung biopsy and pursuing a plan of CT surveillance, helping to avoid unnecessary procedures. Patients with Intermediate results proceeded on the standard diagnostic pathway, and patients re-classified as high risk were considered for more aggressive evaluation to avoid missing a false negative bronchoscopy result. CLINICAL IMPLICATIONS: Bronchoscopy is frequently used for evaluation of pulmonary lesions, but its sensitivity for detecting lung cancer can be limited. Use of the Percepta GSC bronchial genomic classifier can provide additional information when bronchoscopy is inconclusive, with a high NPV for a Low result and a high PPV for a High result, helping to guide decision making. DISCLOSURES: No relevant relationships by Sonya Bracone, source=Web Response No relevant relationships by Abhijit Raval, source=Web Response No relevant relationships by Ashka Raval, source=Web Response

In acute dyspnea with diagnostic uncertainty, ACP suggests POCUS may be added to the standard diagnostic pathway.

Qaseem A, Etxeandia-Ikobaltzeta I, Mustafa RA, et al. Appropriate use of point-of-care ultrasonography in patients with acute dyspnea in emergency department or inpatient settings: a clinical guideline from the American College of Physicians. Ann Intern Med. 2021;174:985-93. 33900792.

Risk of missing colorectal cancer with a COVID-adapted diagnostic pathway using quantitative faecal immunochemical testing.

BackgroundCOVID-19 has brought an unprecedented challenge to healthcare services. The authors’ COVID-adapted pathway for suspected bowel cancer combines two quantitative faecal immunochemical tests (qFITs) with a standard CT scan with oral preparation (CT mini-prep). The aim of this study was to estimate the degree of risk mitigation and residual risk of undiagnosed colorectal cancer.MethodDecision-tree models were developed using a combination of data from the COVID-adapted pathway (April–May 2020), a local audit of qFIT for symptomatic patients performed since 2018, relevant data (prevalence of colorectal cancer and sensitivity and specificity of diagnostic tools) obtained from literature and a local cancer data set, and expert opinion for any missing data. The considered diagnostic scenarios included: single qFIT; two qFITs; single qFIT and CT mini-prep; two qFITs and CT mini-prep (enriched pathway). These were compared to the standard diagnostic pathway (colonoscopy or CT virtual colonoscopy (CTVC)).ResultsThe COVID-adapted pathway included 422 patients, whereas the audit of qFIT included more than 5000 patients. The risk of missing a colorectal cancer, if present, was estimated as high as 20.2 per cent with use of a single qFIT as a triage test. Using both a second qFIT and a CT mini-prep as add-on tests reduced the risk of missed cancer to 6.49 per cent. The trade-off was an increased rate of colonoscopy or CTVC, from 287 for a single qFIT to 418 for the double qFIT and CT mini-prep combination, per 1000 patients.ConclusionTriage using qFIT alone could lead to a high rate of missed cancers. This may be reduced using CT mini-prep as an add-on test for triage to colonoscopy or CTVC.

Point-of-Care Ultrasonography in Patients With Acute Dyspnea: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians.

Dyspnea is a common and often debilitating symptom with a complex diagnostic work-up. To evaluate the benefits, harms, and diagnostic test accuracy of point-of-care ultrasonography (POCUS) in patients with acute dyspnea. (PROSPERO: CRD42019126419). Searches of multiple electronic databases without language limitations (January 2004 to August 2020) and reference lists of pertinent articles and reviews. Five randomized controlled trials (RCTs) and 44 prospective cohort-type studies in patients with acute dyspnea evaluated POCUS as a diagnostic tool to determine the underlying cause of dyspnea. Two investigators independently screened the literature for inclusion. Data abstraction by a single investigator was confirmed by a second investigator; 2 investigators independently rated risk of bias and determined certainty of evidence. Point-of-care ultrasonography, when added to a standard diagnostic pathway, led to statistically significantly more correct diagnoses in patients with dyspnea than the standard diagnostic pathway alone. In-hospital mortality and length of hospital stay did not differ significantly between patients who did or did not receive POCUS in addition to standard diagnostic tests. Finally, POCUS consistently improved the sensitivities of standard diagnostic pathways to detect congestive heart failure, pneumonia, pulmonary embolism, pleural effusion, or pneumothorax; specificities increased in most but not all studies. Most studies assessed diagnostic test accuracy, which has limited utility for clinical decision making. Studies rarely reported on the proportion of indeterminate sonography results, and no evidence is available on adverse health outcomes of false-positive or false-negative POCUS results. Point-of-care ultrasonography can improve the correctness of diagnosis in patients with acute dyspnea. American College of Physicians.

Appropriate Use of Point-of-Care Ultrasonography in Patients With Acute Dyspnea in Emergency Department or Inpatient Settings: A Clinical Guideline From the American College of Physicians.

The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the appropriate use of point-of-care ultrasonography (POCUS) in patients with acute dyspnea in emergency department (ED) or inpatient settings to improve the diagnostic, treatment, and health outcomes of those with suspected congestive heart failure, pneumonia, pulmonary embolism, pleural effusion, or pneumothorax. The ACP Clinical Guidelines Committee based this guideline on a systematic review on the benefits, harms, and diagnostic test accuracy of POCUS; patient values and preferences; and costs of POCUS. The systematic review evaluated health outcomes, diagnostic timeliness, treatment decisions, and test accuracy. The critical health, diagnostic, and treatment outcomes evaluated were in-hospital mortality, time to diagnosis, and time to treatment. The important outcomes evaluated were intensive care unit admissions, correctness of diagnosis, disease-specific outcomes, hospital readmissions, length of hospital stay, and quality of life. The critical test accuracy outcomes included false-positive results for suspected pneumonia, pneumothorax, and pulmonary embolism and false-negative results for suspected congestive heart failure, pneumonia, pneumothorax, and pulmonary embolism. Important test accuracy outcomes included false-positive results for suspected congestive heart failure and false-negative and false-positive results for suspected pleural effusion. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. The target audience is all clinicians, and the target patient population is adult patients with acute dyspnea in ED or inpatient settings. ACP suggests that clinicians may use point-of-care ultrasonography in addition to the standard diagnostic pathway when there is diagnostic uncertainty in patients with acute dyspnea in emergency department or inpatient settings (conditional recommendation; low-certainty evidence).

Rapid fluorescence in situ hybridisation optimises induction therapy for acute myeloid leukaemia.

Rapid fluorescence in situ hybridisation optimises induction therapy for acute myeloid leukaemia.

Human Bocavirus infection and respiratory tract disease identified in a UK patient cohort.

Since its first isolation in 2005, Human Bocavirus (HBoV) has been repeatedly associated with acute respiratory tract infections, although its role in pathogenicity remains unclear due to high co-infection rates. To assess HBoV prevalence and associated disease in a cohort of respiratory patients in the East Midlands, UK between 2015 and 2019. We initially investigated the undiagnosed burden of HBoV in a retrospective paediatric cohort sampled between 2015 and 2017 using an in-house PCR assay. HBoV was subsequently incorporated into the standard respiratory diagnostic pathway and we audited a calendar year of HBoV positive results between 2018 and 2019. Our retrospective PCR screening of previously routine diagnostic-negative samples from juvenile patients identified a 9% (n = 30) prevalence of HBoV type 1. These apparent HBoV1 mono-infections were frequently associated with respiratory tract symptoms, often severe requiring ventilation, oxygen and steroid intervention with 31% (n = 9) of individuals requiring intensive care. When HBoV screening was subsequently adopted into the routine respiratory diagnostic pathway, year-round infections were observed in both children and adults peaking in February. 185 of 9098 (2.03%) individuals were found to be HBoV positive with children aged 12-24 months the principally infected group. However, HBoV infection was also observed in patients aged over 60, predominantly as a mono-infection. 23% of the 185 unique patients were HBoV monoinfected and persistent low-level DNA positivity was observed in 15 individuals up to 6-months after initial presentation. HBoV1 is a prevalent respiratory infection in the UK capable of causing serious monoinfections.

The cost trajectory of the diagnostic care pathway for children with suspected genetic disorders

PurposeThis study describes the cost trajectory of the standard diagnostic care pathway for children with suspected genetic disorders in British Columbia, Canada. MethodsAverage annual per-patient costs were estimated using medical records review and a caregiver survey for a cohort of 498 children referred to BC Children’s and Women’s Hospitals (C&W) with unexplained intellectual disability (the TIDE-BC study) and families enrolled in the CAUSES study, which offered diagnostic genome-wide sequencing (GWS; exome and genome sequencing) to 500 families of children with suspected genetic disorders. ResultsDirect costs peaked in the first year of patients’ diagnostic odyssey, with an average of C$2257 per patient (95% confidence interval [CI] C$2074, C$2441) for diagnostic testing and C$631 (95% CI C$543, C$727) for specialist consultations at C&W. In subsequent years, direct costs accrued at a constant rate, with an estimated annual per-patient cost of C$511 (95% CI C$473, C$551) for diagnostic testing and C$334 (95% CI C$295, C$369) for consultations at C&W. Travel costs and caregiver productivity loss associated with attending diagnosis-related physician appointments averaged C$1907/family/year. ConclusionsThe continuing long-term accrual of costs by undiagnosed patients suggests that economic evaluations of diagnostic GWS services should use longer time horizons than have typically been used.

Lead-I ECG for detecting atrial fibrillation in patients attending primary care with an irregular pulse using single-time point testing: A systematic review and economic evaluation.

BackgroundAtrial fibrillation (AF) is the most common type of cardiac arrhythmia and is associated with increased risk of stroke and congestive heart failure. Lead-I electrocardiogram (ECG) devices are handheld instruments that can detect AF at a single-time point.PurposeTo assess the diagnostic test accuracy, clinical impact and cost effectiveness of single-time point lead-I ECG devices compared with manual pulse palpation (MPP) followed by a 12-lead ECG for the detection of AF in symptomatic primary care patients with an irregular pulse.MethodsElectronic databases (MEDLINE, MEDLINE Epub Ahead of Print and MEDLINE In-Process, EMBASE, PubMed and Cochrane Databases of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of s of Reviews of Effects, Health Technology Assessment Database) were searched to March 2018. Two reviewers screened the search results, extracted data and assessed study quality. Summary estimates of diagnostic accuracy were calculated using bivariate models. Cost-effectiveness was evaluated using an economic model consisting of a decision tree and two cohort Markov models.ResultsDiagnostic accuracyThe diagnostic accuracy (13 publications reporting on nine studies) and clinical impact (24 publications reporting on 19 studies) results are derived from an asymptomatic population (used as a proxy for people with signs or symptoms of AF). The summary sensitivity of lead-I ECG devices was 93.9% (95% confidence interval [CI]: 86.2% to 97.4%) and summary specificity was 96.5% (95% CI: 90.4% to 98.8%).Cost effectivenessThe de novo economic model yielded incremental cost effectiveness ratios (ICERs) per quality adjusted life year (QALY) gained. The results of the pairwise analysis show that all lead-I ECG devices generate ICERs per QALY gained below the £20,000-£30,000 threshold. Kardia Mobile is the most cost effective option in a full incremental analysis. Lead-I ECG tests may identify more AF cases than the standard diagnostic pathway. This comes at a higher cost but with greater patient benefit in terms of mortality and quality of life.LimitationsNo published data evaluating the diagnostic accuracy, clinical impact or cost effectiveness of lead-I ECG devices for the target population are available.ConclusionsThe use of single-time point lead-I ECG devices in primary care for the detection of AF in people with signs or symptoms of AF and an irregular pulse appears to be a cost effective use of NHS resources compared with MPP followed by a 12-lead ECG, given the assumptions used in the base case model.RegistrationThe protocol for this review is registered on PROSPERO as CRD42018090375.

3-D Multi-parametric Contrast-Enhanced Ultrasound for the Prediction of Prostate Cancer

Trans-rectal ultrasound-guided 12-core systematic biopsy (SBx) is the standard diagnostic pathway for prostate cancer (PCa) because of a lack of sufficiently accurate imaging. Quantification of 3-D dynamic contrast-enhanced ultrasound (US) might open the way for a targeted procedure in which biopsies are directed at lesions suspicious on imaging. This work describes the expansion of contrast US dispersion imaging algorithms to 3-D and compares its performance against malignant and benign disease. Furthermore, we examined the feasibility of a multi-parametric approach to predict SBx-core outcomes using machine learning. An area under the receiver operating characteristic (ROC) curve of 0.76 and 0.81 was obtained for all PCa and significant PCa, respectively, an improvement over previous US methods. We found that prostatitis, in particular, was a source of false-positive readings.

Plucked hair follicles from patients with chronic discoid lupus erythematosus show a disease-specific molecular signature

ObjectiveWhen faced with clinical symptoms of scarring alopecia—the standard diagnostic pathway involves a scalp biopsy which is an invasive and expensive procedure. This project aimed to assess if plucked hair...

One-Stop MRI and MRI/transrectal ultrasound fusion-guided biopsy: an expedited pathway for prostate cancer diagnosis.

To assess the feasibility, safety, and outcomes of an expedited One-Stop prostate cancer (PCa) diagnostic pathway. We identified 370 consecutive patients who underwent multiparametric magnetic resonance imaging (mpMRI) and transrectal ultrasound fusion prostate biopsy (MRI/TRUS-PBx) from our institutional review board-approved database. Patients were divided according to diagnostic pathway: One-Stop (n = 74), with mpMRI and same-day PBx, or Standard (n = 296), with mpMRI followed by a second visit for PBx. mpMRIs were performed and interpreted according to Prostate Imaging-Reporting and Data System (PI-RADS v2). Grade group ≥ 2 PCa defined clinically significant PCa (csPCa). Statistical significance was considered when p < 0.05. Age (66 vs 66years, p = 0.59) and PSA density (0.1 vs 0.1ng/mL2, p = 0.26) were not different between One-Stop vs Standard pathway, respectively. One-Stop patients lived further away from the hospital than Standard patients (163 vs 31km; p < 0.01), and experienced shorter time from mpMRI to PBx (0 vs 7days; p < 0.01). The number (p = 0.56) and distribution of PI-RADS lesions (p = 0.67) were not different between the groups. All procedures were completed successfully with similar perioperative complications rate (p = 0.24). For patients with PI-RADS 3-5 lesions, the csPCa detection rate (49% vs 41%, p = 0.55) was similar for One-Stop vs Standard, respectively. The negative predictive value of mpMRI (PI-RADS 1-2) for csPCa was 78% for One-Stop vs 83% for Standard (p = 0.99). On multivariate analysis, age, prostate volume and PI-RADS score (p < 0.01), but not diagnostic pathway, predicted csPCa detection. A One-Stop PCa diagnostic pathway is feasible, safe, and provides similar outcomes in a shorter time compared to the Standard two-visit diagnostic pathway.

Economic evaluation of genomic sequencing in the paediatric population: a critical review.

Systematic evidence is critical to the formulation of national health policy to provide public funding for the integration of genomic sequencing into routine clinical care. The purpose of this review is to present systematic evidence on the economic evaluation of genomic sequencing conducted for paediatric patients in clinical care, and to identify any gaps in the methodology of economic evaluations. We undertook a critical review of the empirical evidence from economic evaluations of genomic sequencing among paediatric patients searching five electronic databases. Our inclusion criteria were limited to literature published in the English language between 2010 and 2017 in OECD countries. Articles that met our inclusion criteria were assessed using a recognised checklist for a well-designed economic evaluation. We found 11 full-text articles that met our inclusion criteria. Our analysis found that genomic sequencing markedly increased the diagnostic rate to 16-79%, but lowered the cost by 11-64% compared to the standard diagnostic pathway. Only five recent studies in paediatric clinical cohorts met most of the criteria for a well-designed economic evaluation and demonstrated cost-effectiveness of genomic sequencing in paediatric clinical cohorts of patients. Our review identified the need for improvement in the rigour of the methodologies used to provide robust evidence for the formulation of health policy on public funding to integrate genomic sequencing into routine clinical care. Nonetheless, there is emerging evidence of the cost-effectiveness of genomic sequencing over usual care for paediatric patients.

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness.

BackgroundEpileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost‐effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways.MethodsWe conducted a retrospective cost‐effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well‐phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after “first‐tier” testing. Sensitivity analysis was included with a range of commercial exome and multigene panels.ResultsThe diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost‐effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost‐effective. The clinical utility of all diagnoses was reported.ConclusionOur study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions.

Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions

Optimal use of whole-exome sequencing (WES) in the pediatric setting requires an understanding of who should be considered for testing and when it should be performed to maximize clinical utility and cost-effectiveness. To investigate the impact of WES in sequencing-naive children suspected of having a monogenic disorder and evaluate its cost-effectiveness if WES had been available at different time points in their diagnostic trajectory. This prospective study was part of the Melbourne Genomics Health Alliance demonstration project. At the ambulatory outpatient clinics of the Victorian Clinical Genetics Services at the Royal Children's Hospital, Melbourne, Australia, children older than 2 years suspected of having a monogenic disorder were prospectively recruited from May 1 through November 30, 2015, by clinical geneticists after referral from general and subspecialist pediatricians. All children had nondiagnostic microarrays and no prior single-gene or panel sequencing. All children underwent singleton WES with targeted phenotype-driven analysis. The study examined the clinical utility of a molecular diagnosis and the cost-effectiveness of alternative diagnostic trajectories, depending on timing of WES. Of 61 children originally assessed, 44 (21 [48%] male and 23 [52%] female) aged 2 to 18 years (mean age at initial presentation, 28 months; range, 0-121 months) were recruited, and a diagnosis was achieved in 23 (52%) by singleton WES. The diagnoses were unexpected in 8 of 23 (35%), and clinical management was altered in 6 of 23 (26%). The mean duration of the diagnostic odyssey was 6 years, with each child having a mean of 19 tests and 4 clinical genetics and 4 nongenetics specialist consultations, and 26 (59%) underwent a procedure while under general anesthetic for diagnostic purposes. Economic analyses of the diagnostic trajectory identified that WES performed at initial tertiary presentation resulted in an incremental cost savings of A$9020 (US$6838) per additional diagnosis (95% CI, A$4304-A$15 404 [US$3263-US$11 678]) compared with the standard diagnostic pathway. Even if WES were performed at the first genetics appointment, there would be an incremental cost savings of A$5461 (US$4140) (95% CI, A$1433-A$10 557 [US$1086- US$8004]) per additional diagnosis compared with the standard diagnostic pathway. Singleton WES in children with suspected monogenic conditions has high diagnostic yield, and cost-effectiveness is maximized by early application in the diagnostic pathway. Pediatricians should consider early referral of children with undiagnosed syndromes to clinical geneticists.