Genedrive kit for detecting single nucleotide polymorphism m.1555A>G in neonates and their mothers: a systematic review and cost-effectiveness analysis

Abstract

Background Neonates with suspected sepsis are commonly treated with gentamicin, an aminoglycoside. These antibiotics are associated with high risk of ototoxicity, including profound bilateral deafness, in people with the m.1555A>G mitochondrial genetic variant. Objective This early value assessment summarised and critically assessed the clinical effectiveness and cost-effectiveness of the Genedrive MT-RNR1 ID Kit for identifying the gene m.1555A>G variant in neonates and mothers of neonates needing antibiotics or anticipated to need antibiotics. Following feedback from the scoping workshop and specialist assessment subgroup meeting, we also considered the Genedrive MT-RNR1 ID Kit for identifying the m.1555A>G variant in mothers prior to giving birth. Data sources For clinical effectiveness, we searched three major databases in October 2022: MEDLINE, EMBASE and CINAHL (Cumulative Index to Nursing and Allied Health Literature). For cost-effectiveness, in addition to the three mentioned databases we searched Cochrane and RePEc-IDEAS. Study selection Study selection and risk-of-bias assessment were conducted by two independent reviewers (Ryan PW Kenny and Akvile Stoniute for clinical effectiveness and Hosein Shabaninejad and Tomos Robinson for cost-effectiveness). Any differences were resolved through discussion, or by a third reviewer (Nick Meader). Study appraisal Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. One study (n = 751 neonates recruited) was included in the clinical effectiveness review and no studies were included in the cost-effectiveness review. All except one outcome (test failure rate: low risk of bias) were rated as being at moderate risk of bias. The study reported accuracy of the test (sensitivity 100%, 95% confidence interval 29.2% to 100%; specificity 99.2%, 95% confidence interval 98% to 99.7%), number of neonates successfully tested (n = 424/526 admissions), test failure rate (17.1%, although this was reduced to 5.7%), impact on antibiotic use (all those with a m.1555A>G genotype avoided aminoglycosides), time taken to obtain a sample (6 minutes), time to genotyping (26 minutes), time to antibiotic treatment (55.18 minutes) and the number of neonates with m.1555A>G (n = 3). Limitations The economic component of this work identified key evidence gaps for which further data are required before a robust economic evaluation can be conducted. These include the sensitivity of the Genedrive MT-RNR1 ID Kit for identifying the gene m.1555A>G variant in neonates, the magnitude of risk for aminoglycoside-induced hearing loss in neonates with m.1555A>G, and the prevalence of the m.1555A>G variant. Other potentially important gaps include how data regarding maternal inheritance may potentially be used in the clinical pathway. Conclusions This early value assessment suggests that the Genedrive MT-RNR1 ID Kit has the potential to identify the m.1555A>G variant and to be cost-effective. The Genedrive MT-RNR1 ID Kit dominates the current standard of care over the lifetime, as it is less costly and more effective. For a 50-year time horizon, the Genedrive MT-RNR1 ID Kit was also the dominant strategy. For a 10-year time horizon, the incremental cost-effectiveness ratio was estimated to be £103 per quality-adjusted life-year gained. Nevertheless, as anticipated, there is insufficient evidence to conduct a full diagnostic assessment of the clinical effectiveness and cost-effectiveness of the Genedrive MT-RNR1 ID Kit in neonates directly or in their mothers. This report includes a list of research priorities to reduce the uncertainty around this early value assessment and to provide the additional data needed to inform a full diagnostic assessment, including cost-effectiveness modelling. Study registration This study is registered as PROSPERO (CRD42022364770). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135636) and is published in full in Health Technology Assessment; Vol. 28, No. 75. See the NIHR Funding and Awards website for further award information. Plain language summary Our immune system usually fights off invading germs, such as bacteria, viruses, fungi or parasites, in order to prevent infection. Sometimes the immune system stops fighting the ‘invaders’ and begins to turn in on itself. This life-threatening reaction is known as sepsis. Bacterial infections and sepsis are significant causes of death and illness in newborns. Newborns with suspected bacterial infection or sepsis are normally treated with an aminoglycoside antibiotic called gentamicin (a type of medicine that is meant to kill bacteria). These antibiotics are associated with a very high risk of ototoxicity (damage to the ear, including deafness) among people with the m.1555A>G MT-RNR1 gene variant [a specific change to the small section of deoxyribonucleic acid storing biological information] within their mitochondrial deoxyribonucleic acid (small circles of deoxyribonucleic acid located in the mitochondria, the cell’s energy producer). The aim of this review was to summarise and critically evaluate existing evidence on how effective (the degree to which a test does more harm than good) and cost-effective (how effective a test is in relation to its cost) the Genedrive MT-RNR1 ID Kit is for identifying the m.1555A>G gene variant in newborns or in their mothers. We collected and analysed all relevant research studies, one moderate quality study was included in the clinical effectiveness review and no studies were included in the cost-effectiveness review. The quality of the included study was assessed as moderate for most of the outcomes (things measured to monitor the degree to which the test does more good than harm) reported due to uncertainty regarding the failure rate of the test. The results suggested that the test was capable of identifying newborns with the m.1555A>G variant. This was accomplished by successfully testing 424 out of 526 patients, with three newborns identified as carrying the gene and avoiding aminoglycoside treatment. Because of these small numbers, there does remain some uncertainty regarding the accuracy of the test. Additionally, time to antibiotic administration was not negatively impacted by the test. Similar time for treatment initiation was taken for those tested as for those not tested. This review shows that the Genedrive MT-RNR1 ID Kit has the potential to identify the m.1555A>G variant and the potential to provide value for money for the National Health Service. However, as expected, there is not enough evidence to conduct a full assessment of the clinical effectiveness and cost-effectiveness of Genedrive MT-RNR1 ID Kit in newborns directly, or their mothers. This could be addressed by generating further evidence. The risk and severity of hearing loss from aminoglycoside use is of particular interest, as is further testing of the Genedrive MT-RNR1 ID Kit in both neonates and mothers or neonates who need treatment. Such testing conducted in other settings would be of great importance. Scientific summary Background Sepsis and bacterial infections are a significant cause of mortality and morbidity in neonates (up to and including a corrected gestational age of 28 days). Expert opinion suggests that the incidence of culture-confirmed neonatal infection is around 1 in 2000 deliveries. But a larger proportion of babies will go on to receive precautionary antibiotic treatment for suspected infection [e.g. 30–60 in 1000 for those admitted to neonatal intensive care units (NICUs)]. Treatment for suspected infection or sepsis is commonly conducted using gentamicin, an antibiotic of the aminoglycoside family. This antibiotic is associated with a high risk of ototoxicity in those with a genetic variation of the mitochondrial MT-RNR1 gene, specifically m.1555A>G. The purpose of this assessment was to investigate the use of the Genedrive MT-RNR1 ID Kit for identifying the m.1555A>G variant in neonates with suspected infection or sepsis. This technology has the potential to identify those at most risk of ototoxicity from aminoglycoside antibiotics and inform treatment decisions within the time frame recommended by National Institute for Health and Care Excellence (NICE) guidance. Aim The overall aim of this early value assessment was to summarise and critically appraise existing evidence on the clinical effectiveness and cost-effectiveness of the Genedrive MT-RNR1 ID Kit for identifying the m.1555A>G gene variant in neonates or their mothers. Methods A rapid review methodology was used to identify eligible studies for clinical effectiveness and cost-effectiveness. Databases searches were conducted on MEDLINE, EMBASE and CINAHL (Cumulative Index to Nursing and Allied Health Literature) for both aspects of the review; additionally, the cost-effectiveness review searched Cochrane and RePEc-IDEAS from 2010 to November 2022. Search results were screened by two independent reviewers. Only one study met the inclusion criteria for the clinical effectiveness rapid review, and no studies met the eligibility criteria for the cost-effectiveness rapid review. Data extraction and quality appraisal of the clinical effectiveness study were completed by one reviewer and checked for accuracy by another. Quality appraisal was conducted per outcome, the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool was used to assess diagnostic test accuracy outcomes, and the ROBINS-I (Risk Of Bias In Non-randomized Studies – of Interventions) tool was used for all other outcomes. Meta-analyses were not possible as only one study was included in the clinical effectiveness rapid review. Care pathways with and without the use of the Genedrive MT-RNR1 ID Kit were developed and from these a conceptual economic evaluation model was developed. This was used to identify the information required to parameterise the model. Attempts were then made to identify relevant parameter values and evidence gaps where no or few data were identified. Using available information, an early health economic model was developed to provide initial estimates of the incremental cost per quality-adjusted life-year (QALY) gained for the comparison of the use of Genedrive MT-RNR1 ID Kit with current standard care. Results The evidence to inform this early value assessment was extremely limited. Only one study was included in the clinical effectiveness rapid review, for which risk of bias was rated as being moderate for most of the outcomes measured. The included study suggested high diagnostic test accuracy (sensitivity 100%, specificity 99.2%). Estimates of sensitivity were very uncertain due to a small number of true-positive cases (i.e. people with the m.1555A>G variant), but no false negatives were identified. However, there were some false positives (n = 5 of 8), and the specificity estimate was very high with sufficient precision. This was established from 424 successful tests, with a test failure rate of 17.1% (90 patients). The failure rate was reduced to 5.1% in repeated testing of samples after modifications were made to the assay buffer and the test cartridge was redesigned. Overall, three neonates were identified with the genetic variant. The trial research team were able to genotype the m.1555A>G variant using the Genedrive MT-RNR1 ID Kit in 26 minutes. Time to antibiotics when using the Genedrive MT-RNR1 ID Kit did not differ from normal practice (i.e. not using the test kit). Difference between groups was not statistically significant (mean difference –0.87 minutes, 95% confidence interval –5.96 to 4.23 minutes) and the 95% confidence interval was within the predefined boundary for statistical equivalence. We did not identify any studies that reported on the following intermediate, clinical or patient-related outcomes: impact of test implementation and use on healthcare resources, usability of the test, mortality and morbidity. Additionally, no studies assessed the use of the point-of-care test in mothers. No relevant economic evaluations were identified. From the conceptual economic model, key evidence gaps were identified. These include the sensitivity of the Genedrive MT-RNR1 ID Kit for identifying the m.1555A>G gene variant in neonates, the magnitude of risk for aminoglycoside-induced hearing loss (AIHL) in neonates and mothers with m.1555A>G, and the prevalence of the gene m.1555A>G variant. Other potential important gaps include how data regarding maternal inheritance may potentially be used in the clinical pathway. The early health economic model focused on some of those parameters where, on consideration of the available data, the estimates of cost-effectiveness would be most sensitive to changes. The results of this model showed that the use of the Genedrive MT-RNR1 ID Kit for identification of the m.1555A>G genetic variant could potentially be cost-effective, with lower costs (£58.48) and higher effectiveness in terms of QALYs (0.01) over the patient lifetime. In a deterministic sensitivity analysis, the results were shown to be most sensitive to changes in the time horizon, the sensitivity of the Genedrive MT-RNR1 ID Kit system, the proportion of neonates with m.1555A>G variant suffering from AIHL after being exposed to aminoglycosides and the prevalence of the m.1555A>G variant in the UK population. Conclusions There is limited evidence for the assessment of the Genedrive MT-RNR1 ID Kit for identification of the m.1555A>G genetic variant. The test was conducted in two large NICUs and thus may not be generalisable to smaller NICUs or other hospitals. Therefore, the use of the Genedrive MT-RNR1 Kit should be investigated further in varying settings. Furthermore, although modifications were made to the kit to reduce its failure rate, when it was used in the clinical setting this was not completely eradicated. However, there is evidence to suggest that the use of the kit did not substantially impact on time to antibiotics and has the potential to identify the m.1555A>G variant. There were no existing economic evaluations that addressed this topic. The total cost per test to the NHS was estimated to be £130; however, there is uncertainty surrounding this estimate given that this cost is likely to vary by size and type of site. The results of the early economic evaluation model suggest that the use of the Genedrive MT-RNR1 ID Kit to identify the m.1555A>G genetic variant could potentially be cost-effective. Once evidence regarding the reported evidence gaps has been identified, a full diagnostic assessment should be undertaken to establish the cost-effectiveness of the Genedrive MT-RNR1 ID Kit. Suggested priorities for further research This report identifies two key priorities for research required to reduce the uncertainty around this early value assessment and to provide the additional data needed to inform a full diagnostic assessment, including cost-effectiveness modelling. The risk and the severity of AIHL in neonates with the m.1555A>G variant was identified as key uncertainties in the economic model. Limitations of the current literature, which is primarily based on case–control studies in hearing-impaired populations with the m.1555A>G variant, are provided in more detail below. Future studies, perhaps including existing cohorts in the UK, are required to identify sufficient numbers of people with the m.1555A>G variant who have been exposed to aminoglycosides in a sample that includes participants with and participants without hearing impairment. A second priority for research is further validation of the Genedrive MT-RNR1 ID Kit in both neonates and mothers of neonates who need or may need aminoglycoside treatment. The sensitivity of the test was an important uncertainty in the economic model. Further studies including more people with the m.1555A>G variant will increase the precision of the estimated sensitivity of the test. In addition, only the pharmacogenetics to avoid loss of hearing (PALOH) study has investigated the validity of the Genedrive MT-RNR1 ID Kit. This study was conducted in two large NICUs, and further research is needed to assess if the findings of the PALOH study generalise to smaller NICUs and other relevant hospital settings. In addition, our focus group with parents and a review of parents’ comments on internet forums identified that further work may be required to obtain informed consent. A final area for further research is to provide updated and more comprehensive estimates of health state utility values. Data that are currently available are restricted in terms of health states considered or use health-related quality-of-life tools whose relevance to UK decision-makers may be limited. Study registration This study is registered as PROSPERO (CRD42022364770). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135636) and is published in full in Health Technology Assessment; Vol. 28, No. 75. See the NIHR Funding and Awards website for further award information.