The cost of proband and trio exome and genome analysis in rare disease: A micro-costing study.

PURPOSE: Rare disease genomic testing is a complex process involving various resources. Accurate resource estimation is required for informed prioritization and reimbursement decisions. This study aims to analyze the costs and cost drivers of clinical genomic testing. METHODS: Based on genomic sequencing workflows we microcosted limited virtual panel analysis on exome sequencing backbone, proband and trio exome, and genome testing for proband and trio analysis in 2023 Australian Dollars ($). Deterministic and probabilistic sensitivity analyses were undertaken. RESULTS: Panel testing costs AUD $2373 ($733-$6166), and exome sequencing costs $2823 ($802-$7206) and $5670 ($2006-$11,539) for proband and trio analysis, respectively. Genome sequencing costs $4840 ($2153-$9890) and $11,589 ($5842-$16,562) for proband and trio analysis. The most expensive cost component of genomic testing was sequencing (36.9%-69.4% of total cost), with labor accounting for 27.1%-63.2% of total cost. CONCLUSION: We provide a comprehensive analysis of rare disease genomic testing costs, for a range of clinical testing types and contexts. This information will accurately inform economic evaluations of rare disease genomic testing and decision making on policy settings that assist with implementation, such as genomic testing reimbursement.

Microcosting diagnostic genomic sequencing: A systematic review.

PURPOSE: Microcosting can provide valuable economic evidence to inform the translation of genomic sequencing to clinical practice. A systematic literature review was conducted to identify studies employing microcosting methods to estimate the cost of genomic sequencing to diagnose cancer and rare diseases. METHODS: Four electronic databases, Medline, Embase, EconLit, and Cumulated Index to Nursing and Allied Health Literature were searched. Reference lists of identified studies were also searched. Studies were included if they had estimated the cost of genome sequencing or exome sequencing for cancer or rare disease diagnosis using microcosting methods. RESULTS: Seven studies met the inclusion criteria. Cost estimates for genome sequencing and exome sequencing ranged between US$2094 and $9706 and US$716 and $4817 per patient, respectively. All studies disaggregated resource use and cost inputs into labor, equipment, and consumables, with consumables being the main cost component. Considerable differences in the level of detail used to report the steps and resources used in each of the sequencing steps limited study comparisons. CONCLUSION: Defining a standard microcosting methodology is challenging because of the heterogeneous nature of genomic sequencing. Reporting of detailed and complete sequencing procedures, inclusion of sensitivity analyses and clear justifications of resource use, and measurement of unit costs can improve comparability, transferability, and generalizability of study findings.

Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism.

Early diagnosis of inborn errors of metabolism (IEM)-a large group of congenital disorders-is critical, given that many respond well to targeted therapy. Newborn screening programs successfully capture a proportion of patients enabling early recognition and prompt initiation of therapy. For others, the heterogeneity in clinical presentation often confuses diagnosis with more common conditions. In the absence of family history and following clinical suspicion, the laboratory diagnosis typically begins with broad screening tests to circumscribe specialised metabolite and/or enzyme assays to identify the specific IEM. Confirmation of the biochemical diagnosis is usually achieved by identifying pathogenic genetic variants that will also enable cascade testing for family members. Unsurprisingly, this diagnostic trajectory is too often a protracted and lengthy process resulting in delays in diagnosis and, importantly, therapeutic intervention for these rare conditions is also postponed. Implementation of mass spectrometry technologies coupled with the expanding field of metabolomics is changing the landscape of diagnosing IEM as numerous metabolites, as well as enzymes, can now be measured collectively on a single mass spectrometry-based platform. As the biochemical consequences of impaired metabolism continue to be elucidated, the measurement of secondary metabolites common across groups of IEM will facilitate algorithms to further increase the efficiency of diagnosis.

A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.

PURPOSE: To prospectively evaluate the diagnostic and clinical utility of singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic disease. METHODS: Singleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center. This occurred in parallel with standard investigations, including single- or multigene panel sequencing when clinically indicated. The diagnosis rate, clinical utility, and impact on management of singleton WES were evaluated. RESULTS: Of 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group. Clinical management changed following exome diagnosis in 15 of 46 diagnosed participants (32.6%). Twelve relatives received a genetic diagnosis following cascade testing, and 28 couples were identified as being at high risk of recurrence in future pregnancies. CONCLUSIONS: This prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier sequencing test for infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner.Genet Med 18 11, 1090-1096.

Pachyonychia Congenita: A Spectrum of KRT6a Mutations in Australian Patients.

BACKGROUND: Pachyonychia congenita (PC) is a rare inherited disorder of keratinization characterised by hypertrophic nail dystrophy, painful palmoplantar blisters, cysts, follicular hyperkeratosis and oral leukokeratosis. It is associated with mutations in five differentiation-specific keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. OBJECTIVES: Living with Pachyonychia Congenita can be isolating. The aim of this paper is to document a single patient's experience within a national context. METHOD: We report the case of a 2 year old female with an atypical presentation of PC due to a mutation in KRT6A with severely hypertrophic follicular keratoses, skin fragility, relative sparing of nail hypertrophy on one hand and failure to thrive in early infancy. In collaboration with the International Pachyonychia Congenita Research Registry (IPCRR), a database search was performed using Australian residency and KRT6A mutation as inclusion criteria. The IPCRR database was also searched for a matching KRT6A mutation. Six Australian patients were identified in addition to one patient with an identical mutation residing in the United States. The detailed standardized patient questionnaire data was manually collated and analysed. RESULTS: Fingernail hypertrophy and oral leukokeratosis were the most common features. There was no recording of asymmetric distribution in any other Australian patient. Trouble nursing as an infant and follicular hyperkeratosis also occurred in the American patient, however they did not have asymmetric distribution and the oral leukokeratosis appeared later in life. CONCLUSION: This case has unique features. Sharing information can assist patients navigating life with this condition.

Presentation of m.3243A>G (MT-TL1; tRNALeu) variant with focal neurology in infancy.

The Mitochondrial tRNALeu (MT-TL1) mutation, m.3243A>G constitutes the commonest identified mitochondrial genome mutation. Characteristically, giving rise to MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), a phenotypic spectrum associated with this genetic variant is now apparent. We report on the first patient with infantile hemiparesis, without comorbid encephalopathy, attributed to this variant. This further expands the recognized disease spectrum and highlights the need to consider mitochondrial genomic mutations in cases of cryptogenic focal neurological deficit in infancy. The potential for genetic disease modifiers is additionally discussed.

Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: a case report and literature review.

Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.

Patient characteristics of, and remedial interventions for, complaints and medico-legal claims against doctors: a rapid review of the literature.

BACKGROUND: It is uncertain if patient's characteristics are associated with complaints and claims against doctors. Additionally, evidence for the effectiveness of remedial interventions on rates of complaints and claims against doctors has not been synthesised. METHODS: We conducted a rapid review of recent literature to answer: Question 1 "What are the common characteristics and circumstances of patients who are most likely to complain or bring a claim about the care they have received from a doctor?" and Question 2 "What initiatives or interventions have been shown to be effective at reducing complaints and claims about the care patients have received from a doctor?". We used a systematic search (most recently in July 2023) of PubMed, Scopus, Web of Science and grey literature. Studies were screened against inclusion criteria and critically appraised in duplicate using standard tools. Results were summarised using narrative synthesis. RESULTS: From 8079 search results, we reviewed the full text of 250 studies. We included 25 studies: seven for Question 1 (6 comparative studies with controls and one systematic review) and 18 studies for Question 2 (14 uncontrolled pre-post studies, 2 comparative studies with controls and 2 systematic reviews). Most studies were set in hospitals across a mix of medical specialties. Other than for patients with mental health conditions (two studies), no other patient characteristics demonstrated either a strong or consistent effect on the rate of complaints or claims against their treating doctors. Risk management programs (6 studies), and communication and resolution programs (5 studies) were the most studied of 6 intervention types. Evidence for reducing complaints and medico-legal claims, costs or premiums and more timely management was apparent for both types of programs. Only 1 to 3 studies were included for peer programs, medical remediation, shared decision-making, simulation training and continuing professional development, with few generalisable results. CONCLUSION: Few patient characteristics can be reliably related to the likelihood of medico-legal complaints or claims. There is some evidence that interventions can reduce the number and costs of claims, the number of complaints, and the timeliness of claims. However, across both questions, the strength of the evidence is very weak and is based on only a few studies or study designs that are highly prone to bias.

No Women's Land: Australian Women Veterans' Experiences of the Culture of Military Service and Transition.

Women's experiences of military service and transition occur within a highly dominant masculinized culture. The vast majority of research on military veterans reflects men's experiences and needs. Women veterans' experiences, and therefore their transition support needs, are largely invisible. This study sought to understand the role and impact of gender in the context of the dominant masculinized culture on women veterans' experiences of military service and transition to civilian life. In-depth qualitative interviews with 22 Australian women veterans elicited four themes: (1) Fitting in a managing identity with the military; (2) Gender-based challenges in conforming to a masculinized culture-proving worthiness, assimilation, and survival strategies within that culture; (3) Women are valued less than men-consequences for women veterans, including misogyny, sexual harassment and assault, and system failures to recognize women's specific health needs and role as mothers; and (4) Separation and transition: being invisible as a woman veteran in the civilian world. Gendered military experiences can have long-term negative impacts on women veterans' mental and physical health, relationships, and identity due to a pervasive masculinized culture in which they remain largely invisible. This can create significant gender-based barriers to services and support for women veterans during their service, and it can also impede their transition support needs.

Nudging towards COVID-19 and influenza vaccination uptake in medically at-risk children: EPIC study protocol of randomised controlled trials in Australian paediatric outpatient clinics.

INTRODUCTION: Children with chronic medical diseases are at an unacceptable risk of hospitalisation and death from influenza and SARS-CoV-2 infections. Over the past two decades, behavioural scientists have learnt how to design non-coercive 'nudge' interventions to encourage positive health behaviours. Our study aims to evaluate the impact of multicomponent nudge interventions on the uptake of COVID-19 and influenza vaccines in medically at-risk children. METHODS AND ANALYSES: Two separate randomised controlled trials (RCTs), each with 1038 children, will enrol a total of approximately 2076 children with chronic medical conditions who are attending tertiary hospitals in South Australia, Western Australia and Victoria. Participants will be randomly assigned (1:1) to the standard care or intervention group. The nudge intervention in each RCT will consist of three text message reminders with four behavioural nudges including (1) social norm messages, (2) different messengers through links to short educational videos from a paediatrician, medically at-risk child and parent and nurse, (3) a pledge to have their child or themselves vaccinated and (4) information salience through links to the current guidelines and vaccine safety information. The primary outcome is the proportion of medically at-risk children who receive at least one dose of vaccine within 3 months of randomisation. Logistic regression analysis will be performed to determine the effect of the intervention on the probability of vaccination uptake. ETHICS AND DISSEMINATION: The protocol and study documents have been reviewed and approved by the Women's and Children's Health Network Human Research Ethics Committee (HREC/22/WCHN/2022/00082). The results will be published via peer-reviewed journals and presented at scientific meetings and public forums. TRIAL REGISTRATION NUMBER: NCT05613751.

Development of a microcosting protocol to determine the economic cost of diagnostic genomic testing for rare diseases in Australia.

INTRODUCTION: Genomic testing is a relatively new, disruptive and complex health technology with multiple clinical applications in rare diseases, cancer and infection control. Genomic testing is increasingly being implemented into clinical practice, following regulatory approval, funding and adoption in models of care, particularly in the area of rare disease diagnosis. A significant barrier to the adoption and implementation of genomic testing is funding. What remains unclear is what the cost of genomic testing is, what the underlying drivers of cost are and whether policy differences contribute to cost variance in different jurisdictions, such as the requirement to have staff with a medical license involved in testing. This costing study will be useful in future economic evaluations and health technology assessments to inform optimal levels of reimbursement and to support comprehensive and comparable assessment of healthcare resource utilisation in the delivery of genomic testing globally. METHODS: A framework is presented that focuses on uncovering the process of genomic testing for any given laboratory, evaluating its utilisation and unit costs, and modelling the cost drivers and overall expenses associated with delivering genomic testing. The goal is to aid in refining and implementing policies regarding both the regulation and funding of genomic testing. A process-focused (activity-based) methodology is outlined, which encompasses resources, assesses individual cost components through a combination of bottom-up and top-down microcosting techniques and allows disaggregation of resource type and process step. ETHICS AND DISSEMINATION: The outputs of the study will be reported at relevant regional genetics and health economics conferences, as well as submitted to a peer-reviewed journal focusing on genomics. Human research ethics committee approval is not required for this microcosting study. This study does not involve research on human subjects, and all data used in the analysis are either publicly available.

"The Days Are Long But the Nights Are Even Longer": A Mixed-Method Study of Sleep Disturbances Among Patients in an Inpatient Rehabilitation Program.

Objective: To assess sleep quality of patients on a rehabilitation ward and to identify staff practices and beliefs about management of sleep disturbance. Design: Mixed-methods design including patient surveys and staff interviews. Setting: Inpatient rehabilitation ward in a tertiary teaching hospital in Adelaide, Australia. Participants: Of the 345 screened inpatients who had been in a mixed post-acute rehabilitation ward for at least 5 days, 120 (43% women) were included. The mean age was 67.7 years and the main admission reason was functional decline (40%). Patients with stroke or traumatic brain injury were excluded. Eleven (n = 11) staff (a mix of doctors, nurses, and allied health) were interviewed. Main Outcome Measures: The surveys comprised of the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, the Flinders Fatigue Scale, and the Sleep Inertia Questionnaire. The survey results were compared with functional outcomes using the functional independence measure (FIM). Staff interviews delved into barriers to good sleep, ward practices, and knowledge about sleep hygiene. Results: 43% of the surveyed patients reported having healthy amount of sleep. Sleep quality was not significantly correlated with rehabilitation outcomes (assessed using FIM). Staff reported having a good awareness of sleep hygiene; however, acknowledged limitations about the environment and routine which were not conducive to healthy sleep. They identified several actions which could be taken to improve patients' sleep hygiene. Conclusions: Sleep disturbance is common for patients in rehabilitation. Rehabilitation wards should address this often-neglected critical component of rehabilitation to improve patient experience and potential participation in therapy. Introducing a systematic approach for assessing sleep during admission, establishing clear roles regarding sleep assessment and intervention among staff, and ensuring that patients and staff are aware of good sleep hygiene practices may promote better sleep during inpatient rehabilitation.

Randomised controlled trials of behavioural nudges delivered through text messages to increase influenza and COVID-19 vaccines among pregnant women (the EPIC study): study protocol.

BACKGROUND: Influenza and COVID-19 infections during pregnancy may have serious adverse consequences for women as well as their infants. However, uptake of influenza and COVID-19 vaccines during pregnancy remains suboptimal. This study aims to assess the effectiveness of a multi-component nudge intervention to improve influenza and COVID-19 vaccine uptake among pregnant women. METHODS: Pregnant women who receive antenatal care at five tertiary hospitals in South Australia, Western Australia and Victoria will be recruited to two separate randomised controlled trials (RCTs). Women will be eligible for the COVID-19 RCT is they have received two or less doses of a COVID-19 vaccine. Women will be eligible for the influenza RCT if they have not received the 2023 seasonal influenza vaccine. Vaccination status at all stages of the trial will be confirmed by the Australian Immunisation Register (AIR). Participants will be randomised (1:1) to standard care or intervention group (n = 1038 for each RCT). The nudge intervention in each RCT will comprise three SMS text message reminders with links to short educational videos from obstetricians, pregnant women and midwives and vaccine safety information. The primary outcome is at least one dose of a COVID-19 or influenza vaccine during pregnancy, as applicable. Logistic regression will compare the proportion vaccinated between groups. The effect of treatment will be described using odds ratio with a 95% CI. DISCUSSION: Behavioural nudges that facilitate individual choices within a complex context have been successfully used in other disciplines to stir preferred behaviour towards better health choices. If our text-based nudges prove to be successful in improving influenza and COVID-19 vaccine uptake among pregnant women, they can easily be implemented at a national level. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT05613751. Registered on November 14, 2022.

See How They Grow: Testing the feasibility of a mobile app to support parents' understanding of child growth charts.

BACKGROUND: Mobile devices provide new opportunities for the prevention of overweight and obesity in children. We aimed to co-create and test an app that offered comprehensible feedback to parents on their child's growth and delivered a suite of age-specific information about nutrition and activity. METHODS: A two-phased approach was used to co-create the digital growth tool-See How They Grow-and test its feasibility. Phase one used focus groups (parents and professionals such as paediatricians and midwives) and a national on-line survey to gather requirements and build the app. Phase two involved testing the app over 12-weeks, with parents or carers of children aged ≤ 2-years. All research activities were undertaken exclusively through the app, and participants were recruited using social media and hard copy materials given to patents at a child health visit. FINDINGS: Four focus groups and 101 responses to the national survey informed the features and functions to include in the final app. Two hundred and twenty-five participants downloaded the app, resulting in 208 eligible participants. Non-Maori/Non-Pacific (78%) and Maori (14%) had the highest downloads. Fifty-four per cent of participants were parents of children under 6-months. These participants were more likely to regularly use the app than those with children older than 6-months (64% vs 36%, P = 0.011). Over half of the participants entered three measures (n = 101, 48%). Of those that completed the follow-up survey (n = 101, 48%), 72 reported that the app helped them better understand how to interpret growth charts. CONCLUSION: The app was acceptable and with minor modifications, has the potential to be an effective tool to support parents understanding of growth trajectories for their children. A larger trial is needed to evaluate if the app can have a measurable impact on increasing knowledge and behaviour, and therefore on preventing childhood overweight and obesity.

On Clinical Utility and Systematic Reporting in Case Studies of Healthcare Process Mining.

Recently in Environmental Research and Public Health, Helm and colleagues reported on a systematic review of healthcare process mining (HPM) case reports, focusing on the reporting of technical and clinical aspects and discussing standardisation terms in future HCM reports utilising existing ontologies [...].

Interventions for Post-Stroke Shoulder Pain: An Overview of Systematic Reviews.

BACKGROUND: Shoulder pain following stroke leads to poorer quality of life and daily functioning. Whilst many treatment approaches exist, there is currently no systematic overview of the evidence base for these. This review addressed the question "What is the evidence for interventions for treating hemiplegic shoulder pain?" METHODS: An overview of systematic reviews was performed according to PROSPERO protocol (CRD42020140521). Five electronic databases including Cochrane, MEDLINE, Embase and EmCare were searched to June 2019. Included systematic reviews were those of comparative trials of interventions for hemiplegic shoulder pain in adults, reporting pain outcomes using a validated pain scale. Review quality was assessed with AMSTAR2 and those considered at high risk of bias for four or more items were excluded. The most recent, comprehensive review for each intervention category was included. Outcomes of function and quality of life were also extracted. RESULTS: Seven systematic reviews of 11 interventions were included, with varied quality. Reviews showed significant benefits in terms of pain reduction for many interventions including acupuncture (conventional 19 trials, electroacupuncture 5 trials, fire needle 2 trials, warm needle 1 trial and bee venom 3 trials), orthoses (1 trial), botulinum toxin injection (4 trials), electrical stimulation (6 trials) and aromatherapy (1 trial). However, the majority of trials were small, leading to imprecise estimates of effect. Findings were often inconsistent across outcome measures or follow-up times. Outcomes from trials of acupuncture were heterogenous with likely publication bias. CONCLUSION: A number of systematic reviews indicate significant reductions in pain, with a wide range of treatments appearing promising. However, significant limitations mean the clinical importance of these findings are uncertain. Due to complex etiology, practitioners and health systems must consider the range of potential interventions and tailor their approach to individual presentation, guided by their local circumstances, expert opinion and the growing literature base.

Healthcare pathway discovery and probabilistic machine learning.

BACKGROUND AND PURPOSE: Healthcare pathways define the execution sequence of clinical activities as patients move through a treatment process, and they are critical for maintaining quality of care. The aim of this study is to combine healthcare pathway discovery with predictive models of individualized recovery times. The pathway discovery has a particular emphasis on producing pathway models that are easy to interpret for clinicians without a sufficient background in process mining. The predictive model takes the stochastic volatility of pathway performance indicators into account. METHOD: This study utilizes the business process-mining software ProM to design a process mining pipeline for healthcare pathway discovery and enrichment using hospital records. The efficacy of combining learned healthcare pathways with probabilistic machine learning models is demonstrated via a case study that applies the proposed process mining pipeline to discover appendicitis pathways from hospital records. Machine learning methodologies based on probabilistic programming are utilized to explore pathway features that influence patient recovery time. RESULTS: The produced appendicitis pathway models are easy for clinical interpretation and provide an unbiased overview of patient movements through the treatment process. Analysis of the discovered pathway model enables reasons for longer than usual treatment times to be explored and deviations from standard treatment pathways to be identified. A probabilistic regression model that estimates patient recovery time based on the information extracted by the process mining pipeline is developed and has the potential to be very useful for hospital scheduling purposes. CONCLUSION: This study establishes the application of the business process modelling tool ProM for the improvement of healthcare pathway mining methods. The proposed pipeline for healthcare pathway discovery has the potential to support the development of probabilistic machine learning models to further relate healthcare pathways to performance indicators such as patient recovery time.