ABSTRACT
PURPOSE: Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively. METHODS: ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. RESULTS: The ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis. CONCLUSION: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost.
Subject(s)
Exome Sequencing , Exome , Intellectual Disability , Humans , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Male , Female , Exome/genetics , Exome Sequencing/economics , Cohort Studies , Genetic Testing/economics , Genetic Testing/methods , Whole Genome Sequencing/economics , Child , Genome, Human/genetics , DNA Copy Number Variations/genetics , Polymorphism, Single Nucleotide/genetics , Child, PreschoolABSTRACT
INTRODUCTION: This study presents a Mammalian Linear Expression System (MLES), a linear covalently closed (LCC) vector based on pVAX-1. The purpose of this system was to improve gene expression in mammalian cells and to test the efficacy of MLES in transient transfection and transgene expression using in vitro and in vivo models. Additionally, we aimed to evaluate potential inflammatory responses in vivo. MATERIALS AND METHODS: MLES was developed by modifying pVAX-1, and the construct was confirmed by gel electrophoresis. Lipofectamine®2000 was used to assess the transfection efficiency and expression of MLES in various cell lines. In vivo studies were conducted in mice injected with MLES/EGFP, and the resulting transfection efficiency, gene expression, and inflammatory responses were analyzed. RESULTS: MLES exhibited higher transfection efficiency and expression levels compared to pVAX-1 when tested on HEK-293, CHO-K1, and NIH-3T3 cells. When tested in vivo, MLES/EGFP showed elevated expression in the heart, kidney, liver, and spleen compared with pVAX-1/EGFP. Minimal changes are observed in the lungs. Additionally, MLES induced a reduced inflammatory response in mice compared with pVAX-1/EGFP. CONCLUSIONS: MLES offer improved transfection efficiency and reduced inflammation, representing a significant advancement in gene therapy and recombinant protein production. Further research on MLES-mediated gene expression and immune modulation will enhance gene therapy strategies.
Subject(s)
Cricetulus , Gene Expression , Genetic Vectors , Transfection , Transgenes , Animals , Mice , Humans , Genetic Vectors/genetics , HEK293 Cells , Transfection/methods , CHO Cells , NIH 3T3 Cells , Gene Expression/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolismABSTRACT
Microvesicles (MVs) serve as biomarkers and transmitters for cell communication and also act as essential contributors to diseases. Platelets release microvesicles when activated voluntarily, making them a significant source. Platelet-derived microvesicles possess a range of characteristics similar to their parent cells and were shown to exert regulatory impacts on vascular and immunological cells. MVs can alter the activity of recipient cells by transferring their internal components. Furthermore, it has been identified that microvesicles derived from platelets possess the ability to exert immunomodulatory effects on different kinds of cells. Recent research has shown that microvesicles have a bidirectional influence of harming and preventing the receptor cells. Nevertheless, the specific characteristics of the active molecules responsible for this phenomenon are still unknown. The primary focus of this review was to explore the mechanism of vascular tissue regeneration and the specific molecules that play a role in mediating various biological effects throughout this process. These molecules exert their effects by influencing autophagy, apoptosis, and inflammatory pathways.
Subject(s)
Apoptosis , Blood Platelets , Autophagy , Cell Communication , ImmunomodulationABSTRACT
INTRODUCTION: Spinal cord injury (SCI) leads to significant destruction of nerve tissue, causing the degeneration of axons and the formation of cystic cavities. This study aimed to examine the characteristics of human umbilical cord-derived mesenchymal stem cells (HUCMSCs) cultured in a serum-free conditioned medium (CM) and assess their effectiveness in a well-established hemitransection SCI model. MATERIALS AND METHODS: In this study, HUCMSCs cultured medium was collected and characterized by measuring IL-10 and identifying proteomics using mass spectroscopy. This collected serum-free CM was further used in the experiments to culture and characterize the HUMSCs. Later, neuronal cells derived from CM-enriched HUCMSC were tested sequentially using an injectable caffeic acid-bioconjugated gelatin (CBG), which was further transplanted in a hemitransection SCI model. In vitro, characterization of CM-enriched HUCMSCs and differentiated neuronal cells was performed using flow cytometry, immunofluorescence, electron microscopy, and post-transplant analysis using immunohistology analysis, qPCR, in vivo bioluminescence imaging, and behavioral analysis using an infrared actimeter. RESULTS: The cells that were cultured in the conditioned media produced a pro-inflammatory cytokine called IL-10. Upon examining the secretome of the conditioned media, the Kruppel-like family of KRAB and zinc-finger proteins (C2H2 and C4) were found to be activated. Transcriptome analysis also revealed an increased expression of ELK-1, HOXD8, OTX2, YY1, STAT1, ETV7, and PATZ1 in the conditioned media. Furthermore, the expression of Human Stem-101 confirmed proliferation during the first 3 weeks after transplantation, along with the migration of CBG-UCNSC cells within the transplanted area. The gene analysis showed increased expression of Nestin, NeuN, Calb-2, Msi1, and Msi2. The group that received CBG-UCNSC therapy showed a smooth recovery by the end of week 2, with most rats regaining their walking abilities similar to those before the spinal cord injury by week 5. CONCLUSIONS: In conclusion, the CBG-UCNSC method effectively preserved the integrity of the transplanted neuronal-like cells and improved locomotor function. Thus, CM-enriched cells can potentially reduce biosafety risks associated with animal content, making them a promising option for clinical applications in treating spinal cord injuries.
Subject(s)
Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Spinal Cord Injuries , Transcriptome , Umbilical Cord , Spinal Cord Injuries/therapy , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/genetics , Mesenchymal Stem Cells/metabolism , Culture Media, Conditioned/pharmacology , Umbilical Cord/cytology , Umbilical Cord/metabolism , Humans , Animals , Mesenchymal Stem Cell Transplantation/methods , Transcriptome/genetics , Rats , Secretome/metabolism , Cell Differentiation , Neurons/metabolism , Disease Models, Animal , Interleukin-10/genetics , Interleukin-10/metabolism , Cells, Cultured , Proteomics/methodsABSTRACT
The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.
What is the context?â Chemotherapy, radiation treatment, or immunological disorders can cause a decrease in platelet count (thrombocytopenia) or decrease all blood cell types (pancytopenia) in the bone marrow. This can make it challenging to choose the appropriate cancer treatment plan.â Eltrombopag (EPAG) is an oral non-peptide thrombopoietin (TPO) mimetic that activates the cMPL receptor in the body. This activation leads to cell differentiation and proliferation, stimulating platelet production and reducing thrombocytopenia. The cMPL receptor is present in liver cells, megakaryocytes, and hematopoietic cells. However, its effects on stem cell proliferation and differentiation are not entirely understood.What is the new?â This study delves into the molecular interactions and therapeutic applications of EPAG, a small molecule that activates cMPL (TPO-R).â The study offers a comprehensive analysis of the ligand-receptor complex formation, including an examination of downstream signaling elements. Furthermore, molecular dynamics simulations demonstrate the stability of the ligand when interacting with targeted proteins.â The research investigates the presence of TPO-R on stem cell-derived endothelial cells, shedding insight into the ability of EPAG TPO-mimetic to promote angiogenesis and vasculature formation.â The study revealed that EPAG has the potential to protect against UVB-induced radiation damage and stimulate stem cell growth.What is the implications?The study emphasizes the potential of EPAG as a promising option for addressing radiation injury and minimizing the adverse effects of radiotherapy. It could revolutionize treatments not only for thrombocytopenia but also for enhancing the growth of stem cells. Furthermore, the research deepens our understanding of EPAG's molecular mechanisms, providing valuable insights for developing future drugs and therapeutic approaches for cell therapy to treat radiation damage.
Subject(s)
Benzoates , Pyrazoles , Receptors, Thrombopoietin , Humans , Pyrazoles/pharmacology , Benzoates/pharmacology , Receptors, Thrombopoietin/metabolism , Hydrazones/pharmacology , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/drug effects , Hydrazines/pharmacology , Hydrazines/therapeutic use , Molecular Dynamics Simulation , AngiogenesisABSTRACT
PURPOSE: This study aimed to evaluate the cost effectiveness of population-based, expanded reproductive carrier screening (RCS) for a 300 recessive gene panel from health service and societal perspectives. METHODS: A microsimulation model (PreConMod) was developed using 2016 Australian Census data as the base population. Epidemiologic, health, and indirect cost data were based on literature review. The study assessed the incremental cost effectiveness ratio of expanded RCS compared with (1) no population screening and (2) 3-condition screening for cystic fibrosis, spinal muscular atrophy, and fragile X syndrome in a single birth cohort. Averted affected births and health service savings with expanded RCS were projected to year 2061. Both one-way and probability sensitivity analyses were conducted to assess the uncertainty of the parameter inputs. RESULTS: Expanded RCS was cost saving compared with no population screening and cost effective compared with the 3-condition screening (incremental cost effectiveness ratio of Australian dollar [AUD] 6287 per quality-adjusted life year gained) at an uptake rate of 50% for RCS, 59% for in vitro fertilization and preimplantation genetic testing, 90% for prenatal diagnosis testing, and 50% for elective termination of affected pregnancies and a cost of AUD595 per couple screened. Our model predicts that expanded RCS would avert one-third of affected births in a single birth cohort and reduce lifetime health service spending by AUD632.0 million. Expanded RCS was estimated to be cost saving from the societal perspective. CONCLUSION: Expanded RCS is cost effective from health service and societal perspectives. Expanded RCS is projected to avert significantly more affected births and result in health service saving beyond those expected from 3-condition screening or no population screening.
Subject(s)
Genetic Testing , Prenatal Diagnosis , Pregnancy , Female , Humans , Cost-Benefit Analysis , Australia/epidemiology , Reproduction , Quality-Adjusted Life Years , Genetic Carrier ScreeningABSTRACT
OBJECTIVES: To estimate the health care and societal costs of inherited retinal diseases (IRDs) in Australia. DESIGN, SETTING, PARTICIPANTS: Microsimulation modelling study based on primary data - collected in interviews of people with IRDs who had ophthalmic or genetic consultations at the Children's Hospital at Westmead or the Save Sight Institute (both Sydney) during 1 January 2019 - 31 December 2020, and of their carers and spouses - and linked Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Schedule (PBS) data. MAIN OUTCOME MEASURES: Annual and lifetime costs for people with IRDs and for their carers and spouses, grouped by payer (Australian government, state governments, individuals, private health insurance) and type (health care costs; societal costs: social support, National Disability Insurance Scheme (NDIS), income and taxation, costs associated with caring for family members with IRDs); estimated annual national cost of IRDs. RESULTS: Ninety-four people (74 adults, 20 people under 18 years; 55 girls and women [59%]) and 30 carers completed study surveys (participation rate: adults, 66%; children, 66%; carers, 63%). Total estimated lifetime cost was $5.2 million per person with an IRD, of which 87% were societal and 13% health care costs. The three highest cost items were lost income for people with IRDs ($1.4 million), lost income for their carers and spouses ($1.1 million), and social spending by the Australian government (excluding NDIS expenses: $1.0 million). Annual costs were twice as high for people who were legally blind as for those with less impaired vision ($83 910 v $41 357 per person). The estimated total annual cost of IRDs in Australia was $781 million to $1.56 billion. CONCLUSION: As the societal costs associated with IRDs are much larger than the health care costs, both contributors should be considered when assessing the cost-effectiveness of interventions for people with IRDs. The increasing loss of income across life reflects the impact of IRDs on employment and career opportunities.
Subject(s)
National Health Programs , Retinal Diseases , Aged , Adult , Child , Humans , Female , Adolescent , Australia , Employment , Health Care Costs , Cost of IllnessABSTRACT
BACKGROUND: Advances in genomics provide improved opportunities for diagnosis of complex neurogenetic disorders, yet the optimal approach to translate these benefits to the outpatient clinic is unclear. AIMS: We retrospectively reviewed referral indications and outcomes of an integrated multidisciplinary team (MDT) clinic pathway for adults with suspected neurogenetic disorders. The associated cost implications were estimated. METHODS: Consecutive patients who attended the neurogenomics clinic from January 2017 to April 2020 were included. The clinic comprised neurologists, clinical geneticists and genetic counsellors, who assessed each patient concurrently. RESULTS: Ninety-nine new patients were referred spanning 45 different clinical diagnoses. Following MDT clinical assessment, 23% (23/99) of referral diagnoses were revised prior to molecular testing. Eighty-one patients (82%) underwent genetic testing, including 43 exome-based panels, 15 whole-genome sequencing, 14 single gene tests, 27 repeat-primed polymerase chain reaction testing and two chromosomal microarrays. Overall, 33/99 patients (33%) received a diagnosis, either a molecular diagnosis (n = 24, of which 22 were diagnostic and two were predictive) or a clinical diagnosis (n = 9). Of the clinical diagnosis cohort, five patients received a diagnosis without molecular testing and four patients whose negative testing (one diagnostic and three predictive) allowed exclusion of genetic differentials and, hence, confirmation of clinical diagnoses. The diagnostic rate following MDT and diagnostic testing was 30% (28/94), excluding the five predictive testing cases. MDT assessment aligned with eventual molecular diagnoses in 96% of cases. The estimated average costs were AU$1386 per patient undergoing MDT assessment and AU$4159 per diagnosis achieved. CONCLUSIONS: We present an integrated multidisciplinary neurogenomics clinic pathway providing a diagnostic yield of 33% (30% excluding predictive testing cases), with costing implications. The relatively high diagnostic yield may be attributed to multidisciplinary input integrating accurate phenotyping of complex disorders and interpretation of genomic findings.
Subject(s)
Ambulatory Care Facilities , Genetic Testing , Adult , Humans , Retrospective Studies , Exome , Referral and ConsultationABSTRACT
BACKGROUND: Internal Medicine (IM) programs offer elective subspecialty rotations in which residents may enroll to supplement the experience and knowledge obtained during general inpatient and outpatient rotations. Objective evidence that these rotations provide enhanced subspecialty specific knowledge is lacking. The purpose of this study was to determine whether exposure to an endocrinology subspecialty rotation enhanced a resident's endocrinology-specific knowledge beyond that otherwise acquired during IM residency. METHODS: Data were collected on internal medicine resident scores on the American College of Physicians Internal Medicine In-Training Examinations (IM-ITE) for calendar years 2012 through 2018 along with enrollment data as to whether residents had completed an endocrinology subspecialty rotation prior to sitting for a given IM-ITE. Three hundred and six internal medicine residents in the University of Minnesota Internal Medicine residency program with 664 scores total on the IM-ITE for calendar years 2012 through 2018. Percentage of correct answers on the overall and endocrine subspecialty content areas on the IM-ITE for each exam were determined and the association between prior exposure to an endocrinology subspecialty rotation and percentage of correct answers in the endocrinology content area was analyzed using generalized linear mixed-effects models. RESULTS: Two hundred and thirty-three residents (76%) completed an endocrinology subspecialty rotation at some point during their residency; 121 (40%) residents had at least one IM-ITE both before and after exposure to an endocrine subspecialty rotation. Exposure to an endocrinology subspecialty rotation exhibited a positive association with the expected IM-ITE percent correct on the endocrinology content area (5.5% predicted absolute increase). Advancing year of residency was associated with a predicted increase in overall IM-ITE score but did not improve the predictive model for endocrine subspecialty score. CONCLUSIONS: Completion of an endocrinology subspecialty elective was associated with an increase in resident endocrine specific knowledge as assessed by the IM-ITE. These findings support the value of subspecialty rotations in enhancing a resident's subspecialty specific medical knowledge.
Subject(s)
Endocrinology , Internship and Residency , Clinical Competence , Humans , Internal Medicine/education , KnowledgeABSTRACT
BACKGROUND: This study used a linked dataset consisting of all childhood cancers recorded over the course of 10 years in New South Wales (NSW), Australia, to evaluate the hospital and emergency department costs (from a payer perspective) and resources used by patients with childhood cancer. We also analyzed determinants responsible for high-frequency hospital admissions, hospital length of stay (LoS), and hospital costs. METHODS: We analyzed linked data at the individual patient level for a retrospective cohort of 2,966 patients with cancer aged <18 years with a diagnosis date between 2001 and 2012 from the NSW Central Cancer Registry, Australia. We reported costs and use of hospitalization and emergency department presentation 1 year before the date of diagnosis, 1 year after diagnosis, and 2 to 5 years after diagnosis. We also examined the association between cancer types and hospital admission and hospital costs from the payer perspective. Patient characteristics associated with the frequency of hospital admissions, hospital LoS, and hospital costs were also determined using a generalized linear model. RESULTS: Most hospital admission costs occurred in the first year after diagnosis, accounting for >70% of hospital costs within 5 years after diagnosis. The estimated median annual cost of hospitalization in the first year after diagnosis was A$88,964 (interquartile range [IQR], A$34,399-A$163,968) for patients diagnosed at age 0 to 14 years and A$23,384 (IQR, A$5,585-A$91,565) for those diagnosed at age 15 to 17 years. Higher frequency of hospital admissions, hospital LoS, and hospital costs were significantly associated with younger age at cancer diagnosis, cancer metastases, and living in remote/disadvantaged socioeconomic areas. CONCLUSIONS: Our study represents one of the first in Australia to include detailed hospitalization cost information for all childhood cancer cases. This study highlights the high hospital use by pediatric patients and the importance of early diagnosis. Our findings also demonstrate the health inequities experienced by patients from remote areas and the lowest socioeconomic areas.
Subject(s)
Hospital Costs , Neoplasms , Adolescent , Child , Child, Preschool , Hospitalization , Hospitals , Humans , Infant , Infant, Newborn , Length of Stay , Neoplasms/diagnosis , Neoplasms/epidemiology , Neoplasms/therapy , Retrospective StudiesABSTRACT
PURPOSE: To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses. METHODS: We collected information on continuing diagnostic investigation, changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES). RESULTS: The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing. CONCLUSION: These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis.
Subject(s)
Exome Sequencing/economics , Rare Diseases/diagnosis , Rare Diseases/economics , Rare Diseases/genetics , Child , Cost-Benefit Analysis/economics , Exome/genetics , Genetic Testing/economics , Genomics , Humans , Infant , Rare Diseases/epidemiologyABSTRACT
The original PDF version of this Article omitted to list Clara L Gaff as a corresponding author and the affiliations were incorrectly labelled as Present Addresses. Furthermore, Tables 1 and 2 have been updated to clarify that the Australian dollar is used for the values. These errors have now been corrected in the PDF and HTML versions of the Article.
ABSTRACT
BACKGROUND: Intellectual disability and autism spectrum disorder (ASD) influence the interactions of a person with their environment and generate economic and socioeconomic costs for the person, their family and society. AIMS: To estimate costs of lost workforce participation due to informal caring for people with intellectual disability or autism spectrum disorders by estimating lost income to individuals, lost taxation payments to federal government and increased welfare payments. METHOD: We used a microsimulation model based on the Australian Bureau of Statistics' Surveys of Disability, Ageing and Carers (population surveys of people aged 15-64), and projected costs of caring from 2015 in 5-year intervals to 2030. RESULTS: The model estimated that informal carers of people with intellectual disability and/or ASD in Australia had aggregated lost income of AU$310 million, lost taxation of AU$100 million and increased welfare payments of AU$204 million in 2015. These are projected to increase to AU$432 million, AU$129 million and AU$254 million for income, taxation, and welfare respectively by 2030. The income gap of carers for people with intellectual disability and/or ASD is estimated to increase by 2030, meaning more financial stress for carers. CONCLUSIONS: Informal carers of people with intellectual disability and/or ASD experience significant loss of income, leading to increased welfare payments and reduced taxation revenue for governments; these are all projected to increase. Strategic policies supporting informal carers wishing to return to work could improve the financial and psychological impact of having a family member with intellectual disability and/or ASD. DECLARATION OF INTEREST: None.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Intellectual Disability , Australia/epidemiology , Autism Spectrum Disorder/epidemiology , Cost of Illness , HumansABSTRACT
BACKGROUND: Most studies measure the impact of ischemic heart disease (IHD) on individuals using quality of life metrics such as disability-adjusted life-years (DALYs); however, IHD also has an enormous impact on productive life years (PLYs). The objective of this study was to project the indirect costs of IHD resulting from lost PLYs to older Australian workers (45-64 years), government, and society 2015-2030. METHODS: Nationally representative data from the Surveys of Disability, Ageing and Carers (2003, 2009) were used to develop the base population in the microsimulation model (Health&WealthMOD2030), which integrated data from established microsimulation models (STINMOD, APPSIM), Treasury's population and workforce projections, and chronic conditions trends. RESULTS: We projected that 6700 people aged 45-64 were out of the labour force due to IHD in 2015, increasing to 8100 in 2030 (21 increase). National costs consisted of a loss of AU$273 (US$263) million in income for people with IHD in 2015, increasing to AU$443 ($US426) million (62% increase). For the government, extra welfare payments increased from AU$106 (US$102) million in 2015 to AU$143 (US$138) million in 2030 (35% increase); and lost income tax revenue increased from AU$74 (US$71) million in 2015 to AU$117 (US$113) million in 2030 (58% increase). A loss of AU$785 (US$755) million in GDP was projected for 2015, increasing to AU$1125 (US$1082) million in 2030. CONCLUSIONS: Significant costs of IHD through lost productivity are incurred by individuals, the government, and society. The benefits of IHD interventions include not only improved health but also potentially economic benefits as workforce capacity.
Subject(s)
Cost of Illness , Myocardial Ischemia/economics , Australia , Computer Simulation , Efficiency , Employment/economics , Employment/statistics & numerical data , Female , Humans , Male , Middle AgedABSTRACT
PURPOSE: Whole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway. METHODS: WES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID). RESULTS: Reanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis. CONCLUSION: Early application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.
Subject(s)
Exome Sequencing/trends , Exome/genetics , Genetic Diseases, Inborn/genetics , Genetic Testing/trends , Intellectual Disability/genetics , Computational Biology , Cost-Benefit Analysis/economics , Female , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/economics , Genetic Testing/economics , Humans , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Male , Phenotype , Exome Sequencing/economicsABSTRACT
BACKGROUND: While the direct (medical) costs of arthritis are regularly reported in cost of illness studies, the 'true' cost to indivdiuals and goverment requires the calculation of the indirect costs as well including lost productivity due to ill-health. METHODS: Respondents aged 45-64 in the ABS Survey of Disability, Ageing and Carers 2003, 2009 formed the base population. We projected the indirect costs of arthritis using Health&WealthMOD2030 - Australia's first microsimulation model on the long-term impacts of ill-health in older workers - which incorporated outputs from established microsimulation models (STINMOD and APPSIM), population and labour force projections from Treasury, and chronic conditions trends for Australia. All costs of arthritis were expressed in real 2013 Australian dollars, adjusted for inflation over time. RESULTS: We estimated there are 54,000 people aged 45-64 with lost PLYs due to arthritis in 2015, increasing to 61,000 in 2030 (13% increase). In 2015, people with lost PLYs are estimated to receive AU$706.12 less in total income and AU$311.67 more in welfare payments per week than full-time workers without arthritis, and pay no income tax on average. National costs include an estimated loss of AU$1.5 billion in annual income in 2015, increasing to AU$2.4 billion in 2030 (59% increase). Lost annual taxation revenue was projected to increase from AU$0.4 billion in 2015 to $0.5 billion in 2030 (56% increase). We projected a loss in GDP of AU$6.2 billion in 2015, increasing to AU$8.2 billion in 2030. CONCLUSIONS: Significant costs of arthritis through lost PLYs are incurred by individuals and government. The effectiveness of arthritis interventions should be judged not only on healthcare use but quality of life and economic wellbeing.
Subject(s)
Arthritis/economics , Cost of Illness , Disabled Persons/education , Social Welfare/economics , Adult , Aged , Arthritis/epidemiology , Australia/epidemiology , Chronic Disease/economics , Disabled Persons/statistics & numerical data , Efficiency , Employment/statistics & numerical data , Female , Health Care Costs , Humans , Income/statistics & numerical data , Middle Aged , Social Welfare/statistics & numerical data , Taxes/economicsABSTRACT
PURPOSE: To undertake the first prospective cost-effectiveness study of whole-exome sequencing (WES) as an early, routine clinical test for infants with suspected monogenic disorders. METHODS: Cost data for diagnosis-related investigations and assessments were collected for a prospective, sequential clinical cohort of infants (N = 40) who underwent singleton WES in parallel to usual diagnostic care. We determined costs per patient, costs per diagnosis, and incremental costs per additional diagnosis for three alternative strategies for integrating WES into the diagnostic trajectory. We performed a sensitivity analysis to examine the robustness of estimates and bootstrapping (500 replications) to examine their distributions. RESULTS: Standard care achieved an average cost per diagnosis of AU$27,050 (US$21,099) compared with AU$5,047 (US$3,937) for singleton WES. If WES had been performed after exhaustive standard investigation, then there would have been an incremental cost per additional diagnosis of AU$8,112 (US$ 6,327). Using WES to replace some investigations decreases this incremental cost to AU$2,622 (US$2,045), whereas using it to replace most investigations results in a savings per additional diagnosis of AU$2,182 (US$1,702). CONCLUSION: Use of WES early in the diagnostic pathway more than triples the diagnostic rate for one-third the cost per diagnosis, providing strong support for reimbursement as a clinical test.Genet Med advance online publication 26 January 2017.
Subject(s)
Diagnostic Tests, Routine/economics , Genetic Diseases, Inborn/diagnosis , Whole Genome Sequencing/economics , Child, Preschool , Cohort Studies , Cost-Benefit Analysis , Early Diagnosis , Female , Genetic Diseases, Inborn/genetics , Humans , Infant , Infant, Newborn , Insurance, Health, Reimbursement , Male , Prospective StudiesABSTRACT
OBJECTIVE: Thyroid hormone extract is used for the treatment of thyroid disorders, but limited data exist on adverse events commonly noted by the physicians associated with this use. The purpose of this survey was to report adverse events observed by expert physicians managing patients treated for thyroid disease with thyroid hormones. METHODS: Members of the American Thyroid Association, The Endocrine Society, and the American Association of Clinical Endocrinologists developed a survey instrument modeled on the U.S. Food and Drug Administration (FDA)'s reported adverse events for levothyroxine that would effectively assess the clinical experience of frequent prescribers of thyroid hormone. Survey links were emailed to physicians, and the websites of each society provided links to the data collection form. RESULTS: A total of 174 reports of adverse events occurring in patients on thyroid hormone extract were received. Ninety-one of these reports were accompanied by alterations in thyrotropin values and were further analyzed. Of these, 62 (68%) subjects had developed new symptoms associated with altered thyroid-stimulating hormone (TSH). A majority of TSH changes and symptoms described were consistent with thyrotoxicosis (65%), and 2 patients had developed arrhythmias. Reporters noted difficulty in dose adjustment by primary care providers due to confusion in interpreting thyroid function test results while on thyroid extract, which often necessitated subspecialty referrals. CONCLUSION: These adverse event reports should stimulate consideration by the FDA to regulate and monitor thyroid hormone extract use and consider standardizing these extracts to meet current standards of manufacture, hormone content, availability, and shelf-life, like the rigor with which preparations such as levothyroxine are monitored. ABBREVIATIONS: AE = adverse event ATA = American Thyroid Association FDA = Food and Drug Administration LT3 = liothyronine LT4 = levothyroxine PTF = Pharmacovigilance Task Force T3 = triiodothyronine TSH = thyroid-stimulating hormone.
Subject(s)
Drug-Related Side Effects and Adverse Reactions/epidemiology , Hormone Replacement Therapy/adverse effects , Hormone Replacement Therapy/methods , Hypothyroidism/drug therapy , Hypothyroidism/epidemiology , Tissue Extracts/adverse effects , Triiodothyronine/adverse effects , Adult , Adverse Drug Reaction Reporting Systems , Humans , Hypothyroidism/physiopathology , Surveys and Questionnaires , Thyroid Function Tests , Thyroid Gland/physiopathology , Thyrotropin/blood , Thyroxine/therapeutic use , Tissue Extracts/administration & dosage , Triiodothyronine/administration & dosageABSTRACT
Importance: Biotinylated antibodies and analogues, with their strong binding to streptavidin, are used in many clinical laboratory tests. Excess biotin in blood due to supplemental biotin ingestion may affect biotin-streptavidin binding, leading to potential clinical misinterpretation. However, the degree of interference remains undefined in healthy adults. Objective: To assess performance of specific biotinylated immunoassays after 7 days of ingesting 10 mg/d of biotin, a dose common in over-the-counter supplements for healthy adults. Design, Setting, and Participants: Nonrandomized crossover trial involving 6 healthy adults who were treated at an academic medical center research laboratory. Exposure: Administration of 10 mg/d of biotin supplementation for 7 days. Main Outcomes and Measures: Analyte concentrations were compared with baseline (day 0) measures on the seventh day of biotin treatment and 7 days after treatment had stopped (day 14). The 11 analytes included 9 hormones (ie, thyroid-stimulating hormone, total thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine, parathyroid hormone, prolactin, N-terminal pro-brain natriuretic peptide, 25-hydroxyvitamin D) and 2 nonhormones (prostate-specific antigen and ferritin). A total of 37 immunoassays for the 11 analytes were evaluated on 4 diagnostic systems, including 23 assays that incorporated biotin and streptavidin components and 14 assays that did not include biotin and streptavidin components and served as negative controls. Results: Among the 2 women and 4 men (mean age, 38 years [range, 31-45 years]) who took 10 mg/d of biotin for 7 days, biotin ingestion-associated interference was found in 9 of the 23 (39%) biotinylated assays compared with none of the 14 nonbiotinylated assays (P = .007). Results from 5 of 8 biotinylated (63%) competitive immunoassays tested falsely high and results from 4 out of 15 (27%) biotinylated sandwich immunoassays tested falsely low. Conclusions and Relevance: In this preliminary study of 6 healthy adult participants and 11 hormone and nonhormone analytes measured by 37 immunoassays, ingesting 10 mg/d of biotin for 1 week was associated with potentially clinically important assay interference in some but not all biotinylated assays studied. These findings should be considered for patients taking biotin supplements before ordering blood tests or when interpreting results. Trial Registration: clinicaltrials.gov Identifier: NCT03034707.
Subject(s)
Biotin/pharmacology , Diagnostic Errors , Drug Interactions , Immunoassay , Adult , Artifacts , Cross-Over Studies , Female , Healthy Volunteers , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Parathyroid Hormone/blood , Peptide Fragments/blood , Prolactin/blood , Prostate-Specific Antigen/blood , Thyroid Function Tests , Thyroid Hormones/blood , Vitamin D/analogs & derivatives , Vitamin D/bloodABSTRACT
This article examines the relationship between health and workforce participation beyond the age of 65 years in Australia. This study found that people with a chronic health condition were less likely to be employed than those without a health condition (OR, 0.59; 95% CI [0.38, 0.92]). Among those with a chronic health condition, those in income quartile 2 (OR, 0.27; 95% CI [0.11, 0.67]) and 3 (OR, 0.38; 95% CI, [0.15-0.93]) were significantly less likely to be employed relative to those in income quartile 4. Older workers with a chronic health condition were less likely to work beyond the age of 65; however, among those with a chronic health condition, those with very high income and those with very low income were the most likely to keep working.