AIMS:Due to the ageing population in Europe, a significant increase in the incidence of atrial fibrillation (AF) is anticipated. This is predicted to have a detrimental impact on public health costs, particularly among the elderly, because of an increased number of stroke cases. Early detection of AF is crucial for initiating treatment with oral anticoagulants (OACs) to reduce the risk of stroke. This study aims to assess the cost-effectiveness of implementing AF screening programmes in eight European countries: Denmark, Germany, Ireland, Italy, the Netherlands, Serbia, Spain, and Sweden. METHODS AND RESULTS:The analysis concerned invitation to AF population screening for 75-year-olds. A Markov cohort model was used, considering the prevalence of AF, screening yield, the use of different OACs, estimated clinical events, mortality, quality of life and costs. The model used country-specific parameters to produce specific cost-effectiveness estimates. Probabilistic sensitivity analyses were conducted to assess the impact of parametric uncertainties on the results. Inviting 75-year-olds to AF screening proved to be cost-effective across all eight countries analysed. In all countries, the strategy was dominant, meaning that quality-adjusted life-years were gained at lower costs. The time to financial break-even ranged from 6 to 14 years. CONCLUSION:This study indicates that population-based AF screening of 75-year-olds is a cost-effective strategy across eight European countries, meaning that adoption of such a strategy has the potential to make healthcare systems in these countries more efficient. The heterogeneity among European countries suggests that AF screening programmes may need to be tailored to the specific healthcare systems and conditions of each nation.

Background: Despite the increasing availability of tailored vaccines, vaccine-preventable respiratory diseases (VPRDs), including influenza, respiratory syncytial virus (RSV), COVID-19, and pneumococcal disease (PD), continue to impose a significant health and economic burden. This study assessed the epidemiological and economic burden of VPRD among adults aged ≥65 across four Nordic countries (Denmark, Sweden, Norway, and Finland). Methods: Data on incidence, hospital admissions, and mortality were obtained from national statistics (week 21, 2024–week 20, 2025) and supplemented with peer-reviewed literature. A static model was developed to quantify epidemiological and economic burden associated with VPRD during the 2024/2025 winter season. Results: During the 2024/2025 season, VPRD resulted in approximately 830,000 symptomatic cases, 60,300 hospital admissions, and 7750 deaths across the Nordic countries. COVID-19 showed the highest estimated incidence and numbers of hospital admissions, followed by influenza, PD, and RSV. Mortality was comparable between COVID-19 and influenza, followed by PD and RSV. Annual healthcare costs were approximately €1132 million, with productivity losses constituting an additional 7%. Conclusions: Despite national vaccination efforts, VPRDs remain a major health and economic burden in the Nordic countries. Strengthening immunization programs through improved vaccine uptake, broader coverage, and use of advanced vaccines may contribute to further reducing this burden.

BACKGROUND AND PURPOSE:Advanced breast cancer (ABC) involves substantial end-of-life (EOL) healthcare use and costs. Understanding cost drivers can inform care delivery and resource allocation. Patient/material and methods: We conducted a retrospective, population-based study of individuals (n = 1,437) who died with breast cancer in the Stockholm Region (2015-2023). Healthcare utilization and costs during the last 12 months of life were obtained from the Stockholm Regional Healthcare Data Repository (VAL) and estimated using the Region Stockholm cost model. Variables included age, sex, socioeconomic status (Mosaic), Charlson Comorbidity Index, Hospital Frailty Risk Score (HFRS), systemic therapy, and place of death. Descriptive statistics and generalized linear models assessed cost associations. RESULTS:Total costs rose toward EOL, increasing 140% in the final 3 months versus the prior quarter. Hospitalizations and specialized palliative care drove costs, while outpatient visits declined. Younger age (18-69 years), high frailty (HFRS > 15), and systemic therapy were independently associated with higher costs. Hospital death was associated with lower expenditures than dying elsewhere (rate ratio [RR]: 0.84, 95% confidence interval [CI]: 0.78-0.91). The top 5% of cost users were mainly younger, frail patients receiving systemic therapy. INTERPRETATION:ABC-related costs escalate in the final year of life, driven by hospitalizations, palliative care, and systemic therapies. Younger, frailer patients incur higher costs, while those dying in hospital settings are associated with lower costs. Early palliative integration and frailty-based risk stratification were associated with distinct patterns of healthcare utilization and costs toward the EOL.

Atrial fibrillation (AF) is increasingly diagnosed early, close to its first occurrence due to: (i) increased public awareness with self-screening; (ii) health care initiatives including population screening and opportunistic case finding; and (iii) increased use and surveillance of implantable cardiac devices. At its onset, AF is often low burden, and cardiovascular co-morbidities may be absent or at an early stage. Thus, the management of recent-onset AF has become an issue of growing importance. Professional guidelines have traditionally focused on anticoagulant thromboprophylaxis, generally recommending a cautious approach to rhythm control, and priority has been given to rate control to alleviate symptoms. In recent guidelines, the importance of managing lifestyle and co-morbidities has increased. The AF-SCREEN collaboration proposes that a vigorous approach to active management of recent-onset AF may be warranted. This includes addressing co-morbidities and promoting healthy lifestyles to prevent the emergence or progression of AF and associated cardiovascular disease, as well as the initiation of active rhythm control ± anticoagulation to prevent AF-related morbidity and mortality, including stroke and heart failure (HF). Intuitively, intervention early after AF onset would be beneficial since lifestyle and co-morbidity management, plus rhythm control and anticoagulation, are important contributors to improved outcomes in patients with established AF, but robust evidence is lacking for recent-onset AF. There is a delicate balance between achieving favourable outcomes such as preventing strokes, HF and AF progression vs the complications and potential adverse effects of interventions. Given the serious long-term consequences, innovative approaches are necessary to determine the value and risks of initiating active therapy very early in the course of AF. More data are needed to guide the best management of recent-onset AF, bearing AF burden in mind. Long-term studies using large national databases linked to electronic medical records and rhythm monitoring devices offer excellent opportunities. Shorter-term studies focusing on reducing AF burden to slow AF progression and studies focusing on outcomes such as HF could be used in both randomized clinical trials and observational cohort studies.

Pulmonary arterial hypertension (PAH) is a heterogenic diagnosis including idiopathic and hereditary PAH (IPAH/HPAH) and groups associated to connective tissue disease (APAH-CTD) and congenital heart disease (APAH-CHD). Pre- and post-diagnosis societal costs in PAH subgroups are not well known. By linking Swedish national databases, societal costs in a national PAH cohort 5 years before and 5 years after diagnosis were estimated and compared to an age, sex, and geographically matched control group (1:5 match). Incident patients diagnosed 2008-2019 were included (patient/control; IPAH/HPAH = 393/1965, APAH-CTD = 261/1305, APAH-CHD = 89/445). Pre-diagnosis mean societal costs were 2.9, 3.4, and 4.3 times higher for IPAH/HPAH, APAH-CTD and APAH-CHD patients, respectively, than controls. Post-diagnosis, mean costs had increased 3.1, 2.0, and 1.6 times further for IPAH/HPAH, APAH-CTD and APAH-CHD respectively, while it decreased in all control groups. Main cost driver pre-diagnosis were indirect costs (productivity loss) in both patient and control groups, however, 2.7-4.5 times higher in the patient groups. Post-diagnosis, the main cost driver for all groups were health care costs (in- and outpatient-care, drugs) that had increased 7.8, 5.4 and 6.8 times for IPAH/HPAH, APAH-CTD and APAH-CHD, respectively. Corresponding increase for controls were 17%-48%. For the PAH groups, drug treatment accounted for 70%-81% of the direct costs, while hospitalizations were the main driver for the control groups. In conclusion, PAH was associated with large societal costs. Pre-diagnosis, APAH-CHD had the highest societal costs, both in relation to their control group and compared to the other patient groups. Post-diagnosis, highest societal costs were seen in IPAH/HPAH.

In early 2022, new treatment recommendations for heart failure (HF) were introduced in Sweden. This study aims to evaluate and analyze the pharmaceutical treatment patterns of HF patients over time in Sweden, in relation to the updated treatment recommendations. This observational study is based on registry data. The study population consisted of patients ≥18 years old who, at any time between 2017 and 2023, had an HF diagnosis, defined using ICD-10 code I50 (n = 212,757). Descriptive statistics were presented for the study population. Based on data from the national drug prescription registry, the treatment patterns between 2021 and 2023 were analyzed using biannual datasets before and after the introduction of treatment recommendations. The mean age of the study population was 79 years and 56

AIM: Cardiovascular disease poses a significant health and economic challenge in Europe, yet the adoption of novel cost-effective treatments like icosapent ethyl remains limited. This study aims to estimate the absolute and relative value of eliminating suboptimal implementation of icosapent ethyl in Sweden. METHODS: This study estimates the effects of optimal and actual implementation of icosapent ethyl in Sweden with a five-year perspective by combining available cost-effectiveness evidence with epidemiology data from the Swedeheart registry and Swedish health authorities. The implementation analysis is based on the expected value of perfect implementation framework which estimates the value of increasing implementation from the current level of prescriptions up to an optimal level, where 80% of patients with indication for icosapent ethyl receives it. FINDINGS AND INTERPRETATION: The results provide an upper limit of the value that could be gained by improving implementation of icosapent ethyl in five years in Sweden. Optimal implementation of icosapent ethyl in Sweden over five years could prevent 1,228 cardiovascular events, including 99 deaths, while generating a health gain of 3,538 QALYs and net value of implementation of 497 QALYs. Regional differences and delays in implementation play a major role in the suboptimal uptake of care. Enhancing implementation strategies could lead to additional gains in QALYs and significantly reduce CV events and healthcare costs. CONCLUSION: There is significant health, QALY and monetary gains in ensuring improved implementation of icosapent ethyl in Sweden. There is a need for tailored interventions to address factors influencing prescribing practices. However, challenges remain with a lack of clear national or local guidelines. By decreasing the large regional variations, one could enhance patient outcomes.

10541 Background: Genetic testing for hereditary breast and ovarian cancer (HBOC) has relied on clinical and family history criteria. This approach, has been shown to overlook a significant number of mutation carriers who could benefit from preventative measures. Increasing evidence supports genetic testing in an unselected population, which facilitates the identification of more carriers and allows for the implementation of risk reduction strategies. The aim of this study is to evaluate the cost-effectiveness of utilising an expanded gene-panel in an unselected female population. Methods: A Microsoft Excel-based simulation model of a hypothetical cohort of unselected and previously untested 30 years old women was devised to assess three strategies. Strategy 1: genetic testing of unselected women for mutations of a 6-gene panel BRCA1 , BRCA2 , PALB2 , ATM , CHEK2 and TP53 , Strategy 2: screening to individuals fulfilling family history (FH) criteria for HBOC testing and Strategy 3: no genetic screening. New Generation sequencing (NGS) using TrueSight hereditary cancer panel from Illumina was used as testing platform. The analysis includes quality adjusted life year (QALY) as a health outcome. The incremental cost-effectives ratio (ICER) is calculated using health-care costs and QALYs per treatment strategy, illustrating the additional cost in relation to the additional health benefit (QALYs) associated with the 6 gene-panel strategy compared to the FH-based strategy. One-way sensitivity analyses expressed as ICER, evaluates the uncertainty and the impact of specific parameters on the results. Results: A cohort of100 000 unselected women was simulated through the model over 80 cycles as well as women meeting criteria for HBOC investigation. The mutation carriers detected were 1307 and 191 for the unselected population group and FH respectively. As direct effect, 339 risk reducing surgeries (mastectomy or/and salpingo-oophorectomy) were performed in the strategy 1 compared with 50 in the strategy 2. The probabilistic analysis shows that if the willingness to pay is €100.000 per QALY, the unselected population-based testing has 75% probability of being cost-effective. Conclusions: Population-based screening with a six-gene panel has 75% probability to be cost-effective if the willingness to pay is over €100 000. This strategy reduces the number of (HBOC) cases and cancer specific mortality which strengthens the benefits of this screening strategy in cancer prevention. Outcomes. Scenario Outcomes Population-based FH-based Difference Life years 2 713 534 2 713 369 165 QALY 2 147 507 2 147 312 196 Cost per life years gained (€) 98 079 ICER (cost per QALY gained) (€) 82 642 Costs (€) Screening 13 311 720 163 417 13 148 304 Risk reducing Surgery 4 557 420 666 608 3 890 812 Surveillance 45 330 899 43 413 884 1 917 015 Cancer 180 119 575 182 884 672 -2 765 098 Total Cost 243 319 615 227 128 581 16 191 034

BACKGROUND:Treatment with mechanical thrombectomy (MT) remains inaccessible for many patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) and under-utilization prevails across healthcare systems. Increasing the number of thrombectomy centers and ambulance helicopters may alleviate these issues. AIM:This study aims to determine the most effective combination of optimally located ambulance helicopters and thrombectomy centers for the economically constrained healthcare system. METHODS:This nation-wide, observational study analyses anonymized patient-level registry data stretching over a 6-year study period in Sweden. It combines optimization modeling with cost-effectiveness analysis to generate combinations of optimally located thrombectomy centers and ambulance helicopters to compare with the current eight locations of thrombectomy centers in Sweden and no ambulance helicopters. The analysis extends to evaluate the cost-effectiveness of increasing the number of thrombectomy centers and ambulance helicopters when the current eight locations remain fixed. RESULTS:The most cost-effective solution comprises 11 thrombectomy centers and 14 ambulance helicopters, corresponding to densities of 1.05 and 1.34 per one million inhabitants, respectively. It yields an estimated annual incremental net monetary benefit (INMB) close to €13.6 million. In the extended scenario analysis, the most cost-effective solution comprised nine thrombectomy centers and 13 ambulance helicopters, with an estimated annual INMB of €3.8 million. CONCLUSIONS:The most cost-effective combination of optimally located thrombectomy centers and ambulance helicopters brings about substantial health gains for patients with AIS due to LVO, compared with the current eight locations of thrombectomy centers in Sweden and ambulance helicopters.

To evaluate the cost-effectiveness of AI-assisted digital mammography (AI-DM) compared to conventional biennial breast cancer digital mammography screening (cDM) with double reading of screening mammograms, and to investigate the change in cost-effectiveness based on four different sub-strategies of AI-DM. A decision-analytic state-transition Markov model was used to analyse the decision of whether to use cDM or AI-DM in breast cancer screening. In this Markov model, one-year cycles were used, and the analysis was performed from a healthcare perspective with a lifetime horizon. In the model, we analysed 1000 hypothetical individuals attending mammography screenings assessed with AI-DM compared with 1000 hypothetical individuals assessed with cDM. The total costs, including both screening-related costs and breast cancer-related costs, were €3,468,967 and €3,528,288 for AI-DM and cDM, respectively. AI-DM resulted in a cost saving of €59,320 compared to cDM. Per 1000 individuals, AI-DM gained 10.8 quality-adjusted life years (QALYs) compared to cDM. Gained QALYs at a lower cost means that the AI-DM screening strategy was dominant compared to cDM. Break-even occurred at the second screening at age 42 years. This analysis showed that AI-assisted mammography for biennial breast cancer screening in a Swedish population of women aged 40–74 years is a cost-saving strategy compared to a conventional strategy using double human screen reading. Further clinical studies are needed, as scenario analyses showed that other strategies, more dependent on AI, are also cost-saving. Question To evaluate the cost-effectiveness of AI-DM in comparison to conventional biennial breast cDM screening. Findings AI-DM is cost-effective, and the break-even point occurred at the second screening at age 42 years. Clinical relevance The implementation of AI is clearly cost-effective as it reduces the total cost for the healthcare system and simultaneously results in a gain in QALYs.

AIMS AND BACKGROUND:Whole-genome sequencing (WGS) is increasingly applied in clinical practice and expected to replace standard-of-care (SoC) genetic diagnostics in hematological malignancies. This study aims to assess and compare the fully burdened cost ('micro-costing') per patient for Swedish laboratories using WGS and SoC, respectively, in pediatric and adult patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). METHODS:The resource use and cost details associated with SoC, e.g. chromosome banding analysis, fluorescent in situ hybridization, and targeted sequencing analysis, were collected via activity-based costing methods from four diagnostic laboratories. For WGS, corresponding data was collected from two of the centers. A simulation-based scenario model was developed for analyzing the WGS cost based on different annual sample throughput to evaluate economy of scale. RESULTS:The average SoC total cost per patient was €2,465 for pediatric AML and €2,201 for pediatric ALL, while in adults, the corresponding cost was €2,458 for AML and €1,207 for ALL. The average WGS cost (90x tumor/30x normal; sequenced on the Illumina NovaSeq 6000 platform) was estimated to €3,472 based on an annual throughput of 2,500 analyses, however, with an annual volume of 7,500 analyses the average cost would decrease by 23% to €2,671. CONCLUSION:In summary, WGS is currently more costly than SoC, however the cost can be reduced by utilizing laboratories with higher throughput and by the expected decline in cost of reagents. Our data provides guidance to decision-makers for the resource allocation needed when implementing WGS in diagnostics of hematological malignancies.

Background Mechanical thrombectomy has emerged as standard of care in treatment of patients with acute ischemic stroke attributable to large‐vessel occlusion. Efforts to reduce the time from symptom onset to treatment initiation remain critically important to improve functional outcomes in patients treated with either intravenous thrombolysis, mechanical thrombectomy, or both. The use of ambulance helicopters in prehospital acute stroke care could potentially reduce symptom onset to treatment time to mechanical thrombectomy. This study aims to optimize the use of ambulance helicopters in prehospital transportation of patients with presumed acute stroke attributable to large‐vessel occlusion given economic constraints in health care budget. Methods By means of an economic model within a decision‐analytical framework, this study evaluates the cost‐effectiveness of complementary ambulance helicopters compared with road ambulances only for prehospital acute transportation of patients with presumed stroke and potential eligibility for mechanical thrombectomy, in regard to the number and locations of ambulance helicopters in Sweden. Results A single, optimally located complementary ambulance helicopter was cost‐effective compared with road ambulances only. The most cost‐effective solution in the base‐case scenario with the current 8 thrombectomy centers comprised 13 optimally located helicopters. It reduced mean onset to treatment time with intravenous thrombolysis and onset to treatment time with mechanical thrombectomy by 7.9 and 32.1 minutes, respectively, and produced health gains equal to 91 quality‐adjusted life‐years per year. When the willingness to pay per quality‐adjusted life‐years gained was set at Euro (EUR) 80 000, the incremental net monetary benefit per patient reached EUR 2240. The solution with 13 optimally located helicopters prevailed as the most cost‐effective in the extended scenario analysis with 11 thrombectomy centers, reaching an estimated incremental net monetary benefit per patient at EUR 1754. Furthermore, mean incremental net monetary benefit per patient reached global maximum (EUR 6046) at the geodesic distance of 165.2 km between patient location and the nearest thrombectomy center in the base‐case scenario, and at 238.5 km in the extended scenario with an estimated incremental net monetary benefit per patient at EUR 7994. Conclusion This study demonstrates the cost‐effectiveness of ambulance helicopters as a complementary mode of transportation to road ambulances. The most cost‐effective solution of complementary ambulance helicopters comprises 13 optimally located heliports across Sweden.

A budget impact analysis estimates the short-term difference between the cost of the current treatment strategy and a new treatment strategy, in this case to implement population screening for atrial fibrillation (AF). The aim of this study is to estimate the financial impact of implementing population-based AF-screening of 75-year-olds compared with the current setting of no screening from a healthcare payer perspective in eight European countries. The net budget impact of AF-screening was estimated in country-specific settings for Denmark, Germany, Ireland, Italy, Netherlands, Serbia, Spain, and Sweden. Country-specific parameters were used to allow for variations in healthcare systems and to reflect the healthcare sector in the country of interest. Similar results can be seen in all countries AF-screening incurs savings of stroke-related costs since AF treatment reduces the number of strokes. However, the increased number of detected AF and higher drug acquisition will increase the drug costs as well as the costs of physician- and control visits. The net budget impact per invited varied from €10 in Ireland to €122 in the Netherlands. The results showed the increased costs of implementing AF-screening were mainly driven by increased drug costs and screening costs. In conclusion, across Europe, though the initial cost of screening and more frequent use of oral anti-coagulants will increase the healthcare payers' costs, introducing population screening for AF will result in savings of stroke-related costs.

Value-based reimbursement programmes have become increasingly common in attempts to bend the cost curve of healthcare without negative effects on quality. The aim of this study was to analyse the effect of introducing a value-based reimbursement programme on the cost to third-party payer. We performed a retrospective observational study with a before and after design based on the introduction of a value-based reimbursement programme in Sweden. We analysed patient level cost data from inpatient and outpatient care of patients undergoing lumbar spine surgery, 2006–2015. The average 1-year episode cost decreased 11 percent during the first 2 years with the value-based reimbursement. The number of patients increased 22 percent during the same period, causing the total cost to increase by 8 percent. The value to third-party payer increased after the introduction of the value-based reimbursement since more patients were treated and attained a positive outcome. The decreased episode cost may be a result of better coordinated post-discharge care. Another explanation could be that costs previously borne by the third-party payer are shifted onto the healthcare providers. Thus, it is crucial that providers find a sustainable way of delivering care in the long term to retain value. Interlinking patient records facilitates a holistic perspective among healthcare providers raising awareness of health care utilization through the whole care chain.

BackgroundDespite the proven cost effectiveness of mechanical thrombectomy (MT) in patients with acute ischemic stroke (AIS) due to large vessel occlusion, treatment within 6 hours from symptom onset remains inaccessible for many patients. We aimed to find the optimal number and location of treatment facilities with respect to the cost effectiveness of MT in patients with AIS, first by the most cost effective implementation of comprehensive stroke centers (CSCs), and second by the most cost effective addition of complementary thrombectomy capable stroke centers (TSCs). MethodsThis study was based on nationwide observational data comprising 18 793 patients with suspected AIS potentially eligible for treatment with MT. The most cost effective solutions were attained by solving the p median facility location-allocation problem with the objective function of maximizing the incremental net monetary benefit (INMB) of MT compared with no MT in patients with AIS. Deterministic sensitivity analysis (DSA) was used as the basis of the results analysis. ResultsThe implementation strategy with seven CSCs produced the highest annual INMB per patient of all possible solutions in the base case scenario. The most cost effective implementation strategy of the extended scenario comprised seven CSCs and four TSCs. DSA revealed sensitivity to variability in MT rate and the maximum willingness to pay per quality adjusted life year gained. ConclusionThe combination of optimization modeling and cost effectiveness analysis provides a powerful tool for configuring the extent and locations of CSCs (and TSCs). The most cost effective implementation of CSCs in Sweden entails 24/7 MT services at all seven university hospitals.

Abstract Aims Previous studies on the cost-effectiveness of screening for atrial fibrillation (AF) are based on assumptions of long-term clinical effects. The STROKESTOP study, which randomised 27 975 persons aged 75/76 years into a screening invitation group and a control group, has a median follow-up time of 6.9 years. The aim of this study was to estimate the cost-effectiveness of population-based screening for AF using clinical outcomes. Methods and results The analysis is based on a Markov cohort model. The prevalence of AF, the use of oral anticoagulation, clinical event data, and all-cause mortality were taken from the STROKESTOP study. The cost for clinical events, age-specific utilities, utility decrement due to stroke, and stroke death was taken from the literature. Uncertainty in the model was considered in a probabilistic sensitivity analysis. Per 1000 individuals invited to the screening, there were 77 gained life years and 65 gained quality-adjusted life years. The incremental cost was €1.77 million lower in the screening invitation group. Gained quality-adjusted life years to a lower cost means that the screening strategy was dominant. The result from 10 000 Monte Carlo simulations showed that the AF screening strategy was cost-effective in 99.2% and cost-saving in 92.7% of the simulations. In the base-case scenario, screening of 1000 individuals resulted in 10.6 [95% confidence interval (CI): −22.5 to 1.4] fewer strokes (8.4 ischaemic and 2.2 haemorrhagic strokes), 1.0 (95% CI: −1.9 to 4.1) more cases of systemic embolism, and 2.9 (95% CI: −18.2 to 13.1) fewer bleedings associated with hospitalization. Conclusion Based on the STROKESTOP study, this analysis shows that a broad AF screening strategy in an elderly population is cost-effective. Efforts should be made to increase screening participation.

The dynamic process of synthesis and degradation of extracellular matrix molecules, including various collagens, is important in normal physiological functions and pathological conditions. Existing models of collagen enzymatic degradation reactions are derived from bulk biochemical assays. In this study, we have imaged in real-time individual collagen I molecules and their proteolysis by Clostridium histolyticum collagenases in phosphate-buffered saline (PBS) with atomic force microscopy (AFM). We have also imaged the Likely binding and unbinding of collagenase molecules to single triple-helical collagen I molecules and subsequent proteolysis of subsets of the collagen molecules. The proteolysis of collagen molecules was inhibited by reduced calcium and acidification. Results from AFM study of collagen proteolysis are consistent with SDS-PAGE biochemical assays. The real-time proteolysis of single collagen I molecules followed simple Michaelis-Menton kinetics previously derived from bulk biochemical assays. This is the;first report of imaging real-time proteolysis of single macromolecules and its inhibition on a molecular scale. A strong correspondence between the kinetics of proteolysis of single collagen molecules and the kinetics of proteolysis derived from bulk biochemical assays will have a wide applicability in examining real-time enzymatic reactions and their regulation at single molecule structural level. Such real-time study of single molecule proteolysis could provide a better understanding of the interactions between proteases and target proteins as well as proteases and protease inhibitors.

Whole genome sequencing (WGS) has the potential to be a comprehensive genetic test, especially relevant for individuals with neurodevelopmental disorders, syndromes and congenital malformations. However, the cost consequences of using whole genome sequencing as a first-line genetic test for these individuals are not well understood. The study objective was to compare the healthcare costs and diagnostic yield when WGS is performed as the first-line test instead of chromosomal microarray analysis (CMA). Two cohorts were analyzed retrospectively using register data, cohort CMA (418 patients referred for CMA at the department of Clinical Genetics, Karolinska University Hospital, during 2015) and cohort WGS (89 patients included in a WGS-first prospective study in 2017). The analysis compared healthcare consumption over a 2-year period after referral for genetic testing, the diagnostic yield over a 2- and 3-year period after referral was also compiled. The mean healthcare cost per patient in cohort WGS was $2,339 lower compared to cohort CMA ($ − 2339, 95% CI − 12,238–7561; P = 0.64) including higher costs for genetic investigations ($1065, 95% CI 834–1295; P < 0.001) and lower costs for outpatient care ($ − 2330, 95% CI − 3992 to (− 669); P = 0.006). The diagnostic yield was 23% higher for cohort WGS (cohort CMA 20.1%, cohort WGS 24.7%) (0.046, 95% CI − 0.053–0.145; P = 0.36). WGS as a first-line diagnostic test for individuals with neurodevelopmental disorders is associated with statistically non-significant lower costs and higher diagnostic yield compared with CMA. This indicates that prioritizing WGS over CMA in health care decision making will yield positive expected outcomes as well as showing a need for further research.

PURPOSE:Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics.METHODS:We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421).RESULTS:The diagnostic yield was 35% (GS-first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed.CONCLUSION:Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time- and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients.