Last update: 20240919

[@van2022hospital] Hospital-related costs of sepsis around the world: A systematic review exploring the economic burden of sepsis.

The article titled "Hospital-related costs of sepsis around the world: A systematic review exploring the economic burden of sepsis" by M. van den Berg et al., published in the **Journal of Critical Care**, focuses on the global economic impact of sepsis, highlighting the substantial financial burden this condition places on healthcare systems. Here are the essential details:

### Overview: - **Purpose**: To assess and summarize the hospital-related costs of sepsis worldwide, considering how these expenses impact health budgets globally. - **Methodology**: Systematic review guided by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) standards, covering literature from January 2010 to January 2022. Data was sourced from databases like PubMed, EMBASE, and Cochrane, focusing on studies reporting direct healthcare costs associated with adult sepsis patients.

### Key Findings: - **Economic Burden**: The study reports significant variability in sepsis-related healthcare costs across different countries. These costs are influenced by factors such as sepsis severity, local healthcare practices, and the cost calculation methods employed. - **Cost Range**: The review highlights a wide range of reported hospital costs for sepsis, from €1,101 to €91,951 per patient stay. Such variation reflects differences in national healthcare systems, treatment protocols, and patient demographics. - **Healthcare Impact**: Sepsis treatment can be a major financial strain on healthcare budgets, particularly due to the high costs of ICU care and extended hospital stays required by sepsis patients.

### Economic Implications: - **Resource Allocation**: The high costs associated with sepsis underscore the need for efficient resource allocation, emphasizing prevention, early diagnosis, and effective management to reduce the incidence and severity of sepsis. - **Policy and Planning**: The study advocates for better data collection and reporting on sepsis costs to aid policymakers and healthcare providers in developing strategies that balance clinical outcomes with economic feasibility.

### Challenges and Recommendations: - **Data Variability**: The lack of standardized definitions and varying methodologies for cost calculation complicates comparisons across studies. The authors recommend adopting uniform sepsis definitions and cost-calculation methods to improve the reliability of economic evaluations. - **Future Research**: There is a call for more comprehensive studies that include a broader range of countries and healthcare settings to develop a more detailed understanding of the global economic impact of sepsis.

### Conclusion: The systematic review highlights the significant economic burden of sepsis on healthcare systems worldwide, stressing the importance of strategic investments in healthcare infrastructure and research to mitigate the costs associated with this severe and prevalent condition.

[@meng2017use] Use of exome sequencing for infants in intensive care units: ascertainment of severe single-gene disorders and effect on medical management

The article from **JAMA Pediatrics** titled "Use of Exome Sequencing for Infants in Intensive Care Units" presents a comprehensive analysis of the diagnostic utility and implications of clinical exome sequencing in critically ill infants. Here are the key details and statistics:

### Study Details: - **Objective:** To determine the diagnostic yield and clinical impact of exome sequencing in critically ill infants suspected of having monogenic disorders. - **Setting:** The study was conducted at Texas Children’s Hospital, Houston, Texas, with exome sequencing performed at Baylor College of Medicine. - **Participants:** 278 unrelated infants within the first 100 days of life who underwent exome sequencing between December 2011 and January 2017.

### Methodology: - **Types of Exome Sequencing:** Proband exome, trio exome, and critical trio exome, which is a rapid genomic assay for seriously ill infants. - **Main Measures:** Diagnostic yield of exome sequencing, effect on medical management, age at diagnosis, and molecular findings.

### Key Findings: - **Diagnostic Yield:** A molecular diagnosis was achieved in 102 out of 278 infants (36.7%). For critical trio exome sequencing, the diagnostic rate was higher at 50.8%. - **Impact on Medical Management:** Diagnoses influenced medical management in 53 of the diagnosed infants (52.0%), affecting decisions on care redirection, initiation of new subspecialist care, and changes in treatment. - **Age and Turnaround Time:** The average age at testing was 28.5 days. The mean turnaround time for critical trio exome sequencing was notably shorter at 13.0 days compared to other methods.

### Conclusions and Relevance: - **Clinical Utility:** Exome sequencing is a powerful tool in the neonatal and pediatric intensive care settings, substantially impacting clinical decision-making and patient management. - **Significance:** This study underscores the effectiveness of rapid genomic diagnostics in aiding timely and informed medical decisions in critical care settings.

This detailed analysis highlights the transformative potential of exome sequencing in managing and diagnosing critically ill infants, paving the way for more targeted and efficient genetic testing practices.

[@lunke2023integrated] Integrated multi-omics for rapid rare disease diagnosis on a national scale.

The article from **Nature Medicine** titled "Integrated multi-omics for rapid rare disease diagnosis on a national scale" details a comprehensive study focused on implementing whole-genome sequencing (WGS) for rapid diagnosis of rare diseases in critically ill infants and children across Australia. Here are the key points and statistics from the study:

### Study Overview: - **Objective:** To assess the effectiveness of integrating multi-omic approaches, including WGS and transcriptome sequencing, for rapid diagnosis in a national healthcare setting. - **Participants:** 290 critically ill infants and children suspected of genetic conditions. - **Methods:** Rapid WGS was employed, with an average time from sample receipt to clinical report of 2.9 days. Additional bioinformatics analyses and functional assays were utilized for cases that remained undiagnosed after initial WGS.

### Key Results: - **Diagnostic Yield:** Initial diagnostic yield from standard WGS was 47%. Extended bioinformatic analysis and functional testing increased the yield to 54 - **Impact on Management:** Diagnostic insights altered critical care management in 77% of diagnosed patients, influencing major clinical decisions in 60 - **Diagnostic Spectrum:** Identified a range of genetic abnormalities from structural chromosomal issues to intronic retrotransposon insertions affecting gene splicing. - **Extended Analyses:** Long-read sequencing and manual RNA data analyses added significant diagnostic value, pinpointing complex variants and clarifying uncertain cases.

### Notable Diagnoses and Technologies: - **Striking Findings:** Use of technologies like STRipy for identifying triplet repeat expansions and Nanopore sequencing for detecting complex structural variants. - **Innovative Integration:** Integration of multi-omic data (genomic, transcriptomic, proteomic) significantly enhanced diagnostic precision and facilitated personalized treatment plans.

### Challenges and Innovations: - **Multi-omic Integration:** While highly effective, integrating multi-omic data into routine diagnostics posed challenges regarding resource allocation and operational implementation. - **Future Prospects:** The study underscores the potential for such integrated diagnostic approaches to become standard care, urging improvements in bioinformatics and the functional assessment of variants of uncertain significance (VUS).

### Conclusion: This landmark study demonstrates the critical role of rapid, integrated multi-omic diagnostics in enhancing patient outcomes in a national healthcare setting, providing a model for other countries and systems aiming to improve the diagnostics and management of rare genetic diseases.

This study is a pivotal reference for those interested in the application of genomics and multi-omics in clinical settings, emphasizing the need for comprehensive diagnostic strategies that are both rapid and robust, capable of addressing the complex nature of rare diseases.

[@jensson2023actionable] Actionable genotypes and their association with life span in Iceland

The study detailed in the New England Journal of Medicine explores the prevalence and impact of actionable genotypes on life span in a large Icelandic cohort. The study focuses on 57,933 Icelanders whose genomes were sequenced to identify variants in 73 genes listed in the American College of Medical Genetics and Genomics (ACMG) Secondary Findings recommendations.

### Key Points of the Study:

1. **Identification of Actionable Genotypes**: - Out of the large sample, 2,306 individuals (4.0%) carried at least one actionable genotype. - These genotypes were associated with various diseases for which preventive or therapeutic measures exist.

2. **Impact on Life Span**: - Carriers of actionable genotypes exhibited a shorter median survival compared to non-carriers. - Particularly, genotypes linked to cancer genes were associated with a reduction in life span by approximately three years compared to noncarriers.

3. **Methodology**: - Genomes were sequenced and analyzed to identify both coding and splice variants in specific genes. - Variants were classified based on pathogenicity from data in the ClinVar database, frequency of the variants, and their disease associations.

4. **Survival Analysis**: - Survival analysis indicated that carriers of actionable genotypes had a higher probability of earlier death compared to non-carriers. - The study specifically analyzed the causes of death, linking genotype to mortality risks associated with the diseases related to the actionable genes.

5. **Clinical and Research Implications**: - The findings support the importance of genetic screening in clinical settings to potentially extend life expectancy through targeted interventions. - It underscores the necessity of updating and refining actionable gene lists to reflect new genetic data and clinical applicability.

### Conclusion:

The research provides significant insights into how genetic screening for specific actionable genotypes can inform clinical practices and potentially guide personalized preventive strategies. This study highlights the utility of genomic data in understanding the genetic underpinnings of disease and their direct impact on life expectancy, emphasizing the role of precision medicine in future healthcare.

[@sanchis2023genome] Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders This article in The American Journal of Human Genetics presents a detailed study on genome sequencing (GS) and its utility in diagnosing neurodevelopmental disorders (NDDs) in a cohort of 465 families involving 692 individuals. The main focus was to assess the diagnostic capabilities of short-read genome sequencing (srGS) enhanced by long-read genome sequencing (lrGS) for identifying causal genetic variants in individuals with NDDs.

**Key Findings:** 1. **Diagnostic Yield:** - Causal variants were identified in 36% of the affected individuals (177 out of 489). - An additional 23% (112 out of 489) had variants of uncertain significance. - The majority of identified variants (88%) were coding nuclear SNVs or insertions/deletions, with the rest being structural variants (SVs), non-coding variants, and mitochondrial variants.

2. **Utility of Long-Read GS:** - Long-read GS was crucial for resolving complex structural variants and phasing distal variants that were challenging to interpret with short-read GS alone. - It particularly helped in cases where structural variants were in technically difficult regions or where complex variant phasing was required.

3. **Genetic Diversity:** - The study encompassed a diverse array of neurodevelopmental phenotypes and leveraged genetic data from a large and varied cohort, which enriched the understanding of the genetic underpinnings of NDDs.

4. **Clinical Impact:** - Identifying genetic causes of NDDs has profound clinical implications, including ending diagnostic odysseys for families, influencing management strategies, and informing reproductive choices.

**Methodological Approach:** - The study applied a combination of short-read and long-read GS to provide a comprehensive genomic analysis, which enhanced the ability to detect a wide range of genetic variations, including small and large CNVs, inversions, and complex rearrangements.

• The researchers re-analyzed the data multiple times as new genetic information became available, which improved the diagnostic yield over time.

**Challenges and Recommendations:** - The authors discussed the limitations related to the detection of non-coding and complex variants and recommended ongoing re-analysis of genetic data as new genetic insights emerge. - They highlighted the importance of integrating long-read sequencing data to resolve complex cases that are not discernible through conventional short-read sequencing techniques.

In summary, this study underscores the significant advancements and potential of genome sequencing in enhancing the diagnostic precision for neurodevelopmental disorders and emphasizes the need for continual updates and integration of newer genetic technologies to maximize diagnostic yields.

[@abou2023rapid] A rapid whole-genome sequencing service for infants with rare diseases in the United Arab Emirates This correspondence in Nature Medicine discusses the use of rapid whole-genome sequencing (rWGS) as a diagnostic tool for infants with rare diseases in the United Arab Emirates (UAE). Here’s a brief summary:

**Background:** - Rapid whole-genome sequencing (rWGS) has proven to be a cost-effective diagnostic tool for critically ill children with rare diseases, primarily in high-income countries. The correspondence addresses the limited access and implementation of rWGS in lower-income regions.

**Implementation and Results:** - The correspondence references a pilot study named "Little Falcon," initiated in Dubai, UAE. This study evaluates the diagnostic efficacy and clinical utility of rWGS in a diverse patient population, including Middle Eastern, Asian, and African patients, who are genetically under-represented. - An initial feasibility study involving five infants demonstrated a quick turnaround of results (average of 37 hours), leading to three successful diagnoses and informed critical management changes.

**Challenges and Future Directions:** - The correspondence highlights the challenges of implementing rWGS in less resourced countries due to the high investment and infrastructure requirements. It suggests that establishing rWGS networks connecting regional hospitals to genomic sequencing hubs could be a viable solution. - The ongoing "Little Falcon" study aims to enroll 200 critically ill patients to further establish the diagnostic utility of rWGS and assess its economic impact on healthcare.

**Significance:** - This study not only aims to enhance local healthcare outcomes but also contributes to the global understanding of rare genetic diseases through the discovery of new genes and the development of new treatments.

The correspondence underscores the importance of expanding access to advanced genomic diagnostics globally, particularly in regions with limited resources, to improve outcomes for patients with rare diseases.

[@wojcik2024genome] Genome Sequencing for Diagnosing Rare Diseases The study detailed in the New England Journal of Medicine examines the diagnostic yield of genome sequencing in identifying rare diseases, especially in cases where previous genetic tests such as exome sequencing were inconclusive. Here’s a brief summary:

**Background:** - Genome sequencing is investigated as a diagnostic tool for rare diseases, enhancing the detection capabilities beyond exome sequencing by capturing more extensive and diverse genetic variations, including structural and non-coding variants.

**Methods and Results:** - The study involved sequencing the genomes of 822 families suspected of having rare monogenic diseases. - A significant diagnostic yield was found with genome sequencing identifying causative genetic variants in about 29.3 - Notably, genome sequencing was crucial for identifying specific variants in 8.2

**Conclusions:** - The results underscore genome sequencing’s enhanced capability to diagnose rare diseases by detecting a broader range of pathogenic variations. - The study supports the potential of genome sequencing as a primary diagnostic tool over exome sequencing, given its ability to provide a more comprehensive genetic analysis.

This paper highlights the evolving importance of genome sequencing in clinical diagnostics, offering insights into its application in enhancing the understanding and treatment of rare genetic disorders.

[@wright2023genomic] Genomic diagnosis of rare pediatric disease in the United Kingdom and Ireland

In the benchmark study detailed in the New England Journal of Medicine, the Deciphering Developmental Disorders (DDD) project in the United Kingdom and Ireland utilized genomic sequencing to identify the molecular causes of rare pediatric diseases. Here’s a summarized overview, which underscores the potential benefits a precision medicine unit can bring to patient care and cost management in a hospital setting:

**Study Overview:** - The DDD study involved over 13,500 families with children suffering from severe, often monogenic, developmental disorders that were difficult to diagnose. - This large-scale study integrated genomic data analysis (exome sequencing and microarray analyses) with extensive clinical phenotyping.

**Key Findings:** - Approximately 41% of the probands received a genetic diagnosis through the study, demonstrating the effectiveness of genomic sequencing in identifying rare genetic disorders. - The study highlighted the importance of family trio recruitment (parent-offspring), which significantly increased diagnostic yields.

**Impact on Patient Care:** - Early and accurate genetic diagnosis can lead to targeted treatments, potentially improving long-term health outcomes and quality of life for pediatric patients. - Identifying genetic causes helps in understanding disease mechanisms, which is crucial for developing effective therapeutic strategies.

**Cost Implications:** - While the initial costs of genomic sequencing are high, the long-term savings from precise diagnosis and targeted therapy can be substantial. Accurate diagnostics prevent the need for multiple, often inconclusive, tests and reduce the trial-and-error approach in treatment strategies. - Early intervention based on precise diagnoses can decrease hospital stays, reduce complications from inappropriate treatments, and lower the overall healthcare costs.

**Ethical and Operational Considerations:** - The study also navigated complex ethical considerations, emphasizing the need for careful management of genomic data and maintaining patient confidentiality. - It highlighted the necessity of integrating clinical and genetic data securely, ensuring that sensitive information is protected while enabling important research.

**Conclusion and Recommendation:** Implementing a precision medicine unit within a hospital could replicate the success of the DDD study by providing similar diagnostic and treatment advantages. This could lead to improved patient outcomes and more efficient use of healthcare resources. The ability to conduct high-throughput genomic analyses in-house would facilitate quicker diagnostics, tailored treatments, and overall better management of rare pediatric disorders. The initial investment in genomic technology and expertise could be offset by the longer-term savings and enhanced patient care effectiveness.