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| Name | Class |
|---|---|
| Karius, Inc. | INDUSTRY |
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The purpose of this study is to evaluate the use of a blood test: Karius® plasma-based next-generation sequencing test (Karius Test), to see if we can detect and measure the infection causing agent in children with musculoskeletal infections (MSKI).
children admitted to Riley Hospital for Children (RHC) with musculoskeletal infections (osteomyelitis, septic arthritis, or pyomyositis) over a 12-month period will be prospectively enrolled. Eligible subjects will be identified by referral from the infectious diseases and orthopedic services at RHC. Blood samples will be obtained on the day of admission (within 48hrs), and 24 hours after the admission sample for real-time NGS (next-generation sequencing) testing at Karius Laboratory (Redwood City, CA). If a pathogen is identified by NGS, in either of the first two samples, subsequent samples will be sent every 48-72 hours while inpatient, and then collected every 1-2 weeks after hospital discharge, while being treated for MSKI (maximum 3 follow-up samples). If both of the initial inpatient NGS samples are negative, no further samples will be sent for NGS. Pathogen identification by NGS will be compared to standard cultures methods, and quantitative cfDNA (cell-free DNA) will be evaluated over time.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Karius Test | Experimental | Participants will have additional blood drawn for the purposes of analysis with the Karius test. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Karius Test | Diagnostic Test | Next-generation sequencing of blood and synovial fluid samples for pathogen identification in children with musculoskeletal infections |
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| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With a Pathogen Identified by the Initial Karius Test (IP1) and Standard Culture Methods | We evaluated the total number of participants that had a pathogen identified by the initial (IP1) Karius Test ("positive Karius Test"). We compared the results of the Karius Test to cultures (gold standard) for each participant. Karius Test results that matched cultures results (same genus and species) were considered "positive agreement". We also evaluated at the number of participants who had negative cultures, but had a positive Karius Test. | Inpatient Sample 1 (IP1) - Within 48 hours of admission |
| Number of Participants With a Pathogen Identified by the Karius Test (at Time Point IP2) and Standard Culture Methods | We evaluated the total number of participants that had a pathogen identified by the Karius Test ("positive Karius Test") at time point IP2 (within 48 hours of the initial sample). We compared the results of the Karius Test to those with a positive culture (gold standard) for each participant. Karius Test results that matched cultures results (same genus and species) were considered "positive agreement". Karius Test results that identified an organism different from the organism identified in culture were considered "discordant results" Karius Tests results that did not identify any organism were consider "negative" | Inpatient Sample 2 (IP2) - Within 48 hours of the initial sample |
| Measure | Description | Time Frame |
|---|---|---|
| Microbial Cell Free DNA Level (cfDNA) in Molecules Per Microliter (MPM) | We compared the microbial cfDNA level (on initial samples, IP1) between patients with non-severe MSKI to those with severe MSKI (defined as need for intensive care unit (ICU) care; infection in two or more non-contiguous anatomic sites (disseminated disease); need for more than 1 debridement procedure; deep vein thrombosis or thromboembolic disease; or pathologic fracture). Only those with a positive agreement between initial Karius Test (IP1) and culture were analyzed (n=15). Mann-Whitney U was used to compare median microbial cfDNA between those with non-severe vs. severe MSKI. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jack G Schneider, MD | Indiana University School of Medicine - Pediatrics | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Riley Hospital for Children | Indianapolis | Indiana | 46202 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Pediatric Musculoskeletal Infections | Children 6 months to 18 years of age admitted to Riley Hospital for Children (Indianapolis, IN), from July 2019 to May 2022. Potential study participants were identified by daily screening of the pediatric infectious diseases and hospitalist patient censuses, and approached for enrollment if there was a strong clinical suspicion of MSKI as evidenced by fever, musculoskeletal pain (e.g. tenderness to palpation of a joint/bone, or refusal to bear weight); and elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 19, 2021 |
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| From hospital admission to hospital discharge, up to 3 months |
| Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point IP1 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell count (WBC), common inflammatory markers followed in children with MSKI. Spearman's correlation was used to compare the MPM value to the CRP, ESR and WBC | Inpatient Sample 1 (IP1) - Within 48 hours of admission |
| Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point IP2 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). Spearman's correlation was used to compare the MPM value to the CRP | Inpatient Sample 2 (IP2) - Within 48 hours of the admission sample |
| Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Timepoint IP3 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI) at time point IP3 in participants with positive agreement between the Karius Test and culture. Spearman's correlation was used to compare the MPM value to the CRP | Inpatient Sample 3 (IP3) - Within 48 hours of the second inpatient sample |
| Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point IP4 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). | Inpatient Sample 4 (IP4) - Within 48 hours of the third inpatient sample |
| Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point OP1 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). | Outpatient Sample 1 (OP1) - 1-2 weeks after hospital discharge |
| Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point OP2 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). | Outpatient Sample 2 (OP2) - 3-6 weeks after hospital discharge |
| Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point OP3 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). | Outpatient Sample 3 (OP3) - 6-8 weeks after hospital discharge |
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Children with musculoskeletal infections
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| ID | Title | Description |
|---|---|---|
| BG000 | Pediatric Musculoskeletal Infections | Children 6 months to 18 years of age admitted to Riley Hospital for Children (Indianapolis, IN), from July 2019 to May 2022. Potential study participants were identified by daily screening of the pediatric infectious diseases and hospitalist patient censuses, and approached for enrollment if there was a strong clinical suspicion of MSKI as evidenced by fever, musculoskeletal pain (e.g. tenderness to palpation of a joint/bone, or refusal to bear weight); and elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
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| Age, Continuous | Median | Inter-Quartile Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With a Pathogen Identified by the Initial Karius Test (IP1) and Standard Culture Methods | We evaluated the total number of participants that had a pathogen identified by the initial (IP1) Karius Test ("positive Karius Test"). We compared the results of the Karius Test to cultures (gold standard) for each participant. Karius Test results that matched cultures results (same genus and species) were considered "positive agreement". We also evaluated at the number of participants who had negative cultures, but had a positive Karius Test. | 36 children had a culture obtained (either blood or surgical or both) 33 children had a Karius Test available for analysis (1 sample failed quality control and 2 participants did not have an initial inpatient Karius Test sample drawn) 23 children had a positive culture, however, 1 participant with a positive culture had a Karius sample that failed quality control, leaving 22 available for positive agreement analysis | Posted | Count of Participants | Participants | Inpatient Sample 1 (IP1) - Within 48 hours of admission |
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| Primary | Number of Participants With a Pathogen Identified by the Karius Test (at Time Point IP2) and Standard Culture Methods | We evaluated the total number of participants that had a pathogen identified by the Karius Test ("positive Karius Test") at time point IP2 (within 48 hours of the initial sample). We compared the results of the Karius Test to those with a positive culture (gold standard) for each participant. Karius Test results that matched cultures results (same genus and species) were considered "positive agreement". Karius Test results that identified an organism different from the organism identified in culture were considered "discordant results" Karius Tests results that did not identify any organism were consider "negative" | 23 children had a positive culture, however, 5 participant with a positive culture did not have an IP2 Karius sample drawn, leaving 18 available for positive agreement analysis | Posted | Count of Participants | Participants | Inpatient Sample 2 (IP2) - Within 48 hours of the initial sample |
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| Secondary | Microbial Cell Free DNA Level (cfDNA) in Molecules Per Microliter (MPM) | We compared the microbial cfDNA level (on initial samples, IP1) between patients with non-severe MSKI to those with severe MSKI (defined as need for intensive care unit (ICU) care; infection in two or more non-contiguous anatomic sites (disseminated disease); need for more than 1 debridement procedure; deep vein thrombosis or thromboembolic disease; or pathologic fracture). Only those with a positive agreement between initial Karius Test (IP1) and culture were analyzed (n=15). Mann-Whitney U was used to compare median microbial cfDNA between those with non-severe vs. severe MSKI. | Patients with a positive agreement between the Karius Test and cultures | Posted | Median | Inter-Quartile Range | MPM | From hospital admission to hospital discharge, up to 3 months |
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| Secondary | Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point IP1 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell count (WBC), common inflammatory markers followed in children with MSKI. Spearman's correlation was used to compare the MPM value to the CRP, ESR and WBC | Patients with a positive agreement between Karius Test and culture who had a Karius Test, CRP, ESR and WBC obtained at time point IP1 | Posted | Number | Spearman's correlation coefficient | Inpatient Sample 1 (IP1) - Within 48 hours of admission |
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| Secondary | Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point IP2 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). Spearman's correlation was used to compare the MPM value to the CRP | Patients with a positive agreement between Karius Test and culture who had both a Karius Test and CRP obtained at time point IP2 | Posted | Number | Spearman's correlation coefficient | Inpatient Sample 2 (IP2) - Within 48 hours of the admission sample |
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| Secondary | Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Timepoint IP3 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI) at time point IP3 in participants with positive agreement between the Karius Test and culture. Spearman's correlation was used to compare the MPM value to the CRP | Patients with a positive agreement between Karius Test and culture who had both a Karius Test and CRP obtained at timepoint IP3 | Posted | Number | Spearman's correlation coefficient | Inpatient Sample 3 (IP3) - Within 48 hours of the second inpatient sample |
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| Secondary | Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point IP4 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). | Patients with a positive agreement between Karius Test and culture who had both a Karius Test and CRP obtained at timepoint IP4 | Posted | Number | Spearman's correlation coefficient | Inpatient Sample 4 (IP4) - Within 48 hours of the third inpatient sample |
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| Secondary | Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point OP1 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). | Participants with a Karius Test and CRP drawn at time point OP1 | Posted | Number | Spearman's correlation coefficient | Outpatient Sample 1 (OP1) - 1-2 weeks after hospital discharge |
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| Secondary | Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point OP2 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). | Participants with a Karius Test and CRP drawn at time point OP2 | Posted | Number | Spearman's correlation coefficient | Outpatient Sample 2 (OP2) - 3-6 weeks after hospital discharge |
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| Secondary | Microbial Cell Free DNA (cfDNA) in Molecules Per Microliter (MPM) at Time Point OP3 | We evaluated whether cfDNA level (in MPM) correlated with C-reactive protein (a common inflammatory marker used to track inflammation in children with MSKI). | Participants with a Karius Test and CRP drawn at time point OP3 | Posted | Outpatient Sample 3 (OP3) - 6-8 weeks after hospital discharge |
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Through hospital follow up- up to 1 year
Any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Karius Test | Participants will have additional blood drawn for the purposes of analysis with the Karius test. Karius Test: Next-generation sequencing of blood and synovial fluid samples for pathogen identification in children with musculoskeletal infections | 0 | 36 | 0 | 36 | 0 | 36 |
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The number of participants with the data for the secondary outcomes was very small, thus all of the secondary outcomes were underpowered to show a statistical difference. For secondary outcomes 7,8, and 9, there was not enough data to do the analyses. For secondary outcome 10, no patient data was collected because no patients followed up at this time point.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| James Wood, MD | Indiana University School of Medicine | 317-944-7260 | woodjb@iu.edu |
| Aug 2, 2023 |
| Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001170 | Arthritis, Infectious |
| D010019 | Osteomyelitis |
| D052880 | Pyomyositis |
| D007239 | Infections |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D001850 | Bone Diseases, Infectious |
| D001847 | Bone Diseases |
| D013492 | Suppuration |
| D009220 | Myositis |
| D009135 | Muscular Diseases |
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
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| Unknown or Not Reported |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Positive agreement between culture and Karius Test (both tests identified the same organism) |
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