Initial identification of a blood-based chromosome conformation signature for aiding in the diagnosis of amyotrophic lateral sclerosis
<strong>Background</strong> The identification of blood-based biomarkers specific to the diagnosis of amyotrophic lateral sclerosis (ALS) is an active field of academic and clinical research. While inheritance studies have advanced the field, a majority of patients do not have a known ge...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2018
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| _version_ | 1797051698595758080 |
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| author | Salter, M Corfield, E Ramadass, A Grand, F Green, J Westra, J Lim, C Farrimond, L Feneberg, E Scaber, J Thompson, A Ossher, L Turner, M Talbot, K Cudkowicz, M Berry, J Hunter, E Akoulitchev, A |
| author_facet | Salter, M Corfield, E Ramadass, A Grand, F Green, J Westra, J Lim, C Farrimond, L Feneberg, E Scaber, J Thompson, A Ossher, L Turner, M Talbot, K Cudkowicz, M Berry, J Hunter, E Akoulitchev, A |
| author_sort | Salter, M |
| collection | OXFORD |
| description | <strong>Background</strong> The identification of blood-based biomarkers specific to the diagnosis of amyotrophic lateral sclerosis (ALS) is an active field of academic and clinical research. While inheritance studies have advanced the field, a majority of patients do not have a known genetic link to the disease, making direct sequence-based genetic testing for ALS difficult. The ability to detect biofluid-based epigenetic changes in ALS would expand the relevance of using genomic information for disease diagnosis. <strong>Methods</strong> Assessing differences in chromosomal conformations (i.e. how they are positioned in 3-dimensions) represents one approach for assessing epigenetic changes. In this study, we used an industrial platform, EpiSwitch™, to compare the genomic architecture of healthy and diseased patient samples (blood and tissue) to discover a chromosomal conformation signature (CCS) with diagnostic potential in ALS. A three-step biomarker selection process yielded a distinct CCS for ALS, comprised of conformation changes in eight genomic loci and detectable in blood. <strong>Findings</strong> We applied the ALS CCS to determine a diagnosis for 74 unblinded patient samples and subsequently conducted a blinded diagnostic study of 16 samples. Sensitivity and specificity for ALS detection in the 74 unblinded patient samples were 83∙33% (CI 51∙59 to 97∙91%) and 76∙92% (46∙19 to 94∙96%), respectively. In the blinded cohort, sensitivity reached 87∙50% (CI 47∙35 to 99∙68%) and specificity was 75∙0% (34∙91 to 96∙81%). <strong>Interpretations</strong> The sensitivity and specificity values achieved using the ALS CCS identified and validated in this study provide an indication that the detection of chromosome conformation signatures is a promising approach to disease diagnosis and can potentially augment current strategies for diagnosing ALS. |
| first_indexed | 2024-03-06T18:23:14Z |
| format | Journal article |
| id | oxford-uuid:0707df80-621e-42ca-ae6b-da1594d883cb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:23:14Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:0707df80-621e-42ca-ae6b-da1594d883cb2022-03-26T09:05:33ZInitial identification of a blood-based chromosome conformation signature for aiding in the diagnosis of amyotrophic lateral sclerosisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0707df80-621e-42ca-ae6b-da1594d883cbEnglishSymplectic Elements at OxfordElsevier2018Salter, MCorfield, ERamadass, AGrand, FGreen, JWestra, JLim, CFarrimond, LFeneberg, EScaber, JThompson, AOssher, LTurner, MTalbot, KCudkowicz, MBerry, JHunter, EAkoulitchev, A<strong>Background</strong> The identification of blood-based biomarkers specific to the diagnosis of amyotrophic lateral sclerosis (ALS) is an active field of academic and clinical research. While inheritance studies have advanced the field, a majority of patients do not have a known genetic link to the disease, making direct sequence-based genetic testing for ALS difficult. The ability to detect biofluid-based epigenetic changes in ALS would expand the relevance of using genomic information for disease diagnosis. <strong>Methods</strong> Assessing differences in chromosomal conformations (i.e. how they are positioned in 3-dimensions) represents one approach for assessing epigenetic changes. In this study, we used an industrial platform, EpiSwitch™, to compare the genomic architecture of healthy and diseased patient samples (blood and tissue) to discover a chromosomal conformation signature (CCS) with diagnostic potential in ALS. A three-step biomarker selection process yielded a distinct CCS for ALS, comprised of conformation changes in eight genomic loci and detectable in blood. <strong>Findings</strong> We applied the ALS CCS to determine a diagnosis for 74 unblinded patient samples and subsequently conducted a blinded diagnostic study of 16 samples. Sensitivity and specificity for ALS detection in the 74 unblinded patient samples were 83∙33% (CI 51∙59 to 97∙91%) and 76∙92% (46∙19 to 94∙96%), respectively. In the blinded cohort, sensitivity reached 87∙50% (CI 47∙35 to 99∙68%) and specificity was 75∙0% (34∙91 to 96∙81%). <strong>Interpretations</strong> The sensitivity and specificity values achieved using the ALS CCS identified and validated in this study provide an indication that the detection of chromosome conformation signatures is a promising approach to disease diagnosis and can potentially augment current strategies for diagnosing ALS. |
| spellingShingle | Salter, M Corfield, E Ramadass, A Grand, F Green, J Westra, J Lim, C Farrimond, L Feneberg, E Scaber, J Thompson, A Ossher, L Turner, M Talbot, K Cudkowicz, M Berry, J Hunter, E Akoulitchev, A Initial identification of a blood-based chromosome conformation signature for aiding in the diagnosis of amyotrophic lateral sclerosis |
| title | Initial identification of a blood-based chromosome conformation signature for aiding in the diagnosis of amyotrophic lateral sclerosis |
| title_full | Initial identification of a blood-based chromosome conformation signature for aiding in the diagnosis of amyotrophic lateral sclerosis |
| title_fullStr | Initial identification of a blood-based chromosome conformation signature for aiding in the diagnosis of amyotrophic lateral sclerosis |
| title_full_unstemmed | Initial identification of a blood-based chromosome conformation signature for aiding in the diagnosis of amyotrophic lateral sclerosis |
| title_short | Initial identification of a blood-based chromosome conformation signature for aiding in the diagnosis of amyotrophic lateral sclerosis |
| title_sort | initial identification of a blood based chromosome conformation signature for aiding in the diagnosis of amyotrophic lateral sclerosis |
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