3943e100473a3713b14995b4721205ed bbac161.pdf 6af181f74ced11991e4be5dfcf371f39934c40d6 bbac161.pdf de7645dea63157397287d960b10b752c7dffd0611bda78334f5180979b4d6bdf bbac161.pdf Title: Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary Subject: AcademicSubjects/SCI01060, DOI: 10.1093/bib/bbac161, Briefings in Bioinformatics, 23(5), 5, 00 00 0000. Abstract: High-throughput genomic technologies are increasingly used in personalized cancer medicine. However, computational tools to maximize the use of scarce tissues combining distinct molecular layers are needed. Here we present a refined strategy, based on the R-package ‘conumee’, to better predict somatic copy number alterations (SCNA) from deoxyribonucleic acid (DNA) methylation arrays. Our approach, termed hereafter as ‘conumee-K’, improves SCNA prediction by incorporating tumor purity and dynamic thresholding. We trained our algorithm using paired DNA methylation and SNP Array 6.0 data from The Cancer Genome Atlas samples and confirmed its performance in cancer cell lines. Most importantly, the application of our approach in cancers of unknown primary identified amplified potentially actionable targets that were experimentally validated by Fluorescence in situ hybridization and immunostaining, reaching 100% specificity and 93.3% sensitivity. Keywords: Author: Creator: LaTeX with hyperref package Producer: Acrobat Distiller 22.0 (Windows); modified using iTextSharp 4.1.6 by 1T3XT CreationDate: Fri Sep 16 15:46:54 2022 CEST ModDate: Tue Jan 31 17:29:02 2023 CET Tagged: yes UserProperties: no Suspects: no Form: none JavaScript: no Pages: 9 Encrypted: no Page size: 595.26 x 782.337 pts Page rot: 0 File size: 1113575 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ILGOPE+MTMI Type 1C Custom yes yes yes 47 0 ILGOPD+CaeciliaLTStd-LightItalic Type 1C Custom yes yes yes 48 0 ILGOLE+CaeciliaLTStd-Heavy Type 1C Custom yes yes yes 49 0 ILGOLD+MTSYN Type 1C Custom yes yes yes 50 0 ILGOHD+CaeciliaLTStd-Italic Type 1C Custom yes yes yes 51 0 ILGOCE+CaeciliaLTStd-Roman Type 1C Custom yes yes yes 52 0 ILGNPE+CaeciliaLTStd-Light Type 1C Custom yes yes yes 53 0 ILGNPD+CaeciliaLTStd-Bold Type 1C Custom yes yes yes 54 0 PUTDCF+ArialMT TrueType WinAnsi yes yes no 1 0 ILGPOP+BLEX Type 1C Custom yes yes no 74 0 ILHACP+CaeciliaLTStd-BoldItalic Type 1C Custom yes yes yes 75 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-06-29 02:28:59 CEST RepresentationInformation: bbac161.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-01-31 17:29:28 CET Size: 1113575 Format: PDF Version: 1.7 Status: Well-Formed, but not valid SignatureMatches: PDF-hul ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f3' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f15' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f14' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f4' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f4' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f5' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f6' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f7' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f4' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f3' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f4' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f4' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f4' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f4' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f8' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f9' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f4' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f10' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f9' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f9' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f11' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f9' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f9' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f9' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f12' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f13' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f13' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f14' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f15' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f16' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f9' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f9' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f17' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'f4' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'myrefsref2' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'myrefsref8' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'myrefsref15' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'myrefsref26' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'myrefsref39' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'myrefsref40' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'myrefsref41' cannot be found Offset: 873117 ID: PDF-HUL-122 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'myrefsref42' cannot be found Offset: 873117 MIMEtype: application/pdf Profile: Tagged PDF PDFMetadata: Objects: 1377 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: true NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseOutlines Language: en Outlines: Item: Title: Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6a1aab78 Children: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@462d5aee Item: Title: Materials and methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@69b0fd6f Item: Title: Experimental allidation of potential actionable targets Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@757942a1 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4a87761d Item: Title: Conclusion and Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@66d1af89 Item: Title: Data availability Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@8646db9 Item: Title: Competing interests Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@37374a5e Item: Title: Key Points Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4671e53b Item: Title: Supplementary Data Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@2db7a79b Item: Title: Authors' contributions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6950e31 Item: Title: Acknowledgements Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@b7dd107 Item: Title: Funding Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@42eca56e Info: Title: Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary Author: Subject: AcademicSubjects/SCI01060, DOI: 10.1093/bib/bbac161, Briefings in Bioinformatics, 23(5), 5, 00 00 0000. Abstract: High-throughput genomic technologies are increasingly used in personalized cancer medicine. However, computational tools to maximize the use of scarce tissues combining distinct molecular layers are needed. Here we present a refined strategy, based on the R-package ‘conumee’, to better predict somatic copy number alterations (SCNA) from deoxyribonucleic acid (DNA) methylation arrays. Our approach, termed hereafter as ‘conumee-K’, improves SCNA prediction by incorporating tumor purity and dynamic thresholding. We trained our algorithm using paired DNA methylation and SNP Array 6.0 data from The Cancer Genome Atlas samples and confirmed its performance in cancer cell lines. Most importantly, the application of our approach in cancers of unknown primary identified amplified potentially actionable targets that were experimentally validated by Fluorescence in situ hybridization and immunostaining, reaching 100% specificity and 93.3% sensitivity. Keywords: Creator: LaTeX with hyperref package Producer: Acrobat Distiller 22.0 (Windows); modified using iTextSharp 4.1.6 by 1T3XT CreationDate: Fri Sep 16 16:16:54 CEST 2022 ModDate: Tue Jan 31 17:29:02 CET 2023 ID: 0x03ad1c1f822a62067d08a652b8de257f, 0x399a956604a8c1a240d19633d5ddfc56 Filters: FilterPipeline: FlateDecode FilterPipeline: DCTDecode Images: Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 2001 ImageHeight: 1961 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 2001 ImageHeight: 2141 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Fonts: Type1: Font: BaseFont: ILGOPD+CaeciliaLTStd-LightItalic FontSubset: true FirstChar: 40 LastChar: 144 FontDescriptor: FontName: ILGOPD+CaeciliaLTStd-LightItalic Flags: Serif, Symbolic, Italic FontBBox: -166, -267, 1033, 909 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ILGOLE+CaeciliaLTStd-Heavy FontSubset: true FirstChar: 46 LastChar: 144 FontDescriptor: FontName: ILGOLE+CaeciliaLTStd-Heavy Flags: Serif, Symbolic, ForceBold FontBBox: -170, -277, 1146, 970 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ILGOLD+MTSYN FontSubset: true FirstChar: 2 LastChar: 138 FontDescriptor: FontName: ILGOLD+MTSYN Flags: Symbolic FontBBox: 0, -954, 1043, 900 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ILGOHD+CaeciliaLTStd-Italic FontSubset: true FirstChar: 66 LastChar: 117 FontDescriptor: FontName: ILGOHD+CaeciliaLTStd-Italic Flags: Serif, Symbolic, Italic FontBBox: -166, -270, 1053, 915 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ILGOCE+CaeciliaLTStd-Roman FontSubset: true FirstChar: 37 LastChar: 169 FontDescriptor: FontName: ILGOCE+CaeciliaLTStd-Roman Flags: Serif, Symbolic FontBBox: -167, -270, 1136, 926 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ILGNPE+CaeciliaLTStd-Light FontSubset: true FirstChar: 35 LastChar: 243 FontDescriptor: FontName: ILGNPE+CaeciliaLTStd-Light Flags: Serif, Symbolic FontBBox: -164, -266, 1130, 908 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ILGNPD+CaeciliaLTStd-Bold FontSubset: true FirstChar: 40 LastChar: 122 FontDescriptor: FontName: ILGNPD+CaeciliaLTStd-Bold Flags: Serif, Symbolic, ForceBold FontBBox: -166, -273, 1141, 938 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ILGPOP+BLEX FontSubset: true FirstChar: 2 LastChar: 2 FontDescriptor: FontName: ILGPOP+BLEX Flags: Symbolic FontBBox: 127, -1154, 384, 46 FontFile3: true EncodingDictionary: Differences: true Font: BaseFont: ILHACP+CaeciliaLTStd-BoldItalic FontSubset: true FirstChar: 105 LastChar: 117 FontDescriptor: FontName: ILHACP+CaeciliaLTStd-BoldItalic Flags: Serif, Symbolic, Italic, ForceBold FontBBox: -169, -273, 1082, 932 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ILGOPE+MTMI FontSubset: true FirstChar: 2 LastChar: 62 FontDescriptor: FontName: ILGOPE+MTMI Flags: Serif, Symbolic, Italic FontBBox: 0, -213, 987, 680 FontFile3: true EncodingDictionary: Differences: true ToUnicode: true TrueType: Font: BaseFont: PUTDCF+ArialMT FontSubset: true FirstChar: 32 LastChar: 121 FontDescriptor: FontName: PUTDCF+ArialMT Flags: Nonsymbolic FontBBox: -664, -324, 2000, 1039 FontFile2: true Encoding: WinAnsiEncoding XMP: application/pdf Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary Blecua Pedro AcademicSubjects/SCI01060, DOI: 10.1093/bib/bbac161, Briefings in Bioinformatics, 23(5), 5, 00 00 0000. Abstract: High-throughput genomic technologies are increasingly used in personalized cancer medicine. However, computational tools to maximize the use of scarce tissues combining distinct molecular layers are needed. Here we present a refined strategy, based on the R-package ‘conumee’, to better predict somatic copy number alterations (SCNA) from deoxyribonucleic acid (DNA) methylation arrays. Our approach, termed hereafter as ‘conumee-K’, improves SCNA prediction by incorporating tumor purity and dynamic thresholding. We trained our algorithm using paired DNA methylation and SNP Array 6.0 data from The Cancer Genome Atlas samples and confirmed its performance in cancer cell lines. Most importantly, the application of our approach in cancers of unknown primary identified amplified potentially actionable targets that were experimentally validated by Fluorescence in situ hybridization and immunostaining, reaching 100% specificity and 93.3% sensitivity. somatic copy number alterationsDNA methylationgene amplificationactionable target identificationcancers of unknown primary © The Author(s) 2022. Published by Oxford University Press. True Pages: Page: Label: 1 Annotations: Annotation: Subtype: Link Rect: 429, 56, 553, 64 Annotation: Subtype: Link Rect: 47, 46, 81, 55 Annotation: Subtype: Link Rect: 529, 558, 541, 570 Annotation: Subtype: Link Rect: 271, 320, 276, 326 Destination: 167 Annotation: Subtype: Link Rect: 281, 320, 286, 326 Destination: 167 Annotation: Subtype: Link Rect: 227, 284, 232, 290 Destination: 167 Annotation: Subtype: Link Rect: 236, 284, 241, 290 Destination: 167 Annotation: Subtype: Link Rect: 149, 224, 154, 231 Destination: 167 Annotation: Subtype: Link Rect: 159, 224, 164, 231 Destination: 167 Annotation: Subtype: Link Rect: 219, 212, 224, 219 Destination: 167 Annotation: Subtype: Link Rect: 228, 212, 233, 219 Destination: 167 Annotation: Subtype: Link Rect: 188, 188, 198, 195 Destination: 167 Annotation: Subtype: Link Rect: 312, 367, 317, 373 Destination: 167 Annotation: Subtype: Link Rect: 460, 271, 465, 278 Destination: 167 Annotation: Subtype: Link Rect: 469, 271, 474, 278 Destination: 167 Page: Label: 2 Annotations: Annotation: Subtype: Link Rect: 143, 722, 153, 728 Destination: 167 Annotation: Subtype: Link Rect: 189, 698, 199, 704 Destination: 167 Annotation: Subtype: Link Rect: 131, 578, 141, 585 Destination: 167 Annotation: Subtype: Link Rect: 270, 555, 280, 561 Destination: 167 Annotation: Subtype: Link Rect: 41, 543, 51, 549 Destination: 167 Annotation: Subtype: Link Rect: 252, 409, 286, 421 Annotation: Subtype: Link Rect: 40, 397, 137, 409 Annotation: Subtype: Link Rect: 96, 389, 106, 395 Destination: 167 Annotation: Subtype: Link Rect: 194, 353, 204, 359 Destination: 195 Annotation: Subtype: Link Rect: 44, 305, 54, 311 Destination: 195 Annotation: Subtype: Link Rect: 125, 240, 254, 252 Annotation: Subtype: Link Rect: 44, 182, 149, 191 Destination: 84 Annotation: Subtype: Link Rect: 44, 146, 149, 155 Destination: 131 Annotation: Subtype: Link Rect: 112, 88, 122, 95 Destination: 195 Annotation: Subtype: Link Rect: 379, 710, 389, 716 Destination: 167 Annotation: Subtype: Link Rect: 405, 698, 415, 704 Destination: 195 Annotation: Subtype: Link Rect: 536, 567, 541, 573 Destination: 167 Annotation: Subtype: Link Rect: 308, 459, 318, 465 Destination: 195 Annotation: Subtype: Link Rect: 306, 310, 316, 316 Destination: 195 Annotation: Subtype: Link Rect: 483, 76, 493, 83 Destination: 195 Page: Label: 3 Annotations: Annotation: Subtype: Link Rect: 48, 549, 163, 559 Destination: null Annotation: Subtype: Link Rect: 130, 492, 135, 498 Destination: 167 Annotation: Subtype: Link Rect: 229, 420, 234, 427 Destination: 167 Annotation: Subtype: Link Rect: 122, 408, 127, 415 Destination: 167 Annotation: Subtype: Link Rect: 186, 311, 291, 320 Destination: null Annotation: Subtype: Link Rect: 73, 299, 188, 308 Destination: null Annotation: Subtype: Link Rect: 312, 710, 322, 716 Destination: 195 Annotation: Subtype: Link Rect: 326, 710, 336, 716 Destination: 195 Annotation: Subtype: Link Rect: 492, 308, 502, 315 Destination: 195 Annotation: Subtype: Link Rect: 542, 244, 547, 250 Destination: 167 Annotation: Subtype: Link Rect: 438, 206, 480, 215 Destination: null Annotation: Subtype: Link Rect: 388, 158, 429, 167 Destination: null Annotation: Subtype: Link Rect: 388, 64, 398, 71 Destination: 195 Annotation: Subtype: Link Rect: 312, 52, 322, 59 Destination: 195 Annotation: Subtype: Link Rect: 329, 52, 339, 59 Destination: 195 Annotation: Subtype: Link Rect: 419, 50, 524, 59 Destination: null Page: Label: 4 Annotations: Annotation: Subtype: Link Rect: 81, 103, 186, 112 Destination: 84 Page: Label: 5 Annotations: Annotation: Subtype: Link Rect: 103, 722, 113, 728 Destination: 195 Annotation: Subtype: Link Rect: 102, 600, 207, 609 Destination: null Annotation: Subtype: Link Rect: 243, 566, 253, 573 Destination: 195 Annotation: Subtype: Link Rect: 148, 528, 257, 538 Destination: null Annotation: Subtype: Link Rect: 122, 457, 163, 466 Destination: null Annotation: Subtype: Link Rect: 177, 421, 291, 430 Destination: null Annotation: Subtype: Link Rect: 139, 349, 244, 358 Destination: 131 Annotation: Subtype: Link Rect: 283, 303, 288, 310 Destination: 167 Annotation: Subtype: Link Rect: 144, 292, 149, 298 Destination: 167 Annotation: Subtype: Link Rect: 160, 289, 200, 298 Destination: null Annotation: Subtype: Link Rect: 155, 229, 195, 239 Destination: null Annotation: Subtype: Link Rect: 228, 124, 233, 130 Destination: 167 Annotation: Subtype: Link Rect: 238, 124, 243, 130 Destination: 167 Annotation: Subtype: Link Rect: 210, 98, 251, 107 Destination: null Annotation: Subtype: Link Rect: 509, 708, 550, 717 Destination: null Annotation: Subtype: Link Rect: 445, 648, 554, 657 Destination: null Annotation: Subtype: Link Rect: 467, 600, 509, 609 Destination: null Annotation: Subtype: Link Rect: 537, 578, 547, 585 Destination: 167 Annotation: Subtype: Link Rect: 348, 552, 389, 562 Destination: null Annotation: Subtype: Link Rect: 378, 540, 483, 550 Destination: null Annotation: Subtype: Link Rect: 478, 471, 488, 477 Destination: 195 Annotation: Subtype: Link Rect: 470, 445, 511, 454 Destination: null Annotation: Subtype: Link Rect: 513, 375, 523, 382 Destination: 167 Annotation: Subtype: Link Rect: 312, 337, 353, 346 Destination: null Annotation: Subtype: Link Rect: 360, 337, 465, 346 Destination: null Annotation: Subtype: Link Rect: 495, 241, 553, 252 Annotation: Subtype: Link Rect: 308, 228, 439, 240 Annotation: Subtype: Link Rect: 448, 232, 458, 238 Destination: 195 Annotation: Subtype: Link Rect: 392, 216, 497, 228 Annotation: Subtype: Link Rect: 509, 220, 519, 226 Destination: 195 Annotation: Subtype: Link Rect: 519, 205, 553, 216 Annotation: Subtype: Link Rect: 308, 193, 360, 204 Annotation: Subtype: Link Rect: 451, 193, 548, 204 Annotation: Subtype: Link Rect: 451, 170, 493, 179 Destination: null Annotation: Subtype: Link Rect: 458, 98, 499, 107 Destination: null Annotation: Subtype: Link Rect: 370, 74, 411, 83 Destination: null Annotation: Subtype: Link Rect: 418, 74, 523, 83 Destination: null Page: Label: 6 Annotations: Annotation: Subtype: Link Rect: 78, 144, 187, 153 Destination: null Annotation: Subtype: Link Rect: 76, 86, 86, 92 Destination: 195 Annotation: Subtype: Link Rect: 94, 84, 202, 93 Destination: null Annotation: Subtype: Link Rect: 306, 144, 414, 153 Destination: null Annotation: Subtype: Link Rect: 418, 144, 523, 153 Destination: null Annotation: Subtype: Link Rect: 345, 60, 453, 69 Destination: null Page: Label: 7 Annotations: Annotation: Subtype: Link Rect: 48, 636, 88, 645 Destination: null Annotation: Subtype: Link Rect: 51, 600, 91, 609 Destination: null Annotation: Subtype: Link Rect: 94, 588, 203, 597 Destination: null Annotation: Subtype: Link Rect: 160, 292, 165, 298 Destination: 167 Annotation: Subtype: Link Rect: 131, 244, 136, 250 Destination: 167 Annotation: Subtype: Link Rect: 187, 244, 192, 250 Destination: 167 Annotation: Subtype: Link Rect: 51, 232, 56, 238 Destination: 167 Annotation: Subtype: Link Rect: 94, 220, 104, 226 Destination: 195 Annotation: Subtype: Link Rect: 64, 76, 74, 83 Destination: 167 Annotation: Subtype: Link Rect: 78, 76, 88, 83 Destination: 167 Annotation: Subtype: Link Rect: 312, 566, 322, 573 Destination: 167 Annotation: Subtype: Link Rect: 326, 566, 336, 573 Destination: 195 Annotation: Subtype: Link Rect: 341, 566, 351, 573 Destination: 195 Annotation: Subtype: Link Rect: 395, 483, 405, 489 Destination: 195 Annotation: Subtype: Link Rect: 410, 483, 420, 489 Destination: 195 Annotation: Subtype: Link Rect: 403, 459, 413, 465 Destination: 195 Annotation: Subtype: Link Rect: 417, 459, 427, 465 Destination: 195 Annotation: Subtype: Link Rect: 474, 459, 484, 465 Destination: 195 Annotation: Subtype: Link Rect: 515, 387, 525, 393 Destination: 195 Annotation: Subtype: Link Rect: 364, 208, 374, 214 Destination: 195 Annotation: Subtype: Link Rect: 380, 208, 390, 214 Destination: 195 Page: Label: 8 Annotations: Annotation: Subtype: Link Rect: 250, 626, 285, 635 Destination: null Annotation: Subtype: Link Rect: 39, 600, 287, 625 Annotation: Subtype: Link Rect: 175, 577, 286, 588 Annotation: Subtype: Link Rect: 40, 565, 61, 576 Annotation: Subtype: Link Rect: 44, 557, 54, 563 Destination: 167 Annotation: Subtype: Link Rect: 59, 557, 69, 563 Destination: 195 Annotation: Subtype: Link Rect: 72, 709, 72, 709 Destination: 1 Annotation: Subtype: Link Rect: 40, 157, 135, 168 Annotation: Subtype: Link Rect: 307, 520, 313, 525 Destination: 230 Annotation: Subtype: Link Rect: 307, 498, 313, 503 Destination: null Annotation: Subtype: Link Rect: 307, 465, 313, 470 Destination: 230 Annotation: Subtype: Link Rect: 307, 443, 313, 448 Destination: 230 Annotation: Subtype: Link Rect: 376, 418, 537, 428 Annotation: Subtype: Link Rect: 307, 410, 313, 415 Destination: 56 Annotation: Subtype: Link Rect: 307, 377, 313, 382 Destination: 230 Annotation: Subtype: Link Rect: 307, 344, 313, 350 Destination: 230 Annotation: Subtype: Link Rect: 307, 301, 313, 306 Destination: null Annotation: Subtype: Link Rect: 307, 268, 313, 273 Destination: 230 Annotation: Subtype: Link Rect: 303, 235, 313, 240 Destination: 230 Annotation: Subtype: Link Rect: 303, 202, 313, 207 Destination: 23 Annotation: Subtype: Link Rect: 303, 180, 313, 185 Destination: 23 Annotation: Subtype: Link Rect: 303, 147, 313, 152 Destination: 23 Annotation: Subtype: Link Rect: 303, 114, 313, 119 Destination: 23 Annotation: Subtype: Link Rect: 303, 92, 313, 98 Destination: null Annotation: Subtype: Link Rect: 303, 59, 313, 65 Destination: 23 Page: Label: 9 Annotations: Annotation: Subtype: Link Rect: 48, 722, 58, 727 Destination: 23 Annotation: Subtype: Link Rect: 48, 689, 58, 694 Destination: 23 Annotation: Subtype: Link Rect: 48, 645, 58, 650 Destination: 23 Annotation: Subtype: Link Rect: 48, 612, 58, 618 Destination: 23 Annotation: Subtype: Link Rect: 48, 568, 58, 574 Destination: 23 Annotation: Subtype: Link Rect: 48, 525, 58, 530 Destination: 23 Annotation: Subtype: Link Rect: 48, 492, 58, 497 Destination: 23 Annotation: Subtype: Link Rect: 48, 448, 58, 453 Destination: 56 Annotation: Subtype: Link Rect: 48, 404, 58, 409 Destination: 56 Annotation: Subtype: Link Rect: 48, 349, 58, 355 Destination: null Annotation: Subtype: Link Rect: 48, 305, 58, 311 Destination: 56 Annotation: Subtype: Link Rect: 48, 273, 58, 278 Destination: 56 Annotation: Subtype: Link Rect: 48, 240, 58, 245 Destination: 56 Annotation: Subtype: Link Rect: 48, 207, 58, 212 Destination: 56 Annotation: Subtype: Link Rect: 62, 171, 219, 181 Annotation: Subtype: Link Rect: 48, 163, 58, 168 Destination: 91 Annotation: Subtype: Link Rect: 309, 722, 319, 727 Destination: 91 Annotation: Subtype: Link Rect: 309, 689, 319, 694 Destination: 91 Annotation: Subtype: Link Rect: 309, 667, 319, 672 Destination: 131 Annotation: Subtype: Link Rect: 309, 623, 319, 629 Destination: 143 Annotation: Subtype: Link Rect: 309, 590, 319, 596 Destination: 143 Annotation: Subtype: Link Rect: 309, 547, 319, 552 Destination: 143 Annotation: Subtype: Link Rect: 309, 503, 319, 508 Destination: 143 Annotation: Subtype: Link Rect: 309, 459, 319, 464 Destination: null Annotation: Subtype: Link Rect: 309, 415, 319, 420 Destination: null Annotation: Subtype: Link Rect: 309, 382, 319, 387 Destination: null Annotation: Subtype: Link Rect: 309, 349, 319, 355 Destination: null Annotation: Subtype: Link Rect: 309, 316, 319, 322 Destination: 143 Annotation: Subtype: Link Rect: 309, 284, 319, 289 Destination: 143 Annotation: Subtype: Link Rect: 309, 251, 319, 256 Destination: 143 Annotation: Subtype: Link Rect: 309, 218, 319, 223 Destination: 143 Annotation: Subtype: Link Rect: 309, 174, 319, 179 Destination: 143 Checksum: 1a761f5f Type: CRC32 Checksum: 3943e100473a3713b14995b4721205ed Type: MD5 Checksum: 6af181f74ced11991e4be5dfcf371f39934c40d6 Type: SHA-1