1 Supplementary Online Content Hanna GB, Boshier PR, Markar SR, Romano A. Accuracy and Methodologic Challenges of Volatile Organic Compound–Based Exhaled Breath Tests for Cancer Diagnosis: A Systematic Review and Pooled Analysis. JAMA Oncol. Published online August 16, 2018. doi:10.1001/jamaoncol.2018.2815 Supplement. eTable 1. Search strategy for cancer systematic review eTable 2. Modification of QUADAS-2 assessment tools eTable 3. QUADAS-2 results eTable 6. STARD assessment of each study eTable 7. Summary of factors reported to influence levels of volatile organic compounds within exhaled breath eFigure 1. Risk of bias and applicability concerns using QUADAS-2 eFigure 2. PRISMA flowchart of literature search eTable 4. Details of studies on exhaled volatile organic compounds in cancer eTable 5. Cancer VOCs in exhaled breath and their chemical class. eFigure 3. Chemical classes of VOCs reported in different tumor sites. This supplementary material has been provided by the authors to give readers additional information about their work. © 2018 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 2 eTable 1. Search strategy for cancer systematic review # Search 1 (cancer or neoplasm* or malignancy).ab. 2 limit 1 to abstracts 3 limit 2 to cochrane library [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 4 limit 3 to english language 5 limit 4 to human 6 limit 5 to yr="2000 -Current" 7 limit 6 to humans 8 (cancer or neoplasm* or malignancy).ti. 9 limit 8 to abstracts 10 limit 9 to cochrane library [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 11 limit 10 to english language 12 limit 11 to human 13 limit 12 to yr="2000 -Current" 14 limit 13 to humans 15 7 or 14 16 (volatile organic compound* or VOC* or Breath or Exhaled).ab. 17 limit 16 to abstracts 18 limit 17 to cochrane library [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 19 limit 18 to english language 20 limit 19 to human 21 limit 20 to yr="2000 -Current" 22 limit 21 to humans 23 (volatile organic compound* or VOC* or Breath or Exhaled).ti. 24 limit 23 to abstracts 25 limit 24 to cochrane library [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update,Ovid MEDLINE(R) In-Process,Ovid MEDLINE(R) Publisher; records were retained] 26 limit 25 to english language 27 limit 26 to human 28 limit 27 to yr="2000 -Current" 29 limit 28 to humans 30 22 or 29 31 15 and 30 32 remove duplicates from 31 © 2018 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 3 Description of the modification and application of QUADAS-2 eTable 2. Modification of QUADAS-2 assessment tools QUADAS-2 QUADAS-2 (modified) Were sampled (A Was a consecutive or patients m) random sample of representative of the patients enrolled? intended population? Patien Did the study include (A t Was a case-control both positive (benign m) selecti design avoided? conditions) as well as on healthy controls? Did the study avoid Did the study avoid (Un inappropriate inappropriate ) exclusions? exclusions? Were the index test Was the index test (A results interpreted and interpretation of m) without knowledge of data performed in Index the results of the standardised and test reference standard? reproducible fashion? If a threshold was Validation of results (A used, was it pre- performed (internal or m) specified? external)? Is the reference Is the reference (Un standard likely to standard likely to ) correctly classify the correctly classify the Refere target condition? target condition? nce Were the reference (O standa standard results m)* rd interpreted without - knowledge of the results of the index test? Was there an Was there an (Un appropriate interval appropriate interval ) between index test between index test and reference and reference standard? standard? Were index test and (Ad reference standard ) Flow - performed prior to and therapeutic timing intervention? Did all patients Did all patients (Un receive the same receive the same ) reference standard? reference standard? Were all patients Were all patients (Un included in the included in the ) RISK OF BIASRISK analysis? analysis? Are there concerns Are there concerns (Un Patien that the included that the included ) t patients and setting patients and setting selecti do not match the do not match the on review question? review question? Are there concerns Are there concerns (A that the index test, its that the authors have m) Index conduct, or not demonstrated test interpretation differs suitable reproducibility from the review and sensitivity of the APPLICABILITY question? chosen index test? © 2018 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 4 Are there concerns Are there concerns (Un Refere that the target that the target ) nce condition as defined condition as defined standa by the reference by the reference rd standard does not standard does not match the question? match the question? Am = amendment. Om = omitted. Ad = addition. Un = unchanged. *Criteria omitted as not applicable in the case of phase 1 biomarker discovery studies REVIEW QUESTION Test population: human subLects Index test(s): VOC analysis within exhaled breath Reference standard: the accepted standard for diagnosis of cancer and/or benign disease in that field Target condition: cancer Setting: hospital, medical centre Intended use of the index test: diagnostic Patient presentation: routine investigation for symptoms of malignancy Prior testing: not applicable © 2018 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 5 eTable 3. QUADAS-2 results APPLICABILITY RISK OF BIAS CONCERNS Ref Ref Pati Flo Pati ere ere ent Inde w ent Inde nce nce sele x and sele x stan stan ctio Test timi ctio test dar dar n ng n d d Barash 1 B L L ? H L L L 2015 2 Li 2014 B L L L H L L L Mangler 3 B H H ? ? ? ? ? 2012 Peng 4 B H H L H ? L L 2010 Phillips 5 B ? L L H L ? L 2003 Phillips 6 B L L L H L ? L 2006 Wang 7 B L L L ? L ? L 2014 Amal 8 O L L ? H L ? L 2015 Peng 9 P H H L H ? L L 2010 1 Guo T H H ? ? L ? L 0 2015 H 1 Gruber & L H L H L ? L 1 2014 N H 1 Hakim & H H L H L L L 2 2011 N 1 Bouza O H H ? H L L L 3 2017 c 1 Szabó O H H ? ? L L L 4 2015 c 1 Altomar Cr H L L ? L ? L © 2018 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 6 5 e 2013 1 Amal Cr ☺ H L H L L L 6 2015 1 Peng Cr H H L H ? L L 7 2010 1 Wang Cr H H L H L ? L 8 2014 E 1 Abela & H H L H L ? L 9 2009 G E 2 Kumar & L H L L L L L 0 2013 G E 2 Kumar & L H L L L L L 1 2015 G 2 Amal G L H L H L L L 2 2013 2 Amal G L H L ? L L L 3 2016 2 Xu G L H L H L L L 4 2013 2 Qin Li L H L H L ? L 5 2010 2 Garcia L H H ? ? L L L 6 2014 a BaLtare 2 L vic H H ? H L ☺ L 7 u 2009 Bousa 2 L mra H H ? H L ? L 8 u 2014 Buszew 2 L ski H H L H L ? L 9 u 2011 © 2018 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 7 Buszew 3 L ski H H ? ? L L L 0 u 2012 3 Chen L ? H ? H L ? L 1 2005 u 3 Corradi L H H L H L ? L 2 2015 u 3 Crohns L H H L H L ? L 3 2009 u 3 Deng L H H ? ? L L L 4 2004 u 3 Feinber L H H L H L ? L 5 g 2016 u 3 Filipiak L H H L H L L L 6 2014 u 3 Fu L ? H ? H L ? L 7 2014 u 3 Fuchs L H H ? H L L L 8 2010 u 3 Gaspar L H H ? ? L ? L 9 2009 u 4 Handa L H H L H L ? L 0 2014 u 4 Kischke L H H H ? L L L 1 l 2010 u 4 L Li 2015 ? L L H L ? L 2 u 4 Ligor L H H ? H L L L 3 2009 u 4 Ligor L H H L H L L L 4 2015 u 4 Ma L H H ? H L ? L 5 2014 u 4 Ma L H H ? ? ? ? ? 6 2015 u © 2018 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 8 4 Peled L ? H L H L ? L 7 2012 u 4 Peng L H H L H L L L 8 2009 u 4 Peng L H H L H ? L L 9 2010 u 5 Phillips L L L L H L ? L 0 2003 u 5 Phillips L H L L H L ? L 1 2007 u 5 Phillips L H L L H L ? L 2 2008 u 5 Poli L L H L H L ? L 3 2005 u 5 Poli L L L H L L L 4 2010 u 5 Rudnick L H ? H L L L 5 a 2011 u Sakum 5 L ura H ? ? L ? L 6 u 2017 Schalls 5 L chmidt H ? ? L L L 7 u 2016 5 Schum L ? H L H L ? L 8 er 2015 u 5 Schum L H H L H L ? L 9 er 2016 u 6 Skeldon L ? H L H L L L 0 2006 u 6 Song L H H L H L L L 1 2010 u Ulanow 6 L ska H H L H L ? L 2 u 2011 © 2018 American Medical Association.