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September 23, 2014; 83 (13) Views & Reviews

Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders

Sharmilee Gnanapavan, Harald Hegen, Michael Khalil, Bernhard Hemmer, Diego Franciotta, Steve Hughes, Rogier Hintzen, Andreas Jeromin, Eva Havrdova, Hayrettin Tumani, Antonio Bertolotto, Manuel Comabella, Jette Frederiksen, José C. Álvarez-Cermeño, Luisa Villar, Daniela Galimberti, Kjell-Morten Myhr, Irena Dujmovic, Franz Fazekas, Carolina Ionete, Til Menge, Jens Kuhle, Geoffrey Keir, Florian Deisenhammer, Charlotte Teunissen, Gavin Giovannoni
First published August 22, 2014, DOI: https://doi.org/10.1212/WNL.0000000000000809
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Abstract

Objective: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development.

Methods: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid biomarker research. A checklist of items integrating the results of other published guidances, literature, conferences, regulatory opinion, and personal expertise was created to ultimately form a structured summary guidance incorporating the key features.

Results: The summary guidance is comprised of a 10-point uniform reporting format ranging from introduction, materials and methods, through to results and discussion. Each item is discussed in detail in the guidance report.

Conclusions: To enhance the future development of body fluid biomarkers, it will be important to standardize the reporting of studies. This guideline by the BioMS-eu consortium is aimed at setting a standard for the reporting of future body fluid biomarker research studies in neurologic disorders. We anticipate that following these guidelines will help to accelerate the selection of biomarkers for clinical development.

GLOSSARY

MS=
multiple sclerosis

Attempts to bring the vast array of postgenomic era body fluid biomarkers as clinical diagnostic and prognostic tools in neuroscience have so far been disappointing. The lack of a rigorous study design, small sample size, and differences in methodology, coupled with analytical inaccuracy has produced differing results and conclusions despite the rigors of the peer review process.1,–,4 Moreover, premature acceptance of poorly validated markers has resulted in numerous publications, which still require further confirmation.5,6 The latter may partly be attributable to the limited scientific progress.

Henceforth, a rationale is needed to ensure that emerging biomarkers in neuroscience are evaluated in, or originate from, well-designed studies with clear-cut methodology, analysis, and commentaries, and presented in a standardized manner. The aim is to provide scientists and clinicians working in the neuroscience field with explicit criteria for planning and reporting biomarker studies. BioMS-eu consortium (http://www.bioms.eu) is a collaborative network working toward improving the quality of biomarker research in multiple sclerosis (MS) and incorporating experts in the broad field of neuroscience biomarkers with experience in the critical process of biomarker validation. This consortium has already published guidelines on standardization of CSF collection7 and biobanking of CSF/blood samples8 as well as consensus definition of control groups.9 We have now developed standardized criteria for biomarker reporting. The guidance described here provides a framework for the reporting of biomarker work from early, exploratory biological research including work on diagnostic biomarkers, disease activity biomarkers, progression biomarkers, and treatment-efficacy biomarkers in neurologic disorders.

METHODS

We use the following definitions, which were established by the NIH Biomarkers Definition Working Group10:

  • Biological marker (biomarker): “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”

  • Clinical endpoint: “a characteristic that reflects how a patient feels, functions, and survives”

  • Surrogate endpoint: “a biomarker that is intended to substitute for a clinical endpoint”

We initially developed a “primer” for biomarker reporting referring to frameworks given by REMARK,11 STARD,12 and CONSORT.13 We also considered elementary standards for reporting biomarker work arising from key conferences (The Biomarker World Congress 2005, Medical Research Council Biomarker Conference 2006), literature,14,–,20 and Food and Drug Administration regulatory recommendations (http://www.fda.gov/). A checklist of items was created and circulated via e-mail to all members of the BioMS-eu network. The merits of including specific recommendations were discussed with all of the members during the annual BioMS-eu meetings in 2007, 2008, and 2010 (a list of the members is provided in the appendix on the Neurology® Web site at Neurology.org) before finalization. The importance and practicality of each of the items were deliberated over. Hereafter, the final format and wording of the guidelines were decided after discussions among the BioMS-eu members by e-mail. The guidelines reflect the consensus of the network at the time of writing, and should be viewed as only recommendations. They will be subject to change in the future, on the basis of emerging evidence.

RESULTS

We started with a checklist of 61 items based on recommendations from previously published guidelines, biomarker publications, and input from the scientific and steering committee of BioMS-eu. This was later reduced to a final optimal format consisting of 10 main items, which are presented here (figure). Items were excluded on the basis of lack of generalizability to different types of biomarker research, items that were desirable but not essential, and those that were considered outside the remit of the guidance. The checklist is divided into introduction, materials and methods, results, and discussion, reflecting the subheadings used in a scientific publication. A detailed commentary on individual items is provided. For studies in which the primary focus is the clinical trial, discovery biomarkers using proteomics or microarrays, or prognostic studies, we recommend that the existing guidelines be used (table).

Figure
Figure Summary guidance for the uniform reporting of biomarker research in neurologic disorders

ROC = receiver operating characteristic.

View this table:
Table

List of other reporting guidelines in biomedical sciences

Commentary on the checklist items.

1–2. The introduction should be sufficient to describe the scientific background and rationale, i.e., hypothesis, the biomarker(s) or its identification if relevant, its relation with pathologic mechanism, as well as an explicit explanation for its/their selection. Provide information on the intended use of the biomarker(s), for example, diagnostic, prognostic, or therapeutic efficacy body fluid biomarkers. In the early stages, the status of a body fluid biomarker as a surrogate endpoint is often unproven, in which case evidence from allied publications may be used to evaluate or support the application for surrogate status in the biomarker(s).

3. This section should contain the study protocol. Include detailed information on study or sample population (species, sex, age, eligibility criteria, comorbidities, and concomitant medications, and if relevant, also reasons for sample exclusion), including pertinent subgroups of patients and of diseased (and disease stage and duration) and healthy controls (refer to consensus on control groups9). The diagnostic or eligibility criteria should be clearly defined so that different groups remain relatively comparable ensuring conformity in future studies. Whenever possible, compare with a reference (gold) standard body fluid biomarker, but if unavailable use a nonclinical reference standard (see checklist item 5). If combining with other body fluid biomarkers, the specific algorithm for determining the grouping should be prespecified.

There should be information on the types of samples used (CSF, plasma, serum, whole blood, peripheral blood mononuclear cells, etc.) and how they were collected and processed; for example, fasting or nonfasting, the type of collection tube used, and whether a standardized operating procedure for controlling preanalytical variables was used. Determination of sample size should be discussed. The sample size may provide different powers of analysis based on the endpoints used depending on endpoint sensitivity and variability. The calculation of a sample size is mandatory in confirmation studies, whose aim is to confirm a newly proposed biomarker, but is not a requirement in preliminary or discovery studies, whose aim is to discover a candidate body fluid biomarker. When samples from specific studies are used for analysis (e.g., randomized controlled trials), reference the applicable study protocols.

4. Study should conform to any applicable ethics regulations. This could be the local ethics committee, or regional/national ethics committees for clinical and multicenter trials, or the committee for nonhuman research.

5. Outline the primary outcome measure (i.e., the body fluid biomarker in reference to the gold standard, which may be a clinical endpoint, or nonclinical in the form of histopathologic assessments) and if applicable, the secondary outcome measure(s) used in the study (e.g., imaging, neurophysiology, other clinical scores [disability scales, patient-reported outcome measures]). In the absence of a suitable reference gold standard test, we propose that the body fluid biomarker be evaluated against the clinical decision for which the biomarker provides information about, not already available as a clinical score, MRI, or laboratory or other outcome measure. If reporting on in vitro or animal experimental work, refer to the relevant outcome measures used in this area of work. Lastly, when using a body fluid biomarker(s) for risk stratification purposes within clinical trials, outline the relevant arguments in support of their use (i.e., has the body fluid biomarker(s) been clearly demonstrated to increase the risk of progression or treatment response) and how the response rate would be objectively assessed between the treatment arms. If using body fluid biomarkers for the enrichment of clinical trials, be aware that initial screening values may be random “highs” in the natural course of the disease, which may regress toward the mean naturally, thereby removing subjects from their original assignments. In such instances, regression toward the mean should be factored into the experimental design and power calculations.21

6. This section should contain a detailed description of the assay methods (avoid using acronyms wherever possible) and the characterization of the analytical performance of these assays. While a majority of body fluid biomarker studies are performed using “research-use only” assays, there is a recommended set of validation criteria that should be evaluated and disclosed in publications.22,23 Please refer to the collection protocol for information on sample handling.7 Additional information on performance characteristics (testing environment, conformity to a recognized standard) should inform on whether the assay is appropriate for the intended use. This includes preanalytical parameters (use of serum separators, special precautions, and storage7) and analytical parameters (sample preparation, source of calibrant and antibodies, analytical performance—parallelism and spike recovery and sensitivity, upper and lower limit of quantitation, imprecision, accuracy, inter- and intraassay coefficient of variation, internal and external quality controls, lot-to-lot variation [whenever possible], and potential interferences—hemolysis, lipemia, drugs, etc.). This should be based in the testing environment where the technique will ultimately be used (i.e., laboratory or at the bedside). If the investigator is using an established method, the method should be cited, and if modified, a description of the changes and reasons for them should also be included. If possible, describe cross-validation with other existing techniques or technologies. Provide assurance that the analyzer is blinded to patient outcomes by commenting on how blinding was achieved.

7. This section should contain a description of the data analysis method(s) used, including methods for dealing with missing values and outliers, intention-to-treat vs per-protocol analysis, where applicable. Correct for multiple comparisons where applicable. When using more complex statistical models (e.g., mixed effects in the study of repeated measures or net reclassification model), provide a clear description of the model and include any assumptions made on the model components. If relevant, use receiver operating characteristic curves to convey the performance characteristics of diagnostic markers and Bland-Altman analysis for cross-validation with other techniques or technologies.

8. The focus of the results section should be on the value of the body fluid biomarker(s) as diagnostic, prognostic, or therapeutic efficacy measure, comparing with the existing reference standard where applicable. Pharmacodynamic data demonstrating modulation of the biological or molecular target by the treatment in question should be included if performed. Measures of sensitivity, specificity, positive and negative predictive value, and odds ratio can be used for risk prediction. Tests with high negative predictive and low positive predictive values (such as oligoclonal bands in MS) may still prove to be good screening tests, and not just good diagnostic tests.

When assessing the usefulness of a body fluid biomarker as a surrogate endpoint, the Austin Bradford Hill criteria for causation or the Prentice criteria for surrogacy can be used.24,–,26 Analysis of risk stratification clinical trials on the basis of body fluid biomarkers should report on the number needed to treat to show an effective clinical outcome, because this would be important for its future implementation as a screening test.

We recommend that summary descriptions of the study or sample populations be assembled in tabular format in order for any variances between the groups to be seen more readily. The table should include any variables that may influence the study outcomes (e.g., disease activity, disability score, comorbidities, and concomitant medications). Similarly, we recommend that the key experimental findings be summarized in tables or graphs, together with a description of the results. Include any other validatory components to those already provided in the assay methods (section 6) in sufficient detail in the figure.

9–10. The discussion section of the work should contain a summary description of the biomarker(s) characteristics, whether the study aims were met, if relevant, relationship to existing biomarkers, be it the same or different marker(s), and intended use(s). It should also address limitations or variability due to pathophysiologic, environmental, or demographic factors. Finally, areas for future work (larger population-based study, add-on study to clinical trials, etc.) should be addressed.

DISCUSSION

Body fluid biomarkers and their implementation at various levels in neuroscience represent the new challenge, but many have failed in this goal, and the high attrition rate at the later stages of development have left many investigators doubtful and cynical of their overall value.5,20 To date, many putative biomarkers have been reported, but so far only a limited few can be introduced into clinical practice. For example, there is limited specificity of anti-myelin antibodies in MS.27 The APOE ε4 allele (a risk-enhancing allele for Alzheimer disease) and plasma clusterin levels, both associated with Alzheimer disease, lack the sensitivity and specificity for predicting its incidence.28,29 Likewise, the astroglial marker S100β, classically used in the immunostaining of brain tumors is not a reliable indicator of tumor burden; furthermore, its variability in different types of traumatic brain injury means it cannot be used to predict the extent of injury.30,31 It is therefore difficult to determine which biomarkers are best suited for future investment. There is a growing need for standardized guidelines relating to reporting of validated biomarker research as deemed by good experimental design, data analysis, and presentation of findings.

We have previously reported on the standardization of CSF collection and biobanking of samples, and selection of control groups for biomarker studies.7,–,9 There are already several precedents, which deal specifically with different aspects of biomedical science, for instance, REMARK (tumor marker prognostic studies),11 STARD (diagnostic accuracy),12 and CONSORT (randomized controlled trials),13 and it is recommended that authors follow this guidance when dealing with specifically prognostic body fluid biomarkers, diagnostic testing, and randomized controlled trials, respectively. Although these guidances report on specific areas of research, none are specific for body fluid biomarker reporting per se, which is currently left to the direction of the journal/reviewer and much more clarity is needed here. The REMARK statement includes a section on assay methods, but the primary focus is on study design and reporting, while STARD focuses on the testing of methods; neither is dedicated to body fluid biomarker validation, or assessing their utility.

The biomarker reporting guidelines outlined here provide a framework wherein clear and transparent reporting of the study aim(s), methods, results, and interpretation of the results can take place, reflecting particularly on possible problem areas. The proposed standards are weighted toward scientific validity with requirements that impose data integrity constraints, in order to permit reproduction of scientific work. A manuscript style was favored by our consortium members because this is universally accessible to all journals across many disciplines. It is important, however, that they do not evolve into critical appraisal tools for evaluating the quality of research submitted, accepting or rejecting work on the basis of whether the work conforms to the criteria.32 Moreover, a less stringent use of the 10-point guideline is needed in reporting preliminary or discovery phase studies. The present guidance should not discourage researchers from reporting preliminary but very interesting new findings, and also where the reported format due to its nature of being a preliminary study cannot conform to the 10-point format. Although these guidelines provide a comprehensive framework for the reporting of biomarker studies, they are not universal, and special consideration needs to be given for microarray17 and proteomic33 studies where there are specific research and industry standards not covered here. Furthermore, we want to state that these guidelines provide a minimum standard and make no claim to be complete.

The development of comprehensive guidelines in practice is a continuous process. Ultimately, their value in reporting biomarker work will depend on how widely they are adopted by the scientific community.

AUTHOR AFFILIATIONS

From the Department of Neuroimmunology (S.G., G.K.), UCL Institute of Neurology, Queen Square, UK; Innsbruck Medical University (H.H., F.D.), Department of Neurology, Innsbruck; Department of Neurology (M.K., F.F.), Medical University of Graz, Austria; Department of Neurology (B.H.), Klinikum rechts der Isar, Technische Universitat Munchen/Munich Cluster for Systems Neurology (SyNergy), Munich/German Competence Network Multiple Sclerosis (KKNMS), Munich, Germany; Laboratory of Neuroimmunology (D.F.), IRCCS–C. Mondino National Neurological Institute, Italy; Isis Pharmaceuticals Inc. (S.H.), US; Department of Neurology (R.H.), Erasmus MC, the Netherlands; Quanterix Inc. (A.J.), Lexington, MA; MS Center (E.H.), Department of Neurology, First Medical Faculty, Charles University in Prague, Czech Republic; University Hospital of Ulm (H.T.), Germany; Neurologia 2 (A.B.), Ospedale S. Luigi, Orbassano, Italy; Centre d'Esclerosi Múltiple de Catalunya (M.C.), Hospital Universitari Vall d'Hebron, Spain; Department of Neurology (J.F.), Glostrup University Hospital, University of Copenhagen, Denmark; Departments of Immunology and Neurology (J.C.Á.-C., L.V.), MS Unit, Hospital Ramon y Cajal, IRYCYS, REEM, Spain; Neurology Unit (D.G.), Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Italy; KG Jebsen Centre for MS Research (K.-M.M.), Department of Clinical Medicine, University of Bergen, Norway; Clinic of Neurology (I.D.), University of Belgrade School of Medicine, Belgrade, Serbia; UMass Memorial Medical Center (C.I.), Worcester, MA; Department of Neurology (T.M.), Heinrich Heine University, Germany; Neurochemistry Laboratory and Biobank (C.T.), VU University Medical Center, the Netherlands; and Department of Neuroimmunology (J.K., G.G.), Queen Mary University of London, UK.

AUTHOR CONTRIBUTIONS

Sharmilee Gnanapavan has organized and prepared the consensus discussions and was the principal author in writing, responding to the comments by the reviewers, and making the final change to the manuscript. Harald Hegen was responsible for responding to the comments by the reviewers and the final manuscript and the discussions on the manuscript. Michael Khalil participated in the consensus discussions and in the final changes to the manuscript. Bernhard Hemmer, Diego Franciotta, and Steve Hughes were involved in the consensus discussions and in editing the manuscript, providing critical comments and suggestions. Rogier Hintzen, Andreas Jeromin, Eva Havrdova, Hayrettin Tumani, Antonio Bertolotto, Manuel Comabella, Jette Frederiksen, José C. Álvarez-Cermeño, Luisa Villar, Daniela Galimberti, Kjell-Morten Myhr, Irena Dujmovic, Franz Fazekas, Carolina Ionete, and Til Menge participated in the consensus discussions and in editing the manuscript. Jens Kuhle drafted and revised the manuscript, including medical writing, for content. Geoffrey Keir was initially involved in the drafting of checklist items. Charlotte Teunissen was involved in the organization and chairing of the consensus discussions and final editing of the manuscript. Florian Deisenhammer was responsible for responding to the comments by the reviewers and the final manuscript and the discussions on the manuscript. Gavin Giovannoni was responsible for the initial formulation of ideas, organization and chairing of the consensus discussions, and final changes to the manuscript.

STUDY FUNDING

No targeted funding reported.

DISCLOSURE

S. Gnanapavan reports no disclosures relevant to the manuscript. H. Hegen participated in meetings sponsored by, or received honoraria for lectures from, pharmaceutical companies marketing treatment for MS (Bayer Schering, Biogen Idec, Merck Serono, and Novartis). M. Khalil has received research support from The Austrian Science Fund (FWF) (J2992-B09). B. Hemmer has served on scientific advisory boards for Novartis, Bayer Schering Pharma, GSK, and Genzyme Corporation; has received funding for travel from Bayer Schering Pharma, Novartis, Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., Roche, and Genentech, Inc.; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering Pharma, Novartis, Biogen Idec, Merck Serono, Roche and Teva Pharmaceutical Industries Ltd.; serves as a consultant to Bayer, Genentech, Micromet, Roche, and Novartis; and has received research support from Biogen Idec, Chugai Pharmaceuticals, Roche, Metanomics, and 5-Prime during the last 3 years. D. Franciotta reports no disclosures relevant to the manuscript. S. Hughes receives royalties from publishing Complete Data Interpretation for MRCP (Churchill Livingstone Press, 2001); is employed as VP Clinical Development at Isis Pharmaceuticals and was previously Director of Medical Research for Biogen Idec. R. Hintzen reports no disclosures relevant to the manuscript. A. Jeromin is a paid medical and scientific advisor with Quanterix Inc. E. Havrdova received honoraria and consulting fees from Genzyme, Biogen Idec, Sanofi-Aventis, Merck Serono, Roche, Teva, and Novartis for consulting services, speaking, and serving on a scientific advisory boards. H. Tumani serves on a scientific advisory board, is a consultant for, and/or has received funding from, the following companies: Bayer HealthCare, Biogen Idec, Genzyme Virotech, Merck Serono, Novartis, Roche, and Teva. A. Bertolotto has been on steering committees in clinical trials sponsored by Biogen Idec and Roche; has received speaker honoraria from Biogen Idec, Merck Serono, Teva, Bayer Schering, Sanofi-Aventis, and Novartis; has been a member of scientific boards supported by Allergan and Almirall; has received research support from Biogen Idec, Biogen-Dompè, Bayer Schering, Merck Serono, Sanofi-Aventis, and from the Italian Multiple Sclerosis Society and from Associazione Ricerca Biomedica Onlus. M. Comabella reports no disclosures relevant to the manuscript. J. Frederiksen has served on scientific advisory boards for and received funding for travel related to these activities and honoraria from Biogen Idec, Sanofi-Aventis, Genzyme, Teva, Novartis, and Almirall. She has received speaker honoraria from Biogen Idec, Merck Serono, and Teva. She has served as advisor on preclinical development for Takeda. J. Álvarez-Cermeño received speaker honoraria from Biogen Idec, Merck Serono, Teva, Bayer Schering, Sanofi-Aventis, and Novartis; has been a member of scientific boards and received research support from Biogen Idec, Bayer Schering, Merck Serono, Sanofi-Aventis, and Novartis. L. Villar has received speaker honoraria from Biogen Idec, Merck Serono, Teva, Bayer Schering, and Novartis. D. Galimberti reports no disclosures relevant to the manuscript. K. Myhr has received research support from Biogen Idec, Merck Serono, and Sanofi-Aventis, and has been principal investigator, investigator, or member of steering committees or advisory boards in MS clinical trials sponsored by Bayer Schering Pharma AG, Biogen Idec, GlaxoSmithKline, Merck Serono, Roche, and Sanofi-Aventis. He has received lecture fees and/or travel grants from Bayer Schering Pharma AG, Biogen Idec, GlaxoSmithKline, Merck Serono, Pfizer, Roche, and Sanofi-Aventis, and is the chair of the advisory board of the Norwegian MS Society. I. Dujmovic received lecture fees and/or travel grants from Merck Serono, Bayer Schering Pharma, Teva, and Boehringer Ingelheim. F. Fazekas, C. Ionete, and T. Menge report no disclosures relevant to the manuscript. J. Kuhle received financial support or compensation from commercial entities (1) Novartis, (2) Roche, (3) Protagen, and (4) Genzyme, and support or compensation from foundations or societies (1) ECTRIMS Research Fellowship programme, 2012, 2013, 2014, (2) Research funds of the University of Basel, 2012, 2013, 2014. G. Keir reports no disclosures relevant to the manuscript. C. Teunissen is member of the International Advisory Board of Innogenetics and Roche and received speaker honorarium from Teva. F. Deisenhammer has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer HealthCare, Biogen Idec, Genzyme-Sanofi, Merck Serono, Novartis, and Teva-Ratiopharm. His institution has received financial support for participation in randomized controlled trials of INFβ-1b (Betaferon, Bayer Schering Pharma), INFβ-1a (Avonex, Biogen Idec; Rebif, Merck Serono), glatiramer acetate (Copaxone, Teva Pharmaceuticals), natalizumab (Tysabri, Biogen Idec), and fingolimod (Gilenya, Novartis) in MS. G. Giovannoni has declared receipt of consulting fees from AbbVie, Schering Healthcare, Biogen Idec, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratoires, Roche, Teva-Aventis, Vertex Pharmaceuticals, UCB Pharma, and Pfizer. Go to Neurology.org for full disclosures.

Footnotes

  • Authors' affiliations are listed at the end of the article.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 1130

  • Supplemental data at Neurology.org

  • Received September 2, 2013.
  • Accepted in final form June 27, 2014.

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