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Therapeutic Area Data Standards User Guide for Traumatic Brain Injury

Version 1.0 (Provisional)

Prepared by the CFAST Traumatic Brain Injury Standards Team

Notes to Readers • This is version 1.0 of the Therapeutic Area Data Standards User Guide for Traumatic Brain Injury. • This document is based on SDTM v1.4 and SDTMIG v3.2, and on CDASH v1.1 and CDASHUG v1.0.

Revision History

Date Version Summary of Changes 2015-12-02 1.0 Provisional First release for provisional use 2015-07-13 1.0 Draft Draft for public review

See Appendix E for Representations and Warranties, Limitations of Liability, and Disclaimers.

CDISC Therapeutic Area Data Standards User Guide for Traumatic Brain Injury (Version 1.0)

© 2015 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional December 2, 2015

CONTENTS

1 INTRODUCTION ................................................................................................................. 3 1.1 PURPOSE ................................................................................................................................................................ 3 1.2 ORGANIZATION OF THIS DOCUMENT ..................................................................................................................... 4 1.3 TRAUMATIC BRAIN INJURY COMMON DATA ELEMENTS ....................................................................................... 5 1.4 CONCEPT MAPS ..................................................................................................................................................... 5 1.5 CONTROLLED TERMINOLOGY ................................................................................................................................ 6 1.6 RELATIONSHIPS TO OTHER STANDARDS ................................................................................................................ 6 1.7 KNOWN ISSUES ...................................................................................................................................................... 6

2 SUBJECT AND INJURY CHARACTERISTICS.............................................................. 8 2.1 PRIOR TBI EXPOSURE AND PRIOR TBI TREATMENT ............................................................................................. 9

3 TRAUMATIC BRAIN INJURY ASSESSMENTS .......................................................... 11 3.1 NEUROLOGICAL ASSESSMENTS ........................................................................................................................... 11

3.1.1 Glasgow Coma Scale............................................................................................................................ 11 3.1.2 Pupil Measurements, Shape, and Reactivity ........................................................................................ 13 3.1.3 Symptoms of Traumatic Brain Injury ................................................................................................... 14 3.1.4 Loss of Consciousness, Post-Traumatic Amnesia, and Alteration of Consciousness ........................... 16

3.2 SECONDARY INSULTS AND COMPLICATIONS ....................................................................................................... 17 3.3 IMAGING .............................................................................................................................................................. 19 3.4 QUESTIONNAIRES, RATINGS, AND SCALES .......................................................................................................... 22

3.4.1 Outcome Measures used in Traumatic Brain Injury Studies ................................................................ 22 3.4.2 Other Measures Relevant to TBI Research .......................................................................................... 24

4 ROUTINE DATA ................................................................................................................ 24 4.1 SUBSTANCE USE .................................................................................................................................................. 24 4.2 HEALTHCARE ENCOUNTERS ................................................................................................................................ 25 4.3 PROCEDURES ....................................................................................................................................................... 26 4.4 PROTECTIVE DEVICES ......................................................................................................................................... 28

APPENDICES ............................................................................................................................. 30 APPENDIX A: PROJECT PROPOSAL ................................................................................................................................ 30 APPENDIX B: CFAST TRAUMATIC BRAIN INJURY STANDARDS TEAM ......................................................................... 30 APPENDIX C: GLOSSARY AND ABBREVIATIONS ........................................................................................................... 31 APPENDIX D: NON-STANDARD VARIABLES ................................................................................................................. 32 APPENDIX E: REFERENCES ........................................................................................................................................... 33

Appendix E1: Works Cited ...................................................................................................................................... 33 Appendix E2: Figures .............................................................................................................................................. 34 Appendix E3: Further Reading ................................................................................................................................ 34

APPENDIX F: REPRESENTATIONS AND WARRANTIES, LIMITATIONS OF LIABILITY, AND DISCLAIMERS ........................ 36

FIGURES Figure 1: Concept Classification Key for Concept Maps .............................................................................................. 5 Figure 2: Presentation of Non-Standard Variables in This Document........................................................................... 6 Figure 3: Leading Causes of TBI in the US, 2006-2010 ............................................................................................... 8

CONCEPT MAPS Concept Map 1: Glasgow Coma Scale ........................................................................................................................ 12 Concept Map 2: Using Imaging to Identify Brain Injuries (Annotated) ...................................................................... 19



1 Introduction This Therapeutic Area Data Standards User Guide for Traumatic Brain Injury (TAUG-TBI) is a provisional standard, which means that it has been published for initial use, but is dependent upon completion of other standards and thus may involve risk of upcoming change. The TAUG-TBI was developed under the Coalition for Accelerating Standards and Therapies (CFAST) initiative. CFAST, a joint initiative of the Clinical Data Interchange Standards Consortium (CDISC) and the Critical Path Institute (C-Path), was launched to accelerate clinical research and medical product development by facilitating the establishment and maintenance of data standards, tools, and methods for conducting research in therapeutic areas important to public health. CFAST partners include TransCelerate BioPharma Inc. (TCB), the U.S. Food and Drug Administration (FDA), and the National Cancer Institute Enterprise Vocabulary Services (NCI-EVS), with participation and input from many other organizations. See http://www.cdisc.org/cfast-0 for a list of CFAST participating organizations. CDISC has developed industry-wide data standards enabling the harmonization of clinical data and streamlining research processes from protocol (study plan) through analysis and reporting, including the use of electronic health records to facilitate study recruitment, study conduct and the collection of high quality research data. CDISC standards, implementations and innovations can improve the time/cost/quality ratio of medical research, to speed the development of safer and more effective medical products and enable a learning healthcare system. The goal of the CFAST initiative is to identify a core set of clinical therapeutic area concepts and endpoints for targeted therapeutic areas and translate them into CDISC standards to improve semantic understanding, support data sharing and facilitate global regulatory submission.

1.1 Purpose The purpose of this TAUG-TBI is to describe how to use CDISC standards to represent data pertaining to traumatic brain injury (TBI) studies. The focus of this Version 1.0 (v1.0) of the TAUG-TBI is traumatic brain injury in adults. See Appendix A for the project proposal that was approved by the CFAST Steering Committee. The TAUG-TBI v1.0 provides advice and examples for Clinical Data Acquisition Standards Harmonization (CDASH) and the Study Data Tabulation Model (SDTM), including:

• Annotated sample case report forms (CRFs) compliant with CDASH • Guidance on which domain models and datasets from the SDTM Implementation Guide for Human

Clinical Trials (SDTMIG) to use in storing raw/collected data • Examples of SDTM datasets, with text describing the situational context and pointing out records of note

The TAUG-TBI v1.0 provides no information on the Analysis Data Model (ADaM). Although the project proposal included key biomarkers as a focus of v1.0 of the TAUG-TBI, this information will be handled in subsequent versions of the TAUG-TBI. Any biomarker data collected in TBI studies, should be modeled using the existing SDMTIG domains. CDISC standards are freely available at www.cdisc.org. It is recommended that implementers consult the foundational standards prior to implementing these TBI clinical data standards. This TAUG-TBI v1.0 describes common kinds of data needed for traumatic brain injury studies, so that those handling the data (e.g., data managers, statisticians, programmers) understand the data and can apply standards appropriately. These descriptions include the clinical situations from which the data arise, and the reasons these data are relevant for TBI. The TAUG-TBI v1.0 strives to define biomedical concepts unambiguously, so that consistent terminology can be used in TBI studies to enable aggregation and comparison of data across studies and drug programs, and so that metadata for these research concepts can be likewise defined.

http://www.cdisc.org/cfast-0

http://www.cdisc.org/



A biomedical concept is a unit of knowledge, created by a unique combination of the characteristics that define observations of real world healthcare and/or clinical research phenomena, which represents biomedical knowledge that borrows from medical knowledge, statistical knowledge, BRIDG, and the CDISC standards. Metadata for biomedical concepts include the properties of the data items that are parts of the concepts, controlled terminology for those data items, and the ways in which the concepts relate to each other. Clinical guidelines, articles, and other works consulted by the team during the creation of this document are referenced where appropriate, using the American Medical Association (AMA) style for citation. For a full list of references, see Appendix D. It is important to note that the biomedical concepts included in this user guide are a sample of the more common concepts for which data are collected in traumatic brain injury studies; they are not intended to influence sponsor decisions as to what data to collect. The examples included are intended to show how particular kinds of data can be represented using CDISC standards. This user guide emphasizes that examples are only examples and should not be over-interpreted. For guidance on the selection of biomedical concepts and endpoints, please refer to the appropriate clinical and regulatory authorities.

1.2 Organization of this Document This document is divided into the following sections:

• Section 1, Introduction, provides an overall introduction to the purpose and goals of the Traumatic Brain Injury project.

• Section 2, Subject and Injury Characteristics, covers data that are usually collected once at the beginning of a study.

• Section 3, Brain Assessments, covers data that are used to evaluate disease severity, control, or progression. These are usually collected repeatedly during a study, and may be used as or for the derivation of efficacy and/or safety endpoints.

• Section 4, Routine Data, covers background data that are collected in most acute TBI studies. Only aspects of these data that arise in TBI studies and are not covered by existing standards are discussed.

• Appendices provide additional background material and describe other supplemental material relevant to TBI.

Sections 2-4 consist primarily of modeling examples, with a minimal introduction to each concept covered. Therefore, the examples have not been called out into separate sub-sections in this document. Instead, readers should assume, with one exception*, that any section within Section 2, Section 3, or Section 4 will have at least one example. An index of the domains used in the examples in this document is below: Domain Page Device Identification † ................................................................................................................................ 7, 21, 29, 30 Device Properties † ...................................................................................................................................................... 21 Device-in-Use † ........................................................................................................................................................... 21 Disease Response and Clinical Classifications ‡ ......................................................................................................... 12 Findings About Events or Interventions .............................................................................................. 11, 16, 17, 18, 19 Healthcare Encounters ................................................................................................................................................. 26 Medical History ................................................................................................................. 10, 14, 17, 18, 19, 21, 22, 29 Morphology ....................................................................................................................................................... 6, 21, 22 Ophthalmology Physiology * .................................................................................................................................. 6, 13 Procedures ............................................................................................................................................................. 27, 28 Substance Use .............................................................................................................................................................. 26

* Domain is not final. ‡ Revision in progress. † Used for ancillary devices only.

* Section 3.4, Questionnaires, Ratings, and Scales. Because QRS supplements are created separately, a section with this title in any CDISC therapeutic area user guide will not include examples.



1.3 Traumatic Brain Injury Common Data Elements The TBI common data elements (CDEs) used in this document were developed by an interagency task force, including the U.S. National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Disability and Rehabilitation Research (NIDRR), Defense Center of Excellence for Psychological Health and Traumatic Brain Injury (DCoE), Department of Veterans Affairs (DVA), and Defense and Veterans Brain Injury Center (DVBIC). The CDEs were initially developed in 2010 and covered acute TBI in adults. In 2012, Version 2 of the NINDS CDEs was developed and organized around four major study types:

1. Epidemiological research 2. Studies on acute, hospitalized patients 3. Studies of rehabilitation for moderate/severe TBI 4. Mild TBI/Concussion research

The concepts from these data elements were used in the creation of examples in this user guide and could be used in other types of TBI studies. The annotated Case Report Forms (CRFs) included in this document were based on the NINDS sample CRFs available on their website. The NINDS CDEs can be found on the NINDS website at: http://www.commondataelements.ninds.nih.gov/tbi.aspx#tab=Data_Standards.

1.4 Concept Maps This document uses concept maps to explain clinical processes and research concepts. Concept maps, also sometimes called mind maps, are diagrams which include “bubbles” representing concepts/ideas/things and labeled arrows that represent the relationships between the concepts/ideas/things. They are generally easier to draw and more accessible than more formal modeling diagrams, such as Unified Modeling Language (UML) diagrams. The diagrams in this document use the following coding for classification of concepts. This classification is based on classes in the Biomedical Research Integrated Domain Group (BRIDG) model (available at http://bridgmodel.nci.nih.gov/). These color-symbol pairs have been used to highlight kinds of things that occur commonly in clinical data and therefore give rise to common patterns of data. Some concepts are not coded; they have a thinner, black outline, and no accompanying symbol. These may include the subject of an observation, as well as characteristics, or attributes, of the coded concepts.

Figure 1: Concept Classification Key for Concept Maps

http://www.commondataelements.ninds.nih.gov/tbi.aspx#tab=Data_Standards

http://bridgmodel.nci.nih.gov/



1.5 Controlled Terminology CDISC Controlled Terminology is a set of standard value lists that are used throughout the clinical research process, from data collection through analysis and submission. Controlled terminology is updated quarterly by the CDISC Terminology Team and published by the National Cancer Institute’s Enterprise Vocabulary Services (NCI EVS) at: http://www.cancer.gov/cancertopics/cancerlibrary/terminologyresources/cdisc. Although the examples in CDISC data standards try to appear plausible, including using controlled terminology where available, they should not be regarded as a definitive source for controlled terminology. Some codelists and/or values applicable to biomedical concepts and data elements in this document may still be in development at the time of publication. Some examples may use values that appear to be controlled terminology, but which are actually generic or "best guess" placeholders. Readers should consult the current CDISC Controlled Terminology (available at the link above) as the ultimate authority for correct controlled terminology codelists and values.

1.6 Relationships to Other Standards This document does not replace the foundational CDISC standards or their implementation guides. Users should read those standards and implementation guides before applying the advice in this user guide. Certain types of data have existing SDTM standards that can be used in traumatic brain injury studies without additional development or customization, and so are not covered in special detail in this document. CDISC data standards are living documents. Due to different update cycles, some of the modeling approaches and controlled terminology presented in the examples in this document may become outdated before the next version is released. Some of the standards used in this document have not yet been published as either final or provisional. These draft standards include a revision of the Disease Response (RS) domain, the proposed Ophthalmology Examinations (OE) domain, and the proposed Related Devices (RELDEV) dataset specification. Until such time as they are released for general use, these standards will be available at: http://wiki.cdisc.org/x/vox0AQ.

1.7 Known Issues • Presentation of Non-Standard Variables: SDTM places qualifiers of a record that are not among the

standard variables in separate, Supplemental Qualifiers, datasets. Reviewers commonly merge the Supplemental Qualifiers datasets with the parent domain to create a reviewable dataset. A proposal to provide an alternate structure for handling these additional, non-standard qualifiers (along with any non-standard Identifiers and Timing variables) in the parent domain has been circulated for review, but is not yet part of the SDTMIG. When non-standard variables (NSVs) are included in SDTM-based examples in this document, they are shown in line with the standard variables, but separated slightly from them by a small gap, and the heading row is shaded black, with white text. This is intended to allow NSVs to be easily recognizable and distinguishable from standard variables.

Figure 2: Presentation of Non-Standard Variables in This Document

• Morphology (MO) domain: Several examples in this document used the MO domain. The MO domain is part of SDTMIG 3.2 and is expected to be part of SDTMIG 3.3, but is to be deprecated in a later version of the SDTMIG. Submissions which use SDTMIG 3.2 can include data in the MO domain. Submissions using 3.3 could choose to represent data in either MO or body system-based physiology/morphology domains. Submissions using later versions of the SDTMIG would submit these data in an appropriate body system-based physiology/morphology domain. Note that the only changes for a record such as that shown in the example would be a change the domain code and in variable domain prefixes. Submissions in versions of

http://www.cancer.gov/cancertopics/cancerlibrary/terminologyresources/cdisc

http://wiki.cdisc.org/x/vox0AQ



the SDTMIG prior to 3.2 would handle data such as these in a custom domain. The sponsor could choose to create a custom domain with a prefix of MO, or could choose to create body system-based physiology/morphology custom domains.

Since it is known that the modeling will change, implementers need to check the latest version of the SDTMIG and Controlled Terminology for further information.

• Imaging results: The NINDS TBI Imaging CRF records the results of a review of an MRI image, including the presence or absence of pre-specified findings, many of which indicate the presence or absence of a medical condition. Although an image may be used to determine the occurrence of a clinical event, these MRI data were treated as findings. CDISC is continuing to discuss the best method for modeling this type of pre-specified imaging findings and is subject to change in the future.

• Disease Response and Clinical Classifications: Scales such as the Glasgow Coma Scale (GCS) shown in Section 3.1.1 do not have a clear home in any of the domains in SDTMIG 3.2 or earlier versions. All previous data examples and QRS Supplements using the CC domain will be re-modeled into the Disease Response and Clinical Classifications (RS) domain. It is expected that SDTMIG 3.3 will expand the definition of the Disease Response (RS) domain to include scales such as this. Submissions using 3.2 or earlier may represent these data in RS, explaining the use of the RS domain for this purpose in the reviewers guide, or may represent the data in a custom domain. Any Controlled Terminology (CT) initially developed for the Clinical Classifications (CC) domain will now be represented in the RS domain and will follow the development process used for the Questionnaires (QS) and Functional Tests (FT) domains. This document uses the RS domain to represent data for the Glasgow Coma Scale (GCS) measure.

• Risk Factors: There is no domain currently described in the SDTMIG for risk-factor information for a TBI, such as military deployments or participation in contact sports, however v2.0 of the Tuberculosis Therapeutic Area User Guide presented risk factors in the draft Environmental Risk Factors (ER) domain. If and when this domain is approved, this type of TBI risk factor information may be represented in the ER domain.

• Occurrence of Events and Interventions: The occurrence of Events and Interventions is under review for alternative approaches by an SDS Sub-Team. The Findings About Events or Interventions (FA) domain approach is used to represent the occurrence of symptoms of traumatic brain Injury. These symptoms are collected without any related timing data, and represent a "snapshot" rather than an assessment of the traumatic brain Injury as a whole. In the FA record, FATESTCD=OCCUR, FAOBJ=<term>, FACAT=<disease area>, FASCAT=<further categorization, such as SIGNS AND SYMPTOMS>. Although the evaluations of loss of consciousness, post-traumatic amnesia, and alteration of consciousness, as well as the information on secondary insults and complications could be considered as "events", they were modeled using the Findings About Events or Interventions (FA) domain approach because the information allowed a response of "Suspected" which is not allowable controlled terminology for the SDTM OCCUR variable. There is some question at present as to whether "Occurrence Indicator” FATEST should have responses limited to Yes/No, or whether Absent/Present, Suspected/Not Suspected Unknown (U), and Not Applicable (NA) are also valid responses. This document includes these results as FAORRES values for the Occurrence Indicator Test. These responses could be included in another FATEST name. This approach will be reviewed by the SDS Team and could result in revised modeling in this TAUG.

• Protective device indicator and historical medical conditions: In Section 4.4, there are many additional related CDEs for historical medical conditions and protective device use that cannot be represented using existing variables in the Events class. The examples represented these data in SUPPMH because it was felt that they did not meet any criteria for using Findings About.

• Protective and other non-medical devices: This document applies a somewhat broad interpretation of what may be considered appropriate to store in the domain models described in the SDTMIG-MD, because TBI-related devices are often not medical in nature. Examples include information about an airbag, and protective helmet type and model. The SDTMIG-MD v1.0 was used to model these protective devices used in TBI studies.

• Multiple devices: DI and SPDEVID can be used to identify either individual devices or more general types of devices, depending on the level of granularity necessary for their identification (see SDTMIG-MD: Section 4.1.1, Assumptions 2 and 10). With the use of RELDEV, complex or composite devices can also be identified. However, there is currently no guidance for occasions when a single record is associated with more than one device with very different relationships to the subject (e.g., for a gunshot injury, a bullet and a helmet).



2 Subject and Injury Characteristics Traumatic brain injury (TBI) is a significant public health problem and is defined as damage to the brain caused by an external mechanical force rather than degenerative or congenital causes. Everyone is at risk for a TBI. It is more common among children and the elderly.1 Incidence is also higher among men than among women. TBI is a major cause of death and disability worldwide: the annual global incidence rate of TBI is estimated at 200 per 100,000 people, and this may be an underestimate.2 TBI affects not only those directly injured, but also caregivers and family members. TBI is a very complex condition because different types of trauma can produce varying types of injuries and symptoms. In the United States, most TBIs are caused by blunt trauma, including falls, motor vehicle collisions (MVC), and collisions with moving or stationary objects (labeled in Figure 4 as “Struck by/against”), as well as unknown or other causes.3 Assaults can also cause blunt trauma. World-wide, the leading cause of TBI are road traffic accidents (RTAs), particularly in developing countries. This includes pedestrians, cyclists and bus passengers.4 For active military personnel, blasts can also be a leading cause of TBI. The symptoms and effects of a TBI can vary greatly, depending on the nature and extent of the injury, and the area(s) of the brain affected.5, 6, 7 An individual may experience no immediate symptoms,6 or symptoms that are mild (e.g., temporary dizziness or disorientation) to severe (e.g., prolonged loss of consciousness, amnesia)3 or death. Symptoms may be acute or persistent. TBI can result in short- or long-term changes in brain function that may affect thinking, sensation, language, and/or emotion.3 Common diagnostic signs and symptoms of TBI include one or more of the following:

• loss of consciousness • memory loss • difficulty speaking • confusion • headache • dizziness

• nausea and/or vomiting • blurry vision • tinnitus • altered sleep patterns • changes in behavior or mood

Figure 3: Leading Causes of TBI in the US, 2006-2010*

TBI may be classified in different ways, including closed and open injuries, contusions, diffuse axonal injuries, and penetrating injuries. Penetrating injuries penetrate the dura and are commonly caused by gunshot wounds to the head. Diffuse axonal injuries, in which axonal damage is initiated by rapid deceleration or rotation, often follow impact injuries such as MVCs or shaking injuries. Structural damage associated with TBI can range from diffuse damage not visible on imaging to hematomas to skull fractures. Sequelae of TBI can include short- or long-term impairment of cognitive, motor, and sensory functions. People with TBI can also experience depression, anxiety, personality changes and other emotional changes. Depending on the injury, the treatment required may be minimal or may include interventions such as medications or surgery, although there

* Image originally released by the Centers for Disease Control and Prevention (CDC). Public domain.



currently exists no medication to facilitate neuronal regrowth or neural plasticity. Patients may receive rehabilitation treatments such as physical, speech, occupational, or other types of therapy. Often lifelong disease management is needed in particular for severe TBI patients. Since there is no known intervention to cure the consequences of TBI, public health needs to focus on prevention. Examples of prevention methods include seatbelt use, airbags, helmet use, fall prevention, and education about child abuse and gun safety. TBI research is challenging because the consequences are so varied across patients. There are multiple ongoing international multi-center prospective, observational studies involving thousands of patients. Data sharing and the development of data repositories may facilitate a better understanding of TBIs via neuroimaging, proteomics, genetic biomarkers, and outcomes. Efforts are currently underway to study the most effective trial designs for TBI studies.8 The majority of the concepts addressed in this therapeutic-area user guide are focused on data for acute TBI in the early stages that are collected in observational studies rather than randomized, controlled interventional clinical trials. Information about subject and the characteristics of the condition of primary interest to the study (in this case, TBI) generally includes demographic data, demographic-like data, and events and activities that have affected the subject prior to or at the start of the study. Basic demographic data collected in TBI studies generally includes date of birth or age, gender, race, and ethnicity. Years of education, socioeconomic status, such as employment status and marital status may also be collected. See the SDTMIG for additional information on the Demographics (DM) and Subject Characteristics (SC) domains, which are used to record these types of data. Additional details that might also be collected include participation in various activities associated with the potential for cumulative TBI (e.g. contact sports such as football, soccer, skiing, judo), and information regarding military service (e.g., branch, deployment length, special duties). See Section 1.7, Known Issues for additional information on risk factors. See SDTMIG Sections 8.6 for guidance on determining where data belong in SDTM-conformant tabulations.

2.1 Prior TBI Exposure and Prior TBI Treatment Characteristics of a TBI can include its type, severity, and location, the circumstances under which it occurred, and any other injuries (TBI or other) that may have occurred either at the same time or previously and exacerbated or were exacerbated by the TBI. In terms of a patient’s prior TBI exposure and treatment, items of interest include the number and type of prior TBIs over a lifetime. The cause of the injury, the type and mechanism of TBI and the elapsed time between injury and presentation for treatment are also of interest. Other hospitalizations or occurrence of serious trauma, broken bone, and treatment for alcohol/substance abuse may be collected as well. Example 1 In the example below, previous TBI episodes for a subject enrolled in a TBI clinical study are represented. The study protocol required each subject to have experienced at least one previous TBI injury that met protocol defined criteria for enrollment. Any protocol defined TBI episode was categorized as a "QUALIFYING EVENT" by the sponsor. All medical history information associated with a TBI and any related injuries were categorized using a MHCAT of TRAUMATIC BRAIN INJURY. Any TBI episodes that met the protocol defined enrollment criteria were subcategorized using MHSCAT= QUALIFYING EVENT and any related TBI injuries collected on the same date were subcategorized using MHSCAT = RELATED INJURY. Row 1: Shows that this subject had an initial head injury in August of 2008. An NSV (INJCAUSE) shows that the cause of the TBI was a motor vehicle

traffic accident.



Row 2: Shows that this subject also had a spinal fracture on the same day, 8 August 2008, which resolved on 1 December 2008. Because the injury was TBI-related, but not itself a TBI, MHCAT=TRAUMATIC BRAIN INJURY and MHSCAT=RELATED INJURY.

Row 3: Shows that this subject had a subsequent head injury 2 years later on 17 September 2010, due to an accidental fall. Row 4: Shows that this subject had a subdural hematoma on 14 February 2014, which qualified them for the current clinical trial. Since this was a

qualifying injury, further information about the fall was captured in additional NSVs, such as the cause of the TBI, the International Classification of Diseases, 9th Revision (ICD-9) External Cause Code, type and mechanism of the TBI, time to presentation to the emergency department, and whether or not the injury was due to abuse and/or alcohol. If a different dictionary was used to code the cause of the injury, it would be captured in the INJCDICT NSV.

Row 5: Shows that this subject also had a skull fracture on 14 February 2014. The skull fracture was a qualifying event to the TBI diagnosis. mh.xpt Row STUDYID DOMAIN USUBJID MHSEQ MHTERM MHDECOD MHCAT MHSCAT MHSTDTC

1 ABC123 MH 001-001 1 HEAD INJURY Head injury TRAUMATIC BRAIN INJURY 2008-08-08 2 ABC123 MH 001-001 2 SPINAL FRACTURE Spinal fractures and dislocations TRAUMATIC BRAIN INJURY RELATED INJURY 2008-08-08 3 ABC123 MH 001-001 3 HEAD INJURY Head injury TRAUMATIC BRAIN INJURY 2010-09-17 4 ABC123 MH 001-001 4 SUBDURAL HEMATOMA Haematoma subdural TRAUMATIC BRAIN INJURY QUALIFYING EVENT 2014-02-14T05:35 5 ABC123 MH 001-001 5 SKULL FRACTURE Skull fracture TRAUMATIC BRAIN INJURY QUALIFYING EVENT 2014-02-14T05:35

Row MHENDTC INJCAUSE INJCSCD INJCDICT TBITYP MECHTBI ABUSEINJ ALCOINFL

1 (cont) Motor Vehicle Traffic Accident 2 (cont) 2008-12-01 Motor Vehicle Traffic Accident 3 (cont) Accidental Fall 4 (cont) Accidental Fall e880 ICD-9 Closed Ground Level Fall No Concern Suspected 5 (cont) Accidental Fall e880 ICD-9 Closed Ground Level Fall No Concern Suspected

Sample value-level metadata for the NSVs used in this example are given below, in tabulated form. Note that, unlike the domain specification tables in the SDTMIG, the metadata provided are descriptive and instance-specific (i.e., instead of specifying what the metadata should be in any instance of a given situation, the table describes what metadata apply to the single, hypothetical instance from which the data in the example arose). This is perhaps most obvious in the “Codelist” column, which contains the names of the codelists used in the creation of the example, with no annotation to indicate whether a codelist (or any terms therein) is from CDISC Controlled Terminology, sponsor-defined, or external. In this example, the NSVs correspond to specific NINDS CDEs, so the codelists used were named after the CDEs represented, and built from said CDEs’ permissible values lists. MH NSV Metadata Variable Label Type Codelist Role Origin INJCAUSE Cause of Injury text Injury cause type Non-Standard Record Qualifier CRF INJCSCD Injury Cause Code text Non-Standard Variable Qualifier of INJCAUSE CRF INJCDICT Injury Cause Code Dictionary text Non-Standard Variable Qualifier of INJCSCD CRF TBITYP TBI Type text TBI type Non-Standard Record Qualifier CRF MECHTBI Mechanism of TBI text TBI mechanism type Non-Standard Record Qualifier CRF ABUSEINJ Injury Due to Abuse text Abusive head trauma likelihood type Non-Standard Record Qualifier CRF ALCOINFL Under the Influence of Alcohol text Influence alcohol likelihood type Non-Standard Record Qualifier CRF



Example 2 The following example shows an alternate method to model questions regarding the number of head injuries and concussions when the detailed medical history data were not available. In this study, the dates of the prior head injuries and concussions were not collected, rather the subject was asked about the total number of events in the prior six months and over the course of a lifetime. Row 1: The subject had two head injuries in the past 6 months. No other information was available regarding these head injuries, so the total number was

included in FA. Row 2: The subject had three concussions throughout his lifetime. Since the evaluation interval was not of fixed duration, FAEVINTX was used to

represent the evaluation interval. famh.xpt Row STUDYID DOMAIN USUBJID FASEQ FATESTCD FATEST FAOBJ FACAT FAORRES FASTRESC FASTRESN FAEVLINT FAEVINTX FADTC

1 DEF456 FA 001-010 1 NUMEVNTS Number of Events

Head Injury

TRAUMATIC BRAIN INJURY 2 2 2 -P6M 2014-

07-17

2 DEF456 FA 001-010 2 NUMEVNTS Number of Events Concussion TRAUMATIC

BRAIN INJURY 3 3 3 LIFETIME 2014-07-17

3 Traumatic Brain Injury Assessments Assessments of a condition of interest are typically done repeatedly over the course of a study and are used to evaluate how a subject is progressing. For TBI studies, this includes assessing symptoms that the subject may be experiencing, encounters with the healthcare system, imaging studies of the brain, and various outcome measures.

3.1 Neurological Assessments

3.1.1 Glasgow Coma Scale The Glasgow Coma Scale is used to assess the severity during the acute stages of TBI, often in the emergency department (ED). It was developed in 1974 by University of Glasgow neurosurgery professors Jennett and Teasdale and is one of the most commonly used instruments to grade TBI severity.9 The GCS measures eye opening, verbal response, and motor response and can be used to determine a patient’s level of consciousness following brain injury. The GCS total score is the sum of the three measures (eye, verbal, and motor). The lower the total score, the more severe the brain injury. The following concept map illustrates the Glasgow Coma Scale assessment.



Concept Map 1: Glasgow Coma Scale

There are several factors that can lead to an unreliable GCS Total Score. These include confounders such as alcohol or drug use, sedation, or hypothermia, as well as ocular injury or tracheostomy. GCS confounders are not always collected when the GCS is administered, but if they are present on the CRF they should be represented as additional questions following the total score (see test codes GCS0105A, GCS0105B, etc. [Rows 5-12] in the example below). Example 1 This example shows results from the GCS CRF on the NINDS website (http://www.commondataelements.ninds.nih.gov/TBI.aspx#tab=Data_Standards). The CRF used a “check all that apply” approach to the confounder question. Each confounder value was treated as a separate question and the result was either CHECKED or NOT CHECKED. Based on conventions used for the questions in the “check-all-that-apply” format, a separate test code was assigned for each of the items in the checklist. For items that are checked, “CHECKED” is used as the result; for items that are not checked, “NOT CHECKED” is used as the result. This approach makes no further assumptions on the selection of confounders and provides reviewers the ability to review the CHECKED confounders relative to the GCS total score. Since the investigator administers the GCS, RSEVAL=INVESTIGATOR. GCS data were represented using the Disease Response and Clinical Classifications (RS) domain, which is being expanded to incorporate the proposed Clinical Classifications (CC) domain (see Section 1.7). Please refer to the Glasgow Coma Scale NINDS Version supplement found on the CDISC website (http://www.cdisc.org/qrs) for further details on implementing this instrument. Rows 1-4: Display the four questions from the NINDS version of the GCS. Rows 5-12: Display the individual confounder questions from the NINDS GCS CRF. rs.xpt Row STUDYID DOMAIN USUBJID RSSEQ RSTESTCD RSTEST RSCAT RSORRES RSSTRESC

1 STUDYX RS P0001 1 GCS0101 GCS01-Best Eye Response GCS NINDS VERSION No eye opening 1 2 STUDYX RS P0001 2 GCS0102 GCS01-Motor Response GCS NINDS VERSION Abnormal extension 2 3 STUDYX RS P0001 3 GCS0103 GCS01-Verbal Response GCS NINDS VERSION Incomprehensible sound 2 4 STUDYX RS P0001 4 GCS0104 GCS01-Total Score GCS NINDS VERSION 5 5 5 STUDYX RS P0001 5 GCS0105A GCS01-Confounder: GCS Accurate GCS NINDS VERSION NOT CHECKED NOT CHECKED 6 STUDYX RS P0001 6 GCS0105B GCS01-Confounder: Alcohol/Drugs of Abuse GCS NINDS VERSION CHECKED CHECKED 7 STUDYX RS P0001 7 GCS0105C GCS01-Confounder: C-spine injury GCS NINDS VERSION NOT CHECKED NOT CHECKED 8 STUDYX RS P0001 8 GCS0105D GCS01-Confounder: Hypoxia/Hypotension GCS NINDS VERSION NOT CHECKED NOT CHECKED 9 STUDYX RS P0001 9 GCS0105E GCS01-Confounder: Hypothermia GCS NINDS VERSION NOT CHECKED NOT CHECKED

http://www.commondataelements.ninds.nih.gov/TBI.aspx#tab=Data_Standards

http://www.cdisc.org/qrs



Row STUDYID DOMAIN USUBJID RSSEQ RSTESTCD RSTEST RSCAT RSORRES RSSTRESC 10 STUDYX RS P0001 10 GCS0105F GCS01-Confounder: Sedation GCS NINDS VERSION NOT CHECKED NOT CHECKED 11 STUDYX RS P0001 11 GCS0105G GCS01-Confounder: Paralytic GCS NINDS VERSION NOT CHECKED NOT CHECKED 12 STUDYX RS P0001 12 GCS0105H GCS01-Confounder: Unknown GCS NINDS VERSION NOT CHECKED NOT CHECKED

Row RSSTRESN RSEVAL VISITNUM RSDTC

1 (cont) 1 INVESTIGATOR 2 2012-11-16 2 (cont) 2 INVESTIGATOR 2 2012-11-16 3 (cont) 2 INVESTIGATOR 2 2012-11-16 4 (cont) 5 INVESTIGATOR 2 2012-11-16 5 (cont) INVESTIGATOR 2 2012-11-16 6 (cont) INVESTIGATOR 2 2012-11-16 7 (cont) INVESTIGATOR 2 2012-11-16 8 (cont) INVESTIGATOR 2 2012-11-16 9 (cont) INVESTIGATOR 2 2012-11-16 10 (cont) INVESTIGATOR 2 2012-11-16 11 (cont) INVESTIGATOR 2 2012-11-16 12 (cont) INVESTIGATOR 2 2012-11-16

3.1.2 Pupil Measurements, Shape, and Reactivity Pupil size, shape, and reactivity are indirect indicators of brain function in TBI patients. 10 Pupils normally range from 2-6 mm and are generally symmetrical in shape and size in patients without a brain injury. Abnormal pupil reactivity can be an indicator of increased intracranial pressure. Example 1 The example below shows the representation of pupil diameter, shape, and reactivity for each eye. The FOCID variable that represents the Focus of Study Specific Interest is an expected variable in the OE domain and was included in the example, even though it was not collected on the NINDS GCS CRF. The values used to populate FOCID are: OD( Oculus Dexter (Right Eye)), OS (Oculus Sinister (Left Eye)), and OU (Oculus Uterque (Both Eyes)). The --LOC variables was populated with pupil because it was the specific anatomical location that was evaluated. The Ophthalmology Finding (OE) domain is not in the SDTMIG v3.2, but because it is of interest to this document, readers can access a draft copy (see Section 1.6) to use in conjunction with this guide. oe.xpt Row STUDYID DOMAIN USUBJID FOCID OESEQ OETESTCD OETEST OEORRES OEORRESU OESTRESC OESTRESN OESTRESU OELOC OELAT

1 STUDYX OE P0001 OS 1 DIAMETER Diameter 3 mm 3 3 mm PUPIL LEFT 2 STUDYX OE P0001 OD 2 DIAMETER Diameter 4 mm 4 4 mm PUPIL RIGHT 3 STUDYX OE P0001 OS 3 SHAPE Shape OVAL OVAL PUPIL LEFT 4 STUDYX OE P0001 OD 4 SHAPE Shape ROUND ROUND PUPIL RIGHT 5 STUDYX OE P0001 OS 5 REACTVTY Reactivity SLUGGISH SLUGGISH PUPIL LEFT 6 STUDYX OE P0001 OD 6 REACTVTY Reactivity BRISK BRISK PUPIL RIGHT



Row VISITNUM MODTC 1 (cont) 2 2012-11-16 2 (cont) 2 2012-11-16 3 (cont) 2 2012-11-16 4 (cont) 2 2012-11-16 5 (cont) 2 2012-11-16 6 (cont) 2 2012-11-16

3.1.3 Symptoms of Traumatic Brain Injury The symptoms of TBI can present immediately after injury, or days later. Symptoms are often assessed during a review of a subject’s medical history and/or at multiple times throughout a study. Symptoms can range from mild to severe, depending on injury severity. Pre-specified symptoms collected on a CRF of a TBI may include: • Headache • Nausea • Vomiting • Balance problems • Fatigue • Sensitivity to light and/or noise

• Numbness/Tingling • Drowsiness • Sleeping more or less than usual • Difficulty falling asleep • Mental fogginess • Difficulty concentrating

• Memory problems • Irritability • Sadness • Emotional disturbances • Nervousness

Example 1 In this study, additional information was collected regarding the signs and symptoms the subject experienced at the time of the presentation for the qualifying TBI. The Medical History domain was used in this example since it serves as the description of the condition since the injury at the time the subject entered the study, rather than of the subject's condition during the study. The MHEVINTX was assigned as SINCE INJURY to reflect the assessment period. MHCAT was used to categorize the medical history information related to the TRAUMATIC BRAIN INJURY and was further categorized using MHSCAT as either the QUALIFYING EVENT or as SIGNS AND SYMPTOMS. MHGRPID groups the TBI signs and symptoms since the injury with the event of CEREBRAL CONTUSION. For the sake of brevity, only the first eleven pre-specified symptoms from the CRF are shown in the dataset below. mh.xpt Row STUDYID DOMAIN USUBJID MHSEQ MHGRPID MHTERM MHCAT MHSCAT MSPRESP MSCOOUR

1 STUDY123 MH 001-999 1 1 CEREBRAL CONTUSION TRAUMATIC BRAIN INJURY QUALIFYING EVENT 2 STUDY123 MH 001-999 2 1 HEADACHE TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y Y 3 STUDY123 MH 001-999 3 1 NAUSEA TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y Y 4 STUDY123 MH 001-999 4 1 VOMITING TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y N 5 STUDY123 MH 001-999 5 1 BALANCE PROBLEMS TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y N 6 STUDY123 MH 001-999 6 1 FATIGUE TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y Y 7 STUDY123 MH 001-999 7 1 SENSITIVE TO LIGHT TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y N 8 STUDY123 MH 001-999 8 1 SENSITIVE TO NOISE TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y Y 9 STUDY123 MH 001-999 9 1 NUMBNESS/ TINGLING TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y Y



Row STUDYID DOMAIN USUBJID MHSEQ MHGRPID MHTERM MHCAT MHSCAT MSPRESP MSCOOUR 10 STUDY123 MH 001-999 10 1 DROWSINESS TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y N 11 STUDY123 MH 001-999 11 1 SLEEPING LESS THAN USUAL TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y UNKNOWN 12 STUDY123 MH 001-999 12 1 SLEEPING MORE THAN USUAL TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y UNKNOWN

Row MHDTC MHSTDTC MHENDTC MHE MHEVINTX

1 (cont) 2013-04-01 2013-04-01T01:00 ONGOING 2 (cont) SINCE INJURY 3 (cont) SINCE INJURY 4 (cont) SINCE INJURY 5 (cont) SINCE INJURY 6 (cont) SINCE INJURY 7 (cont) SINCE INJURY 8 (cont) SINCE INJURY 9 (cont) SINCE INJURY 10 (cont) SINCE INJURY 11 (cont) SINCE INJURY 12 (cont) SINCE INJURY

Example 2 This example shows how symptoms of the TBI were assessed at multiple times throughout the study in order to continue following the subject’s progress. There was no timing information about when these symptoms started or ended, but rather only the presence or absence of these symptoms since the last visit was assessed (FAEVINTX=Since Last Visit). They were captured in the Findings About domain, without a parent Clinical Event (CE) record. Signs and symptoms of the TBI were captured using a CRF such as the following:

Signs and Symptoms Has the subject displayed the following TBI signs or symptoms since the last visit? Headache □ Yes □ No □ Unknown Difficulty falling asleep □ Yes □ No □ Unknown Nausea □ Yes □ No □ Unknown Feeling mentally foggy □ Yes □ No □ Unknown Vomiting □ Yes □ No □ Unknown Feeling slowed down □ Yes □ No □ Unknown Balance problems □ Yes □ No □ Unknown Difficulty concentrating □ Yes □ No □ Unknown Fatigue □ Yes □ No □ Unknown Difficulty remembering □ Yes □ No □ Unknown Sensitivity to light □ Yes □ No □ Unknown Irritability □ Yes □ No □ Unknown Sensitivity to noise □ Yes □ No □ Unknown Sadness □ Yes □ No □ Unknown Numbness/tingling □ Yes □ No □ Unknown More emotional □ Yes □ No □ Unknown Drowsiness □ Yes □ No □ Unknown Nervousness □ Yes □ No □ Unknown Sleeping less than usual □ Yes □ No □ Unknown Other, specify: _______________________ Sleeping more than usual □ Yes □ No □ Unknown

These questions were asked at the Month 1 Follow-up Visit. The only sign and/or symptom the subject had experienced since the last visit was a headache.

CRF annotated to show mapping. FASCAT=SIGNS AND SYMPTOMS

This CRF is only an example and is not meant to imply that any particular layout

is preferable over another.

FAORRES=Y when FATEST=Occurrence Indicator

FAORRES = Y when FATEST=Occurrence Indicator

FAOBJ=<specify>

FAOBJ=HEADACHE …NERVOUSNESS

FAEVINTX=Since Last Visit



face.xpt Row STUDYID DOMAIN USUBJID FASEQ FATESTCD FATEST FAOBJ FACAT FASCAT FAORRES

1 STUDY123 FA 001-999 1 OCCUR Occurrence Indicator Headache TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS Y 2 STUDY123 FA 001-999 2 OCCUR Occurrence Indicator Nausea TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N 3 STUDY123 FA 001-999 3 OCCUR Occurrence Indicator Vomiting TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N 4 STUDY123 FA 001-999 4 OCCUR Occurrence Indicator Balance Problems TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N 5 STUDY123 FA 001-999 5 OCCUR Occurrence Indicator Fatigue TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N 6 STUDY123 FA 001-999 6 OCCUR Occurrence Indicator Sensitive To Light TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N 7 STUDY123 FA 001-999 7 OCCUR Occurrence Indicator Sensitive To Noise TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N 8 STUDY123 FA 001-999 8 OCCUR Occurrence Indicator Numbness/ Tingling TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N 9 STUDY123 FA 001-999 9 OCCUR Occurrence Indicator Drowsiness TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N

10 STUDY123 FA 001-999 10 OCCUR Occurrence Indicator Sleeping Less Than Usual TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N 11 STUDY123 FA 001-999 11 OCCUR Occurrence Indicator Sleeping More Than Usual TRAUMATIC BRAIN INJURY SIGNS AND SYMPTOMS N

Row FASTRESC VISITNUM VISIT FADTC FAEVINTX

1 (cont) Y 3 MONTH 1 2013-05-04 Since Last Visit 2 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit 3 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit 4 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit 5 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit 6 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit 7 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit 8 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit 9 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit 10 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit 11 (cont) N 3 MONTH 1 2013-05-04 Since Last Visit

3.1.4 Loss of Consciousness, Post-Traumatic Amnesia, and Alteration of Consciousness TBI patients are typically evaluated for loss of consciousness (LOC), post-traumatic amnesia (PTA), and alteration of consciousness (AOC). The durations of LOC, PTA, and/or AOC may be indicators of injury severity. Brief LOC (<1 min) associated with sports-related brain injuries does not appear to be related to injury severity.11 Conversely, PTA does appear to provide greater sensitivity to injury severity.12, 13 Self-reported LOC, PTA, and AOC may be the only way of determining the occurrence and severity of TBI in the absence of medical documentation soon after injury or observations of others around the time of injury. Example 1 The example below shows a subject who experienced a concussion based on the NINDS "Neurological Assessment: LOC, PTA, and AOC" CRF. The investigator evaluated the subject. The subject had an episode of LOC that lasted from 1-29 minutes that was recorded in the medical chart. The subject had suspected post-traumatic amnesia lasting from 1-7 days that was reported by a witness (most likely a friend or relative). The patient reported experiencing AOC, but the duration was unknown. The subject's qualifying TBI was a concussion, which was recorded in the MH domain.



mh.xpt Row STUDYID DOMAIN USUBJID MHSEQ MHLNKID MHTERM MHCAT MHSCAT MHDTC MHSTDTC MHENDTC

1 STUDY02 MH P0001 1 1 CONCUSSION TRAUMATIC BRAIN INJURY QUALIFYING EVENT 2013-04-01 2013-04-01T01:00 The Findings About (FA) domain contains further details regarding LOC, PTA, and AOC. For each finding about the concussion, three questions were asked – did it occur, what was the duration range (duration category), and what was the source of this information. famh.xpt Row STUDYID DOMAIN USUBJID FASEQ FALNKID FATESTCD FATEST FAOBJ FACAT

1 STUDY02 FA P0001 1 1 OCCUR Occurrence Indicator Loss Of Consciousness TRAUMATIC BRAIN INJURY 2 STUDY02 FA P0001 2 1 DURRNG Duration Range Loss Of Consciousness TRAUMATIC BRAIN INJURY 3 STUDY02 FA P0001 3 1 PRIMSRC Primary Source of Information Loss Of Consciousness TRAUMATIC BRAIN INJURY 4 STUDY02 FA P0001 4 1 OCCUR Occurrence Indicator Post-Traumatic Amnesia TRAUMATIC BRAIN INJURY 5 STUDY02 FA P0001 5 1 DURRNG Duration Range Post-Traumatic Amnesia TRAUMATIC BRAIN INJURY 6 STUDY02 FA P0001 6 1 PRIMSRC Primary Source of Information Post-Traumatic Amnesia TRAUMATIC BRAIN INJURY 7 STUDY02 FA P0001 7 1 OCCUR Occurrence Indicator Alteration Of Consciousness TRAUMATIC BRAIN INJURY 8 STUDY02 FA P0001 8 1 DURRNG Duration Range Alteration Of Consciousness TRAUMATIC BRAIN INJURY 9 STUDY02 FA P0001 9 1 PRIMSRC Primary Source of Information Alteration Of Consciousness TRAUMATIC BRAIN INJURY

Row FASCAT FAORRES FASTRESC VISIT FADTC

1 (cont) SIGNS AND SYMPTOMS Y Y BASELINE 2013-04-01 2 (cont) SIGNS AND SYMPTOMS 1-29 MINUTES 1-29 MINUTES BASELINE 2013-04-01 3 (cont) SIGNS AND SYMPTOMS MEDICAL CHART MEDICAL CHART BASELINE 2013-04-01 4 (cont) SIGNS AND SYMPTOMS SUSPECTED SUSPECTED BASELINE 2013-04-01 5 (cont) SIGNS AND SYMPTOMS 1-7 DAYS 1-7 DAYS BASELINE 2013-04-01 6 (cont) SIGNS AND SYMPTOMS WITNESS WITNESS BASELINE 2013-04-01 7 (cont) SIGNS AND SYMPTOMS Y Y BASELINE 2013-04-01 8 (cont) SIGNS AND SYMPTOMS UNKNOWN UNKNOWN BASELINE 2013-04-01 9 (cont) SIGNS AND SYMPTOMS SELF-REPORTED SELF-REPORTED BASELINE 2013-04-01

RELREC shows the dataset relationship between the MH and FA domains based on the MHSEQ and FALNKID values related to the MHTERM=Concussion. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID

1 STUDY02 MH MHLNKID ONE MHFA 2 STUDY02 FA FALNKID MANY MHFA

3.2 Secondary Insults and Complications An insult is defined as an injury to the body. In TBI studies, the initial TBI is considered the primary insult, while insults that occurred at the same time as the TBI are referred to as concurrent insults. Secondary insults are metabolic derangements that occur after the TBI, and may cause further damage to the injured brain. Secondary insults can be intracranial or systemic. Secondary insults may include elevated intracranial pressure, cardiac arrest, seizures, inadvertent hypocapnia (low blood carbon dioxide), and hypoxic or hypotensive episodes.14, 15, 16, 17



Example 1 This example represents pre-specified second insults and complications from the NINDS Secondary Insults and Other Complications CRF. In the following example a subject with a concussion did not experience a hypotensive episode or cardiac arrest. The subject had a suspected hypoxic episode and experienced convulsive seizures. Since there was no timing information collected regarding the secondary insults, they were captured in the Findings About domain. If timing information had been collected, the secondary insults would be listed in an Events domain (MH, CE, or AE). The table below shows the subject’s qualifying TBI event was a concussion, which is recorded in the MH domain. mh.xpt Row STUDYID DOMAIN USUBJID MHSEQ MHLNKID MHTERM MHCAT MHSCAT MHDTC MHSTDTC MHENDTC MHENRF

1 STUDY02 MH P0001 1 1 CONCUSSION TRAUMATIC BRAIN INJURY

QUALIFYING EVENT

2013-04-01

2013-04-01T01:00 ONGOING

The FA domain contains further information regarding the occurrence of pre-specified secondary insults and complications based on the NINDS CRF that captured this information. These were represented in a similar manner as the pre-specified signs and symptoms. Row 1: Shows no occurrence of a hypotensive episode. Row 2: Shows hypoxic episode was suspected. Row 3: Shows no occurrence of cardiac arrest. Row 4: Shows the occurrence of seizures. Row 5: Displays the identification of a convulsive seizure. fa.xpt Row STUDYID DOMAIN USUBJID FASEQ FAGRPID FALNKID FATESTCD FATEST FAOBJ FACAT

1 STUDY02 FA P0001 1 1 OCCUR Occurrence Indicator Hypotensive Episode TRAUMATIC BRAIN INJURY 2 STUDY02 FA P0001 2 1 OCCUR Occurrence Indicator Hypoxic Episode TRAUMATIC BRAIN INJURY 3 STUDY02 FA P0001 3 1 OCCUR Occurrence Indicator Cardiac Arrest TRAUMATIC BRAIN INJURY 4 STUDY02 FA P0001 4 1 1 OCCUR Occurrence Indicator Seizures TRAUMATIC BRAIN INJURY 5 STUDY02 FA P0001 5 1 1 SEIZRPRS Seizure Presentation Seizures TRAUMATIC BRAIN INJURY

Row FASCAT FAORRES FASTRESC VISITNUM VISIT FADTC

1 SECOND INSULTS AND OTHER COMPLICATIONS N N 1 BASELINE 2013-04-01 2 SECOND INSULTS AND OTHER COMPLICATIONS SUSPECTED SUSPECTED 1 BASELINE 2013-04-01 3 SECOND INSULTS AND OTHER COMPLICATIONS N N 1 BASELINE 2013-04-01 4 SECOND INSULTS AND OTHER COMPLICATIONS Y Y 1 BASELINE 2013-04-01 5 SECOND INSULTS AND OTHER COMPLICATIONS CONVULSIVE CONVULSIVE 1 BASELINE 2013-04-01

RELREC shows the dataset relationship between the MH and FA domains based on the MHLNKID and FALNKID values related to the MHTERM=Concussion. relrec.xpt Row STUDYID RDOMAIN USUBJID IDVAR IDVARVAL RELTYPE RELID

1 STUDY02 MH MHLNKID ONE MHFA 2 STUDY02 FA FALNKID MANY MHFA



3.3 Imaging Various imaging modalities can help to identify damage to the brain. Magnetic resonance angiography (MRA), computerized axial tomography (CT), and magnetic resonance imaging (MRI) are diagnostic tools commonly used to visualize the brain. Imaging obtained within hours of an injury may appear normal; abnormalities may not be visible on imaging until sometime after the initial TBI. The following concept map shows the various components of the imaging evaluation that occurs following a suspected TBI and where this information is stored in SDTM.

Concept Map 2: Using Imaging to Identify Brain Injuries (Annotated)

Example 1 The subject experienced a gunshot wound to the head. The subject underwent a CT scan to assess the extent of the initial wound and any additional head injuries. Information pertaining to the CT scan equipment used with this particular subject was considered important in this study, and was shown in the Device



Identification (DI), Device Properties (DO), and Device In-Use (DU) domains. CT scan image interpretation results were generally presented in the Morphology (MO) domain for each CT scan. In this case the assessments of the extent of the initial wound and secondary injuries were obtained prior to the study start. The subject’s qualifying TBI was a gunshot to the head, which was recorded in the MH domain. mh.xpt Row STUDYID DOMAIN USUBJID MHSEQ MHGRPID MHLNKID MHTERM MHCAT MHSCAT MHDTC MHSTDTC MHENDTC MHENRF

1 STUDY02 MH P0001 1 1 1 GUNSHOT TO THE HEAD

TRAUMATIC BRAIN INJURY

QUALIFYING EVENT

2012-11-16

2012-11-16T01:00 ONGOING

DI holds the device identifier information that describes the device used to produce the image that was the basis of the interpretation recorded in the MO domain. The link between the MO record and the MH record represented in RELREC below shows that the image was related to the subject's gunshot to the head. di.xpt Row STUDYID DOMAIN SPDEVID DISEQ DIPARMCD DIPARM DIVAL

1 STUDY02 DI ABC001 1 DEVTYPE Device Type CT SCAN 2 STUDY02 DI ABC001 2 MANUF Manufacturer GE 3 STUDY02 DI ABC001 3 TRADENAM Trade Name Optima 4 STUDY02 DI ABC001 4 MODEL Model Number CT540

Fixed properties for the CT scanner are represented in the DO domain. do.xpt Row STUDYID DOMAIN USUBJID SPDEVID DOSEQ DOTESTCD DOTEST DOORRES DOORRESU DOSTRESC DOSTRESN DOSTRESU DODTC VISITNUM

1 STUDY02 DO P0001 ABC001 1 COILTYPE Coil Type HEAD HEAD 2012-11-16 1

2 STUDY02 DO P0001 ABC001 2 COILSTR Coil Strength 1.5 Tesla 1.5 1.5 Tesla 2012-11-

16 1

DU holds device settings information. These settings were linked to the record in the MO domain by their shared SPDEVID and DTC values. DUSTREN and DUSTRESU are expected variables, but they have been represented by an ellipsis for the sake of brevity. du.xpt Row STUDYID DOMAIN USUBJID SPDEVID DUSEQ DUREFID DUTESTCD DUTEST DUORRES DUORRESU DUSTRESC … DUDTC VISITNUM

1 STUDY02 DU P0001 ABC001 2 IMWGTTYP Image Weighting Type T1 T1 … 2012-11-16 1 2 STUDY02 DU P0001 ABC001 3 PULSSEQ Pulse Sequence DWI DWI … 2012-11-16 1 3 STUDY02 DU P0001 ABC001 4 SFTWRVER Software Version XYZ.1 XYZ.1 … 2012-11-16 1

The TBI Imaging CRF (see NINDS TBI CDEs) recorded the interpretation of the CT scan and the pre-specified findings based on the review of the CT scan image. These pre-specified findings may or may not be captured in an Events domain, depending on the study data capture criteria. The example below shows the presence or absence of the pre-specified findings. A subset of the pre-specified CT scan findings, including all complex findings is represented in the example to illustrate how they are represented in SDTM.

http://www.commondataelements.ninds.nih.gov/TBI.aspx#tab=Data_Standards



Row 1: Displays the interpretation of the CT scan performed on the subject with the gunshot to head injury which was recorded in the MH domain. Rows 2-5: Display the presence or absence of specific MO findings observed on the CT scan. Rows 6-7: Display that a cisternal compression was present as observed on the CT scan and the type was “visible but compressed – asymmetric”. If cisternal

compression was not present, the type would not be collected. MOGRPID groups these related records and MOSPID orders them within the group. Rows 8-11: Display that a contusion was present as observed on the CT scan, along with its associated findings. Each finding is a separate MOTEST. If a

contusion was not present, no additional findings would be collected. MOGRPID groups these related records and MOSPID orders them within the group.

Rows 12-13: Display that separate diffuse axonal injury was present in different anatomical locations and lateralities as observed on the CT scan. This is an example of “check all of the findings that apply on the CRF” and each finding is a separate MOTEST with a distinct location.

Rows 14-17: Display an example of a penetrating injury observed on the CT scan with additional findings also collected. In addition, the gunshot caliber was also collected. If no penetrating injury was present, there would be no additional information collected.

Row 18: Displays that a cervicomedullary junction or brainstem injury was present in the midbrain anatomical locations as observed on the CT scan. Rows 19-20: Display that brain swelling was present as observed on the CT scan, along with the extent of the swelling being lobar. If no brain swelling was

present, no additional information would be collected. MOGRPID groups these related records and MOSPID orders them within the group. Row 21: Displays that brain atrophy or encephalomalacia was likely as observed on the CT scan. mo.xpt Row STUDYID DOMAIN USUBJID SPDEVID MOSEQ MOGRPID MOSPID MOLNKID MOTESTCD MOTEST MOORRES

1 STUDY02 MO P0001 ABC001 1 1 INTP Interpretation ABNORMAL 2 STUDY02 MO P0001 ABC001 2 1 SKULFRAC Skull Fracture PRESENT 3 STUDY02 MO P0001 ABC001 3 1 EPIDHEMA Epidural Hematoma ABSENT 4 STUDY02 MO P0001 ABC001 4 1 EXAXHEMA Extraaxial Hematoma ABSENT 5 STUDY02 MO P0001 ABC001 5 1 ASUBHEMA Acute Subdural Hematoma INDETERMINATE 6 STUDY02 MO P0001 ABC001 6 1 1 1 CISTCOMP Cisternal Compression PRESENT

7 STUDY02 MO P0001 ABC001 7 1 2 1 CSTCMTYP Cisternal Compression Type VISIBLE BUT COMPRESSED – ASYMMETRIC

8 STUDY02 MO P0001 ABC001 8 2 1 1 CONTUSN Contusion PRESENT 9 STUDY02 MO P0001 ABC001 9 2 2 1 CONTFND Contusion Findings HEMORRHAGIC

10 STUDY02 MO P0001 ABC001 10 2 3 1 CONTFND Contusion Findings CORTICAL 11 STUDY02 MO P0001 ABC001 11 2 4 1 CONTFND Contusion Findings PROBABLE BRAIN LACERATION 12 STUDY02 MO P0001 ABC001 12 3 1 1 DIFAXINJ Diffuse Axonal Injury PRESENT 13 STUDY02 MO P0001 ABC001 13 3 2 1 DIFAXINJ Diffuse Axonal Injury PRESENT 14 STUDY02 MO P0001 ABC001 14 4 1 1 PENETINJ Penetrating Injury PRESENT

15 STUDY02 MO P0001 ABC001 15 4 2 1 PINJRFND Penetrating Injury Associated Findings INDRIVEN FRAGMENTS

16 STUDY02 MO P0001 ABC001 16 4 3 1 PINJRFND Penetrating Injury Associated Findings CROSSES MIDLINE

17 STUDY02 MO P0001 ABC001 17 4 4 1 GUNCALBR Gunshot Wound Caliber 30-30

18 STUDY02 MO P0001 ABC001 18 1 CMJBSINJ Cervicomedullary Junction/Brainstem Inj PRESENT

19 STUDY02 MO P0001 ABC001 19 5 1 1 BRANSWEL Brain Swelling PRESENT 20 STUDY02 MO P0001 ABC001 20 5 2 1 BSWLEXNT Brain Swelling Extent LOBAR

21 STUDY02 MO P0001 ABC001 21 1 BRANATEN Brain Atrophy Or Encephalomalacia LIKELY



Row MOSTRESC MOLOC MOLAT MOMETHOD MOEVAL VISITNUM MODTC

1 ABNORMAL CT SCAN INVESTIGATOR 1 2012-11-16 2 PRESENT CT SCAN INVESTIGATOR 1 2012-11-16 3 ABSENT CT SCAN INVESTIGATOR 1 2012-11-16 4 ABSENT CT SCAN INVESTIGATOR 1 2012-11-16 5 INDETERMINATE CT SCAN INVESTIGATOR 1 2012-11-16 6 PRESENT CT SCAN INVESTIGATOR 1 2012-11-16 7 VISIBLE BUT COMPRESSED – ASYMMETRIC CT SCAN INVESTIGATOR 1 2012-11-16 8 PRESENT CT SCAN INVESTIGATOR 1 2012-11-16 9 HEMORRHAGIC CT SCAN INVESTIGATOR 1 2012-11-16

10 CORTICAL CT SCAN INVESTIGATOR 1 2012-11-16 11 PROBABLE BRAIN LACERATION CT SCAN INVESTIGATOR 1 2012-11-16 12 PRESENT FRONTAL LEFT CT SCAN INVESTIGATOR 1 2012-11-16 13 PRESENT PONS RIGHT CT SCAN INVESTIGATOR 1 2012-11-16 14 PRESENT CT SCAN INVESTIGATOR 1 2012-11-16 15 INDRIVEN FRAGMENTS CT SCAN INVESTIGATOR 1 2012-11-16 16 CROSSES MIDLINE CT SCAN INVESTIGATOR 1 2012-11-16 17 30-30 CT SCAN INVESTIGATOR 1 2012-11-16 18 PRESENT MIDBRAIN CT SCAN INVESTIGATOR 1 2012-11-16 19 PRESENT CT SCAN INVESTIGATOR 1 2012-11-16 20 LOBAR CT SCAN INVESTIGATOR 1 2012-11-16 21 LIKELY CT SCAN INVESTIGATOR 1 2012-11-16

3.4 Questionnaires, Ratings, and Scales Questionnaires, Ratings, and Scales (QRSs) are typically done repeatedly over the course of a study and are used to evaluate how a subject is progressing. In TBI, these are the most prominent assessments. These are often used to assess the severity of the consequences of injury, rate of recovery and improvement or worsening of specific symptoms and functions QRSs are maintained as standalone guides on the CDISC website at http://www.cdisc.org/qrs. The tables below list the various assessments that are being pursued as potential supplements to the SDTMIG as part of the development work for TAUG-TBI v1.0. Supplements may or may not be finalized at the time of publication of this user guide, and depend on copyright approval where applicable. CDISC cannot produce supplements for copyrighted measures without the permission of the copyright holder. Sponsors should refer to the link above if a measure of interest is not included below, as it may have been developed for another therapeutic area, and new measures are implemented on an ongoing basis by the CDISC QRS Terminology and Standards Development sub-teams. See CDISC COP 017 (http://www.cdisc.org/bylaws-and-policies) for details on implementing or requesting development of standards for SDTM-based submissions.

3.4.1 Outcome Measures used in Traumatic Brain Injury Studies The Common Data Elements Traumatic Brain Injury Outcomes Workgroup identified multiple outcome measures for TBI studies. “Primary clinical research objectives, including documentation of the natural course of recovery from TBI, prediction of later outcome, measurement of treatment effects, and comparison

http://www.cdisc.org/qrs

http://www.cdisc.org/bylaws-and-policies



of outcomes across studies” were the main focus of this effort.18 The workgroup considered several factors in selecting outcome domains that should be assessed after TBI. They chose to concentrate on instruments used to assess function, activity, and participation, since these are outcome domains previously shown to be affected by TBI, and on measures that are relevant to mild, moderate and severe TBI and to cover acute to long-term outcomes.18 The workgroup selected measures that should be assessed following TBI and categorized them by outcome domain. These outcome domains include global outcome, recovery of consciousness, neuropsychological impairment, psychological status, physical function, social role participation, health economic measures, patient-reported outcomes, and other TBI symptoms. The measures listed in the table below have been determined to be important in assessing outcome in traumatic brain injury patients regardless of the time post-injury and include a subset of instruments identified by the TBI Outcomes Workgroup. The majority of these instruments were identified as “Core” or “Basic” measures in the NINDS TBI CDEs.

Full Name and Abbreviation Status of Copyright Permission Global Outcome Glasgow Outcome Scale – Extended (GOS-E) Public Domain Disability Rating Scale Public Domain Expanded Disability Rating Scale (E-DRS-PI) Postacute Interview – Caregiver Version Public Domain Expanded Disability Rating Scale (E-DRS-PI) Postacute Interview – Survivor Version Public Domain Mayo-Portland Adaptability Inventory (MPAI) Public Domain RAND 36-Item Health Survey 1.0 (RAND-36 V1.0) Public Domain Recovery of Consciousness Galveston Orientation and Amnesia Test (GOAT) Permission Granted JFK Coma Recovery Scale–Revised (CRS-R) Permission Granted Neuropsychological Impairment Rey Auditory Verbal Learning Test (RAVLT) Public Domain Trail Making Test (TMT) Permission Granted Controlled Oral Word Association Test (COWAT) subtest of the Multilingual Aphasia Examination (MAE) In progress Wechsler Adult Intelligence Scale (WAIS-III/WAIS-IV) - Processing Speed Permission Denied Wechsler Adult Intelligence Scale (WAIS-III/WAIS-IV) - Letter-Number Sequencing Subtest Permission Denied Wechsler Adult Intelligence Scale (WAIS-III/WAIS-IV) - Digit Span Permission Denied Wechsler Test of Adult Reading (WTAR) Permission Denied Psychological Status PHQ-9 Public Domain PHQ-15 Public Domain PHQ Public Domain GAD-7 Public Domain Alcohol Use Disorders Identification Test (AUDIT) Public Domain Alcohol Use Disorders Identification Test - Consumption Questions (AUDIT-C) Public Domain Posttraumatic Stress Disorder Check List-5 (PCL-5) Public Domain Brief Symptom Inventory 18 (BSI-18) Permission Denied Physical Function Neurological Outcome Scale for Traumatic Brain Injury (NOS-TBI) Permission Granted FIM® Permission Not Pursued



Full Name and Abbreviation Status of Copyright Permission Social Role Participation Craig Handicap Assessment and Reporting Technique - Short Form Paper Version (CHART-SF PAPER VERSION) Public Domain Craig Handicap Assessment and Reporting Technique - Short Form Interview Version (CHART-SF INTERVIEW VERSION) Public Domain Perceived Generic and Disease-Specific Health-Related Quality of Life Satisfaction With Life Scale (SWLS) Public Domain Quality of Life After Brain Injury (QOLIBRI) - short version In progress Health Economic Measures EuroQol Group EQ-5D™- 5L (EQ-5D-5L) Permission Granted EuroQol Group EQ-5D™- 3L (EQ-5D-3L) Permission Granted Patient-reported outcomes (future multidimensional tools) Traumatic Brain Injury–Quality of Life (TBI-QOL) In progress Other TBI-Related Symptoms Rivermead Post-Concussion Symptom Questionnaire (RPQ) Public Domain

3.4.2 Other Measures Relevant to TBI Research The following table includes additional measures that are relevant to TBI studies. These measures are not necessarily outcome measures. For example, these instruments may assess the severity of the injury. Full Name and Abbreviation Status of Copyright Permission Glasgow Coma Scale Public Domain Marshall CT Grade Public Domain Rotterdam CT Score In progress Columbia Suicide Severity Rating Scale (C-SSRS) – Baseline Screening Permission Granted Columbia Suicide Severity Rating Scale (C-SSRS) – Since Last Visit Permission Granted Maddocks Score Public Domain Post-Concussion Symptom Inventory (PCSI) Public Domain Standardized Assessment of Concussion (SAC) In progress Balance Error Scoring System - Modified (M-BESS) Public Domain Sport Concussion Assessment Tool - 3rd Edition (SCAT3) In progress

4 Routine Data 4.1 Substance Use Substance-use data are often collected in TBI studies. Abuse of alcohol and drugs may be a cause of TBI, or the patient may develop a substance-use disorder following TBI. The example below illustrates how to represent substance-use data if collected during the study.



Example 1 At screening, the sponsor solicited the use of alcohol, cigarettes, and illicit drugs by subjects in the last 12 months. Since Subject 001-001 used alcohol, the amount of alcohol used was reported using predefined consumption categories. Since illicit drugs were used, the sponsor solicited information on the use of sedatives and tranquilizers in the last six weeks. Row 1: Subject 001-001 reported using alcohol in the last 12 months, and on average had 3 or 4 drinks per day. Rows 2-3: Subject 001-001 reported using cigarettes and illicit drugs in the past 12 months. Rows 4-5: Since Subject 001-001 used illicit drugs, the sponsor solicited information on any abuse of sedatives and tranquilizers in the last six weeks. Rows 6-8: Subject 001-002 reported no use of alcohol, cigarettes, or illicit drugs in the last 12 months. Since no illicit drugs were used in the last 12 months,

the subject does not have records about the abuse of sedatives or tranquilizers. su.xpt Row STUDYID DOMAIN USUBJID SUSEQ SUTRT SUCAT SUPRESP SUOCCUR SUDOSTXT SUDTC SUEVLINT

1 1234 SU 001-001 1 ALCOHOL ALCOHOL Y Y 3 or 4 drinks on average per day 2014-01-01 -P12M 2 1234 SU 001-001 2 CIGARETTES TOBACCO Y Y 2014-01-01 -P12M 3 1234 SU 001-001 3 ILLICIT DRUGS ILLICIT DRUGS Y Y 2014-01-01 -P12M 4 1234 SU 001-001 4 SEDATIVE ILLICIT DRUGS Y Y 2014-01-01 -P6W 5 1234 SU 001-001 5 TRANQUILIZER ILLICIT DRUGS Y N 2014-01-01 -P6W 6 1234 SU 001-002 1 ALCOHOL ALCOHOL Y N 2014-06-01 -P12M 7 1234 SU 001-002 2 CIGARETTES TOBACCO Y N 2014-01-01 -P12M 8 1234 SU 001-002 3 ILLICIT DRUGS ILLICIT DRUGS Y N 2014-06-01 -P12M

4.2 Healthcare Encounters Standards exist for collecting healthcare encounters and start and stop dates. This information is stored in the Healthcare Encounters (HO) domain. In the SDTMIG, there are existing examples for hospitalizations, Emergency Department (ED) visits, and Intensive Care Units (ICU) stays. There are also precedents for recording the reason for a healthcare encounter as a non-standard variable (HOINDC). Example 1 In the example below, a subject was initially seen at an emergency department and subsequently transferred to a bed in ICU. A week later, the subject was moved out of ICU to a general hospital ward for continued care. Upon discharge from the acute-care hospital, the subject was transferred to a rehabilitation unit for further recovery. The subject spent approximately 2 months in a center focused on rehabilitation. ho.xpt Row STUDYID DOMAIN USUBJID HOSEQ HOTERM HOCAT HOSTDTC HOENDTC HOINDC

1 ABC123 HO 001-001 1 EMERGENCY DEPARTMENT

TBI HEALTHCARE ENCOUNTERS

2014-02-14T08:50

2014-02-14T14:30 MOTOR VEHICLE

ACCIDENT

2 ABC123 HO 001-001 2 INTENSIVE CARE UNIT TBI HEALTHCARE ENCOUNTERS

2014-02-14T14:30 2014-02-21 LIFE-THREATENING TBI

3 ABC123 HO 001-001 3 ACUTE-CARE HOSPITAL TBI HEALTHCARE ENCOUNTERS 2014-02-21 2014-03-03 TBI INJURIES

STABILIZED

4 ABC123 HO 001-001 4 REHABILITATION UNIT TBI HEALTHCARE ENCOUNTERS 2014-03-03 2014-05-04 TBI SEQUELAE



HO NSV Metadata Variable Label Type Role Origin HOINDC Indication text Non-Standard Record Qualifier CRF

4.3 Procedures Data about history of procedures resembles medical history data, in that there may be questions about individual procedures or groups of procedures that are relevant for TBI. Existing standards for procedures cover procedure name and start and end date. Devices used in a procedure, if of interest, can be represented as described in the SDTMIG-MD. Surgical procedures used to treat TBI or injuries concurrent with TBI can be represented as described in the SDTMIG. Often patients recovering from TBI will require ongoing therapy and rehabilitation services on an inpatient or outpatient basis. Examples of types of therapy include:

• Speech therapy • Occupational therapy • Vocational therapy • Physical therapy

• Psychotherapy • Dietary counseling • Recreational therapy • Sensory integration therapy

• Social skills training • Adaptive physical education • Behavior support planning

The types of post-discharge therapies should be recorded in the Procedures (PR) domain. The average length of each session should be captured in the PRDOSE and PRDOSU fields. If an ICD-9 code for the type of therapy was collected it should be captured as a supplemental qualifier. Example 1 Subjects in this study were followed for post-discharge therapies and procedures.

Outpatient Therapy

Did the subject have any outpatient therapy? □ Yes □ No

Type of Therapy (ICD Code)

Therapy Frequency

Average Duration of Therapy Session

Therapy Start Date -- --- ---- (DD-MMM-YYYY) --:-- (24 hour clock)

Therapy Stop Date -- --- ---- (DD-MMM-YYYY) --:-- (24 hour clock)

Therapy Ongoing?

□ Yes □ No □ Unknown

□ Yes □ No □ Unknown

Therapy types, frequencies, and lengths are customized to the specific subject and may vary depending upon the subject's recovery. In order to standardize the verbatim therapy texts, coding from a medical dictionary was applied in PRDECOD. In general, PRSTDTC values should be populated; however, PRENDTC values may not be available and could be represented with PRENRF.

CRF annotated to show mapping. SDTM variables in Red. If CDASH variable differs from SDTM the CDASH variable is in Blue.

PRYN

PRTRT

PRDOSE or PRDOSTXT This CRF is only an example

and is not meant to imply that any particular layout is preferable over another.

PRDOSFRQ

PRDSTXT PRDOSU

PRENDTC PRENDAT PRENTIM

PRONGO

PRSTDTC PRSTDAT PRSTTIM

SUPPPR.DECDCD PRENRTPT PRENTPT

[not submitted]



The ICD-9 or ICD-10 codes for the specified therapies are representing using the NSV DECDCD and the coding dictionary used was represented using the NSV DCDDICT. Since multiple dictionaries or versions of dictionaries may be used in one study, the dictionary version was included as an NSV, rather than in the define.xml file. Row 1: The first subject was prescribed 60 minutes of occupational therapy 4 times per week. Therapy began on June 8, 2010. PRENRF shows that

therapy was ongoing at the time of discharge. Row 2: The second subject received two 90-minute sessions of physical therapy on August 6, 2010, and that was the end of therapy. Row 3: The third subject was prescribed 120 minutes of behavioral support every two weeks. The support began on December 12, 2010. PRENRF shows

that therapy was ongoing at the time of discharge. Row 4: The fourth subject was prescribed 60 minutes of adaptive physical education every week. The support began on December 12, 2010. PRENRF

shows that, at the time of discharge, it was unknown if the subject was continuing this education. Row 5: The fifth subject was to receive two 30-minute sessions of speech therapy per week. The subject received 30 minutes of speech therapy on

August 29, 2011, and that was the end of therapy. pr.xpt Row STUDYID DOMAIN USUBJID PRSEQ PRTRT PRDECOD PRDOSE PRDOSU PRDOSFRQ PRSTDTC

1 ABC123 PR 001-001 1 OCCUPATIONAL THERAPY Occupational Therapy 60 min 4 TIMES PERWEEK 2010-06-08 2 ABC123 PR 001-002 2 PHYSICAL THERAPY Physical Therapy 90 min BID 2010-08-06 3 ABC123 PR 001-003 3 BEHAVIORAL SUPPORT Behavioral Support 120 min EVERY 2 WEEKS 2010-12-12 4 ABC123 PR 001-004 4 ADAPTIVE PHYSICAL EDUCATION Adaptive Physical Education 60 min EVERY WEEK 2010-12-12 5 ABC123 PR 001-005 5 SPEECH THERAPY Speech Therapy 30 min 2 TIMES PER WEEK 2011-08-29

Row PRENDTC PRENRF DECDCD DCDDICT

1 (cont) ONGOING V57.21 ICD-9 2 (cont) 2010-08-06 V57.1 ICD-9 3 (cont) ONGOING 94.33 ICD-9 4 (cont) U V57.1 ICD-9 5 (cont) 2011-08-29 Z50.5 ICD-10

Metadata for the NSVs used in this example are given below. Note that in this example, for any given record, the codelist for DECDCD depended on the value in DCDDICT, making it value-level metadata rather than variable-level metadata. PR NSV Metadata Variable Label Type Codelist Role Origin DECDCD Decode Code text (see value-level metadata) Non-Standard Synonym Qualifier of PRTRT CRF DCDDICT Dictionary Version text Non-Standard Variable Qualifier of DECDCD CRF

Value Level Metadata – PR [DECDCD] Variable Where Codelist DECDCD DCDDICT=‘ICD-9’ ICD-9 DECDCD DCDDICT=‘ICD-10’ ICD-10

For more information on value- vs. variable-level metadata, see the Define-XML 2.0 Specification.



4.4 Protective Devices Whether or not a person was using a protective device when the injury occurred may be collected in TBI studies. Although protective devices are not typically thought of as medical devices, this information is collected in a similar manner and modeled according to the SDTMIG for Medical Devices. Depending on the patient population, the type of information collected will vary. Examples of protective devices include seatbelts, airbags, and helmets. In some studies, specific information regarding the protective device is collected, while in others, only the use or non-use of protective device(s) is of interest. In military TBI studies the use of body armor is also of interest. Example 1 The example below shows how protective device information was collected for three different causes of TBI: automobile accident, sports injury, and exposure to an improvised explosive device. For example, the use of a seatbelt and the deployment of an airbag was of interest in an automobile accident-induced TBI. Additional information regarding the manufacturer of the airbag may also be collected. For sports injuries, the use of helmets may be collected. The manufacturer and model of these devices can be represented in the Device Identifier (DI) domain. Row 1: The first subject had an intracranial hematoma. SPDEVID links this record back to the airbag identified in the DI domain below. NSVs identify

the cause of the TBI as a motor vehicle traffic accident and provide the ICD-9 external injury code. The subject was using protective devices that included a seatbelt and an airbag that deployed.

Row 2: The second subject was diagnosed with a concussion. NSVs identify the cause of the TBI as an “other accident”, which was a head-to-head collision on the athletic field and provide the ICD-9 external injury code. The subject was using protective devices, which were identified in the DI domain. SPDEVID links this record back to the helmet and mouth guard identified in the DI domain below.

Row 3: Shows that the subject’s skull was fractured due to an improvised explosive device during operations of war. The subject was wearing a protective device (body armor, identified through SPDEVID and the DI domain). The ICD-9 external injury code was provided as well.

mh.xpt Row STUDYID DOMAIN USUBJID MHSEQ SPDEVID MHTERM MHDECOD MHCAT MHSCAT MHSTDTC

1 STUDY03 MH 05-689 1 ABC001 INTRACRANIAL HEMATOMA

Intracranial Hematoma

TRAUMATIC BRAIN INJURY

QUALIFYING EVENT 2014-04-03

2 STUDY03 MH 09-325 1 DEF001 CONCUSSION Concussion TRAUMATIC BRAIN INJURY


3 MIL001 MH 04-567 1 ARMR01 SKULL FRACTURE Skull Fracture TRAUMATIC BRAIN INJURY


Row MHENDTC TBITYP INJCAUSE INJCTXT INJCSCD INJCDICT PRTDVIND ABDEPIND INJDVTYP

1 (cont) Closed MOTOR VEHICLE TRAFFIC ACCIDENT e819.1 ICD-9 Y Y

2 (cont) Closed OTHER ACCIDENT HEAD TO HEAD COLLISION ON THE ATHLETIC FIELD e917.0 ICD-9 Y

3 (cont) 2014-11-08 Blast INJURY RESULTING FROM OPERATIONS OF WAR e991.5 ICD-9 Y IMPROVISED

EXPLOSIVE DEVICE



Metadata for the NSVs used in this example are given below. Note that, as in Section 2.1 Example 1, the metadata provided are those applicable to the hypothetical instance from which the data in the example arose. Unlike Section 4.3 Example 1, only one dictionary (represented in INJCDICT) was used, so the codelists for INJCAUSE and INJCSCD were able to be defined at the variable level. MH NSV Metadata Variable Label Type Codelist Role Origin TBITYP TBI Type text TBI type Non-Standard Record Qualifier CRF INJCAUSE Cause of Injury text ICD-9 Non-Standard Record Qualifier CRF INJCSTXT Cause of Injury Text text Non-Standard Record Qualifier CRF INJCSCD Injury Cause Code text ICD-9 Non-Standard Variable Qualifier of INJCAUSE CRF INJCDICT Injury Cause Code Dictionary text Non-Standard Variable Qualifier of INJCSCD CRF PRTDVIND Protective Device Indicator text No Yes Response Non-Standard Record Qualifier CRF ABDEPIND Airbag Deployment Indicator text No Yes Response Non-Standard Record Qualifier CRF INJDVTYP Injury Device Type text Non-Standard Record Qualifier CRF

TBI protective devices are represented in the medical devices domains in a manner similar to what was done for medical devices. The sponsor's protective device identifier for each device was declared in DI, which also holds the manufacturer, model, and other identifying information that was collected. Row 1: Identifies the vehicle's safety system, of which the seatbelt and the airbag are components (see RELDEV dataset below). Rows 2-3: Identify the seatbelt as the type of the device. The seatbelt was manufactured by TWR. Rows 4-5: Identify the airbag as the type of the device. The airbag was manufactured by Acme. Rows 6-8: Identify one component of the head gear as a Model ABC helmet manufactured by Best Sports Helmet Manufacturer. Row 9: Identifies the body armor as the type of protective device. di.xpt Row STUDYID DOMAIN SPDEVID DISEQ DIPARMCD DIPARM DIVAL

1 STUDY03 DI ABC001 1 DEVTYPE Device Type VEHICLE SAFETY SYSTEM 2 STUDY03 DI ABC001-1 1 DEVTYPE Device Type SEATBELT 3 STUDY03 DI ABC001-1 2 MANUF Manufacturer TWR 4 STUDY03 DI ABC001-2 1 DEVTYPE Device Type AIRBAG 5 STUDY03 DI ABC001-2 2 MANUF Manufacturer ACME 6 STUDY03 DI DEF001 1 DEVTYPE Device Type HELMET 7 STUDY03 DI DEF001 2 MANUF Manufacturer BEST SPORTS HELMET MANUFACTURER 8 STUDY03 DI DEF001 3 MODEL Model ABC 9 STUDY03 DI ARMR01 1 DEVTYPE Device Type BODY ARMOR

The relationships between the different components of the vehicle's safety system are stored in the Device-Device Relationships (RELDEV) dataset. reldev.xpt Row STUDYID SPDEVID PARENT LEVEL

1 STUDY03 ABC001 1 2 STUDY03 ABC001-1 ABC001 2 3 STUDY03 ABC001-2 ABC001 2



Appendices Appendix A: Project Proposal CFAST is proposing development of v1.0 of the CDISC Traumatic Brain Injury (TBI) Therapeutic Area Data Standard. Traumatic Brain Injury (TBI) is a form of acquired brain injury, which occurs when a sudden external force causes damage to the brain. TBI can be classified based on severity, mechanism (closed or penetrating head injury) or other features. TBI affects an estimated 10 million people worldwide and more than 3.4 million in the U.S. every year. TBI is a silent epidemic, its symptoms are frequently invisible, thus difficult to diagnose and treat. TBI can lead to motor, cognitive, and social impairments that interfere with an individual’s ability to be productive. In collaboration with OneMind for Research, the workgroup proposes developing a Therapeutic Area User Guide to support clinical research and enable medical product development through the establishment and maintenance of data standards, tools and methods for conducting research in brain injury on a global scale. This project will build from the established NINDS CDEs for TBI to support SDTM (Study Data Tabulation Model) data models supplemented with guidelines to support CRFs consistent with CDASH (Clinical Data Acquisition Standards Harmonization). The workgroup proposes developing a CDISC Therapeutic Area User Guide, including concept maps to show critical information elements and their relationships, domain mappings, rules, controlled terminologies and examples for representing data using SDTM and CDASH. The standardization effort is expected to focus on the following areas of specific interest to TBI:

• Medical history of special interest • Key biomarkers • Physical and neurological assessments (functional assessments) of interest • Clinical observations based on medical imaging • Patient reported outcomes and scales.

Appendix B: CFAST Traumatic Brain Injury Standards Team Name Institution/Organization Rhonda Facile, Team Lead CDISC Dana Booth CDISC Steven Broglio University of Michigan Thomas DeGraba National Intrepid Center of Excellence (NICoE) Sureyya Dikmen University of Washington School of Medicine Christine Fleeman UCB Joseph Giacino Spaulding Rehabilitation Hospital Bron Kisler CDISC Steve Kopko CDISC Geoff Manley University of California, San Francisco Kathleen Mellars CDISC Fellow Jon Neville Critical Path Institute Amy Palmer CDISC Joanne Odenkirchen NINDS Munim Saeed Pharma Medica Research Tasneem Shamalak Chiltern Alex Valadka Virginia Commonwealth University School of Medicine Olga Vovk FITBIR Elizabeth Wilde Baylor College of Medicine Darcy Wold CDISC Diane Wold CDISC Ron Fitzmartin FDA Liaison



Appendix C: Glossary and Abbreviations Term Definition/Description

AOC Alteration of consciousness Biomedical Concept

A high-level building block of clinical research and/or healthcare information that encapsulates lower level implementation details like variables and terminologies.

BRIDG Biomedical Research Integrated Domain Group CDASH Clinical Data Acquisition Standards Harmonization Project CDE Common Data Element CDISC Clinical Data Interchange Standards Consortium CFAST Coalition for Accelerating Standards and Therapies Collected “Collected” refers to information that was recorded and/or transmitted to the sponsor. This

includes data entered by the site on CRFs/eCRFs as well as vendor data such as core lab data. This term is a synonym for “captured”.

Controlled Terminology

A finite set of values that represent the only allowed values for a data item. These values may be codes, text, or numeric. A code list is one type of controlled terminology.

CRF Case report form (sometimes called a case record form). A printed, optical, or electronic document designed to record all required information to be reported to the sponsor for each trial subject.

CT Computerized axial tomography Domain A collection of observations with a topic-specific commonality about a subject. ED Emergency Department Foundational Standards

Used to refer to the suite of CDISC standards that describe the clinical study protocol (Protocol), design (Study Design), data collection (CDASH), laboratory work (Lab), analysis (ADaM), and data tabulation (SDTM and SEND). See http://www.cdisc.org/ for more information on each of these clinical data standards.

GCS Glasgow Coma Scale ICD-9 The International Classification of Diseases, 9th Revision ICU Intensive Care Unit LOC Loss of consciousness MRI Magnetic resonance imaging NCI EVS National Cancer Institute (NCI) Enterprise Vocabulary Services NINDS National Institute of Neurological Disease and Stroke NSV Non-standard variable. A variable not included in SDTM. PTA Post-traumatic amnesia QRS Questionnaires, Ratings and Scales SDS Submission Data Standards. Also the name of the team that maintains the SDTM and SDTMIG. SDTM Study Data Tabulation Model SDTMIG SDTM Implementation Guide (for Human Clinical Trials) SDTMIG-MD SDTM Implementation Guide for Medical Devices TAUG Therapeutic Area User Guide TBI Traumatic Brain Injury

http://www.cdisc.org/



Appendix D: Non-Standard Variables The following table lists the non-standard variables (NSVs) used in this document, and gives their parent domain and variable-level metadata. Parent Domain Variable Label Data

Type Codelist Role Description Notes

HO HOINDC Indication text Non-Standard Record Qualifier

Denotes the indication (reason) for the healthcare encounter.

This NSV is an example of a domain borrowing a standard variable from a different general observations class.

MH ABDEPIND Airbag Deployment Indicator

text (NY) Non-Standard Record Qualifier

Indicates whether an airbag was deployed at the time of injury.

Not flags, but genuine indicators. For these NSVs, a value of N may be just as important, or even more important, than a Y value. MH PRTDVIND Protective Device

Indicator text (NY) Non-Standard

Record Qualifier Indicates whether the subject was using protective devices (e.g., helmet, seat belt).

MH ABUSEINJ Injury Due to Abuse text [C05419] Non-Standard Record Qualifier

The likelihood that the injury was due to abusive head trauma.

Subjective. If the assessor is someone other than the investigator, this may require the creation of an additional NSV to hold the assessor’s role. MH ALCOINFL Under the Influence

of Alcohol text [C18397] Non-Standard

Record Qualifier The likelihood that the subject was under the influence of alcohol at the time of the injury.

MH INJCAUSE Cause of Injury text Ψ Non-Standard Record Qualifier

The external cause of the injury. The codelist for these NSVs matches the value in INJCDICT. The examples in this document populate INJCAUSE with a categorical value, and INJCSCD with the code of a much more specific cause within the category, which is why INJCSCD is a variable qualifier of INJCAUSE and not a synonym.

MH INJCSCD Injury Cause Code text Ψ Non-Standard Variable Qualifier of INJCAUSE

Code to classify the external cause of the injury.

MH INJCSTXT Cause of Injury Text text Non-Standard Record Qualifier

Further specifies the external cause of the injury.

Free-text, used for "Other, Specify" or when the coded external cause of the injury is uninformative.

MH INJCDICT Injury Cause Code Dictionary Version

text Non-Standard Variable Qualifier of INJCAUSE and INJCSCD

The dictionary used to obtain INJCAUSE and INJCSCD.

Include both the name and the version number.

MH INJDVTYP Injury Device Type text Ψ Non-Standard Record Qualifier

The type of device that caused the injury. Which codelist this NSV uses may depend on TBITYP.

MH MECHTBI Mechanism of TBI text [C05424] Non-Standard Record Qualifier

The type of mechanism/forces that caused the TBI.

Examples: Acceleration/Deceleration, Gunshot wound.

MH TBITYP TBI Type text [C05420] Non-Standard Record Qualifier

A broad classification of the type of TBI experienced by the subject.

Examples: Closed, Blast.

PR DECDCD Decode Code text Ψ Non-Standard Variable Qualifier of PRTRT

Coded value of --TRT (or of --MODIFY, if applicable).

The codelist for this NSV depends on (and matches) the value in DCDDICT.

PR DCDDICT Dictionary Version text Non-Standard Variable Qualifier of DECDCD

The dictionary used to obtain DECDCD. Include both the name and the version number.

Ψ Indicates codelist may depend on the value of another variable, (Parentheses indicate CDISC/NCI codelist), [Brackets indicate NINDS CDE ID]

http://evs.nci.nih.gov/ftp1/CDISC/SDTM/SDTM%20Terminology.html#CL.C66742.NY

http://evs.nci.nih.gov/ftp1/CDISC/SDTM/SDTM%20Terminology.html#CL.C66742.NY

https://commondataelements.ninds.nih.gov/ReportViewer.aspx?/nindscdereports/rptAllCDE&rs:Command=Render&rc:Parameters=false&CDEName=&DiseaseName=Traumatic%20Brain%20Injury&SubDiseaseName=Comprehensive&DomainName=+&SubDomainName=History%20of%20Disease/Injury%20Event&Classification=+&IsCopyright=&Population=+&CdeId=+&keyword=&CrfId=F0308&CrfName=Type,%20Place,%20Cause%20and%20Mechanism%20of%20Injury






Appendix E: References

Appendix E1: Works Cited

1. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Divsion of Unintentional Injury Prevention. Traumatic Brain Injury - Injury Center. Centers for Disease Control and Prevention. March 27, 2015. Available at: http://www.cdc.gov/TraumaticBrainInjury/index.html. Accessed March 30, 2015.

2. Bryan-Hancock C, Harrison J. The global burden of traumatic brain injury: preliminary results from the Global Burden of Disease Project. Inj Prev. 2010;16:A17. doi: 10.1136/ip.2010.029215.61.

3. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Divsion of Unintentional Injury Prevention. Injury Prevention & Control: Traumatic Brain Injury. Centers for Disease Control and Prevention. January 12, 2015. Available at: http://www.cdc.gov/traumaticbraininjury/. Accessed March 30, 2015.

4. Roberts I, Mohan, D, Abassi, K. War on the roads. BMJ. 2002;324:1107–1108. 5. Office of Communications and Public Liaison, NINDS, NIH. NINDS Traumatic Brain Injury Information

Page. National Institute of Neurological Disorders and Stroke. Feb 3, 2015. Available at: http://www.ninds.nih.gov/disorders/tbi/tbi.htm. Accessed March 30, 2015.

6. Black PM, Gargollo PC, Lipson AC. Brain Trauma, Concussion, and Coma. BrainLine.org. 2015. Available at: http://www.brainline.org/content/2009/06/brain-trauma-concussion-and-coma_pageall.html. Accessed June 22, 2015.

7. Living With Brain Injury. Brain Injury Association of America. October 12, 2012. Available at: http://www.biausa.org/living-with-brain-injury.htm. Accessed June 22, 2015.

8. Norris J. $17M DoD Award Aims to Improve Clinical Trials for Traumatic Brain Injury. University of California San Francisco. October 1, 2014. Available at: http://www.ucsf.edu/news/2014/10/118596/us-aims-traumatic-brain-injury-clinical-trial-success. Accessed March 30, 2015.

9. Teasdale G, Jennett B. Assessment of Coma and Impaired Consciousness: A Practical Scale. Lancet. 1974;304(7872):81-84. doi: 10.1016/S0140-6736(74)91639-0.

10. Meeker M, Du R, Bacchetti P, et al. Pupil examination: validity and clinical utility of an automated pupillometer. J Neurosci Nurs. 2005;37(1):34-40.

11. Lovell MR, Iverson GL, Collins MW, McKeag D, Maroon JC. Does loss of consciousness predict neuropsychological decrements after concussion? Clin J Sport Med. 1999;9:193–198.

12. Collins MW, Iverson GL, Lovell MR, McKeag DB, Norwig J, Maroon J. On-field predictors of neuropsychological and symptom deficit following sports-related concussion. Clin. J. Sport Med. 2003;13:222–229.

13. Erlanger D, Kaushik T, Cantu R, et al. Symptom-based assessment of the severity of a concussion. J Neurosurg. 2003;98:477–484.

14. McHugh GS, Engel DC, Butcher I, et al. Prognostic value of secondary insults in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007;24(2):287-93.

15. Silverstone P. Pulse oxymetry of at the road side: a study of pulse oxymetry in immediate care. BMJ. 1989;298(6675):711-13.

16. Stocchetti N, Furlan A, Volta F. Hypoxemia and arterial hypotension at the accident side in head injury. J Trauma. 1996;40:764-67.

17. De Witt DS, Jenkins LW, Prough DS. Enhanced vulnerability to secondary ischemic insults after experimental traumatic brain injury. New Horizon. 1995;3(3):376-383.

18. Wilde EA, Whiteneck GG, Bogner J, et al. Recommendations for the use of common outcome measures in traumatic brain injury research. Arch Phys Med Rehabil. 2010;91(11):1650-1660.e17.

http://www.cdc.gov/TraumaticBrainInjury/index.html

http://www.cdc.gov/traumaticbraininjury/

http://www.ninds.nih.gov/disorders/tbi/tbi.htm

http://www.brainline.org/content/2009/06/brain-trauma-concussion-and-coma_pageall.html

http://www.biausa.org/living-with-brain-injury.htm

http://www.ucsf.edu/news/2014/10/118596/us-aims-traumatic-brain-injury-clinical-trial-success

http://www.ucsf.edu/news/2014/10/118596/us-aims-traumatic-brain-injury-clinical-trial-success



Appendix E2: Figures Figure 3: Leading Causes of TBI in the US, 2006-2010, was originally published by the CDC. As a government image, it is in the public domain.

Appendix E3: Further Reading The following works are of interest to this document, but not actively referenced within it.

• CDC - Publications, Reports, & Fact Sheets for Traumatic Brain Injury. List. Available at: http://www.cdc.gov/traumaticbraininjury/factsheets_reports.html.

• Balestreri M, Czosnyka M, Chatfield DA, et al. Predictive value of Glasgow Coma Scale after brain trauma: change in trend over the past ten years. J Neurol Neurosurg Psychiatry. 2004;75(1):161-2.

• Bruns J Jr, Hauser WA. The epidemiology of traumatic brain injury: a review. Epilepsia. 2003;44(10):2-10. • Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial

of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005;365(9475):1957-1959.

• Gao L1, Wu X1. Prediction of clinical outcome in severe traumatic brain injury. Front Biosci (Landmark Ed). 2015;20:763-71.

• Ghajar, J. Traumatic brain injury. Lancet. 2000;356(9233):923-929. • Grove MJ, Lamberty GJ, Gatewood LC, Johnson LM. Traumatic brain injury rehabilitation: analysis of

common data elements. Stud Health Technol Inform. 2013;192:1186. • Haacke EM, Duhaime AC, Gean AD, et al. Common data elements in radiologic imaging of traumatic

brain injury. J Magn Reson Imaging. 2010;32(3):516-43. doi: 10.1002/jmri.22259. • Hähnel S, Herweh C. MRI biomarkers in mild traumatic brain injury. Neurology. 2015;84(6):554-5. doi:

10.1212/WNL.0000000000001244 • Hicks R, Giacino J, Harrison-Felix C, Manley G, Valadka A, Wilde EA. Progress in developing common

data elements for traumatic brain injury research: version two--the end of the beginning. J Neurotrauma. 2013;30(22):1852-61. doi: 10.1089/neu.2013.2938.

• Hiler M, Czosnyka M, Hutchinson P, et al. Predictive value of initial computerized tomography scan, intracranial pressure, and state of autoregulation in patients with traumatic brain injury. J Neurosurg. 2006;104(5):731-7.

• Ker K, Perel P, Blackhall K, Roberts I. How effective are some common treatments for traumatic brain injury? BMJ. 2008;337:a865. doi: 10.1136/bmj.a865.

• Langlois JA, Rutland-Brown W, Thomas KE. Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths. Atlanta, GA: CDC, National Center for Injury Prevention and Control; 2006.

• Lingsma HF, Yue JK, Maas AI, et al. Outcome Prediction after Mild and Complicated Mild Traumatic Brain Injury: External Validation of Existing Models and Identification of New Predictors Using the TRACK-TBI Pilot Study. J Neurotrauma. 2015;32(2):83-94. doi: 10.1089/neu.2014.3384.

• Maas AI, Harrison-Felix CL, Menon D, et al. Standardizing data collection in traumatic brain injury. J Neurotrauma. 2011;28(2):177-87. doi: 10.1089/neu.2010.1617.

• Maas AI, Harrison-Felix CL, Menon D, et al. Common data elements for traumatic brain injury: recommendations from the interagency working group on demographics and clinical assessment. Arch Phys Med Rehabil. 2010;91(11):1641-9. doi: 10.1016/j.apmr.2010.07.232.

• Maas AI, Menon DK, Steyerberg EW, et al. Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): A Prospective Longitudinal Observational Study. Neurosurgery. 2015;76(1):67-80. doi: 10.1227/NEU.0000000000000575.

• Manley GT, Diaz-Arrastia R, Brophy M, et al. Review. Common data elements for traumatic brain injury: recommendations from the biospecimens and biomarkers working group. Arch Phys Med Rehabil. 2010;91(11):1667-72. doi: 10.1016/j.apmr.2010.05.018.

• Manley GT, Maas AI. Traumatic brain injury: an international knowledge-based approach. JAMA. 2013;310(5):473-4. doi: 10.1001/jama.2013.169158.

• Marmarou A, Lu J, Butcher I, et al. IMPACT database of traumatic brain injury: design and description. J Neurotrauma. 2007;24(2):239-50.

http://www.cdc.gov/traumaticbraininjury/factsheets_reports.html



• Marshall, L.F. Head Injury: Past, Present and Future. J Neurosurg. 2000;47:546-561. • Max JE, Pardo D, Hanten G, et al. Psychiatric disorders in children and adolescents six-to-twelve months

after mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2013;25(4):272-82. doi: 10.1176/appi.neuropsych.12040078.

• McCauley SR, Wilde EA, Anderson VA, et al. Recommendations for the use of common outcome measures in pediatric traumatic brain injury research. J Neurotrauma. 2012;29(4):678-705. doi: 10.1089/neu.2011.1838.

• McCulloch KL, Goldman LS, Lowe L, et al. Development of clinical recommendations for progressive return to activity after military mild traumatic brain injury: guidance for rehabilitation providers. J Head Trauma Rehabil. 2015;30(1):56-67. doi: 10.1097/HTR.0000000000000104.

• McMahon PJ, Panczykowski D, Yue JK, et al. Measurement of the GFAP-BDP Biomarker for the Detection of Traumatic Brain Injury Compared to CT and MRI. J Neurotrauma. 2014 Sep 29 [Epub ahead of print].

• Menon DK, Maas AI. Traumatic brain injury in 2014: Progress, failures and new approaches for TBI research. Nat Rev Neurol. 2015;11(2):71-2 doi: 10.1038/nrneurol.2014.261.

• MRC CRASH Trial Collaborators, Perel P, Arango M, et al. Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ. 2008;336(7641):425-9. doi: 10.1136/bmj.39461.643438.25.

• Mushkudiani NA, Engel DC, Steyerberg EW, et al. Prognostic value of demographic characteristics in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007;24(2):259-69.

• Ratcliff JJ, Adeoye O, Lindsell CJ, et al. ED disposition of the Glasgow Coma Scale 13 to 15 traumatic brain injury patient: analysis of the Transforming Research and Clinical Knowledge in TBI study. Am J Emerg Med. 2014;32(8):844-50. doi: 10.1016/j.ajem.2014.04.003.

• Rosenfeld JV, Maas AI, Bragge P, Morganti-Kossmann MC, Manley GT, Gruen RL. Review. Early management of severe traumatic brain injury. Lancet. 2012;380(9847):1088-98. doi: 10.1016/S0140-6736(12)60864-2.

• Stead LG, Bodhit AN, Patel PS, et al. TBI surveillance using the common data elements for traumatic brain injury: a population study. Int J Emerg Med. 2013;6(1):5. doi: 10.1186/1865-1380-6-5.

• Steyerberg EW, Mushkudiani N, Perel P, et al. Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med. 2008;5(8):e165; discussion e165. doi: 10.1371/journal.pmed.0050165.

• Thurmond VA, Hicks R, Gleason T, et al. Advancing integrated research in psychological health and traumatic brain injury: common data elements. Arch Phys Med Rehabil. 2010;91(11):1633-6. doi: 10.1016/j.apmr.2010.06.034.

• Tosetti P, Hicks RR, Theriault E, et al. Toward an international initiative for traumatic brain injury research. J Neurotrauma. 2013;30(14):1211-22. doi: 10.1089/neu.2013.2896.

• Van Beek JG, Mushkudiani NA, Steyerberg EW, et al. Prognostic value of admission laboratory parameters in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007;24(2):315-28.

• Whyte J, Vasterling J, Manley GT. Common data elements for research on traumatic brain injury and psychological health: current status and future development. Arch Phys Med Rehabil. 2010;91(11):1692-6. doi: 10.1016/j.apmr.2010.06.031.

• Yuan F, Ding J, Chen H, et al. Predicting outcomes after traumatic brain injury: the development and validation of prognostic models based on admission characteristics. J Trauma Acute Care Surg. 2012;73(1):137-45. doi: 10.1097/TA.0b013e31824b00ac

• Yue JK1, Vassar MJ, Lingsma HF, et al. Transforming research and clinical knowledge in traumatic brain injury pilot: multicenter implementation of the common data elements for traumatic brain injury. J Neurotrauma. 2013;30(22):1831-44. doi: 10.1089/neu.2013.2970. Epub 2013 Sep 24.

• Yuh EL, Cooper SR, Ferguson AR, Manley GT. Quantitative CT improves outcome prediction in acute traumatic brain injury. J Neurotrauma. 2012;29(5):735-46. doi: 10.1089/neu.2011.2008.



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