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1. Genetic vulnerability and adverse mental health outcomes following mild traumatic brain injury: a meta-analysis of CENTER-TBI and TRACK-TBI cohorts

Author

Ackerlund, Cecilia, Adams, Hadie, Amrein, Krisztina, Andelic, Nada, Andreassen, Lasse, Anke, Audny, Antoni, Anna, Audibert, Gérard, Azouvi, Philippe, Azzolini, Maria Luisa, Bartels, Ronald, Barzó, Pál, Beauvais, Romuald, Beer, Ronny, Bellander, Bo-Michael, Belli, Antonio, Benali, Habib, Berardino, Maurizio, Beretta, Luigi, Blaabjerg, Morten, Bragge, Peter, Brazinova, Alexandra, Brinck, Vibeke, Brooker, Joanne, Brorsson, Camilla, Buki, Andras, Bullinger, Monika, Cabeleira, Manuel, Caccioppola, Alessio, Calappi, Emiliana, Calvi, Maria Rosa, Cameron, Peter, Lozano, Guillermo Carbayo, Carbonara, Marco, Castaño-León, Ana M., Cavallo, Simona, Chevallard, Giorgio, Chieregato, Arturo, Citerio, Giuseppe, Clusmann, Hans, Coburn, Mark Steven, Coles, Jonathan, Cooper, Jamie D., Correia, Marta, Čović, Amra, Curry, Nicola, Czeiter, Endre, Czosnyka, Marek, Dahyot-Fizelier, Claire, Dark, Paul, Dawes, Helen, De Keyser, Véronique, Degos, Vincent, Della Corte, Francesco, Boogert, Hugo den, Depreitere, Bart, Đilvesi, Đula, Dixit, Abhishek, Donoghue, Emma, Dreier, Jens, Dulière, Guy-Loup, Ercole, Ari, Esser, Patrick, Ezer, Erzsébet, Fabricius, Martin, Feigin, Valery L., Foks, Kelly, Frisvold, Shirin, Furmanov, Alex, Gagliardo, Pablo, Galanaud, Damien, Gantner, Dashiell, Gao, Guoyi, George, Pradeep, Ghuysen, Alexandre, Giga, Lelde, Glocker, Ben, Golubović, Jagoš, Gomez, Pedro A., Gratz, Johannes, Gravesteijn, Benjamin, Grossi, Francesca, Gruen, Russell L., Gupta, Deepak, Haagsma, Juanita A., Haitsma, Iain, Helbok, Raimund, Helseth, Eirik, Horton, Lindsay, Huijben, Jilske, Hutchinson, Peter J., Jacobs, Bram, Jankowski, Stefan, Jarrett, Mike, Jiang, Ji-yao, Johnson, Faye, Jones, Kelly, Karan, Mladen, Kolias, Angelos G., Kompanje, Erwin, Kondziella, Daniel, Koskinen, Lars-Owe, Kovács, Noémi, Kowark, Ana, Lagares, Alfonso, Lanyon, Linda, Laureys, Steven, Lecky, Fiona, Ledoux, Didier, Lefering, Rolf, Legrand, Valerie, Lejeune, Aurelie, Levi, Leon, Lightfoot, Roger, Lingsma, Hester, Maegele, Marc, Majdan, Marek, Manara, Alex, Maréchal, Hugues, Martino, Costanza, Mattern, Julia, McFadyen, Charles, McMahon, Catherine, Melegh, Béla, Menovsky, Tomas, Mikolic, Ana, Misset, Benoit, Muraleedharan, Visakh, Murray, Lynnette, Negru, Ancuta, Nelson, David, Newcombe, Virginia, Nieboer, Daan, Nyirádi, József, Oresic, Matej, Ortolano, Fabrizio, Otesile, Olubukola, Parizel, Paul M., Payen, Jean-François, Perera, Natascha, Perlbarg, Vincent, Persona, Paolo, Peul, Wilco, Piippo-Karjalainen, Anna, Pirinen, Matti, Pisica, Dana, Ples, Horia, Polinder, Suzanne, Pomposo, Inigo, Posti, Jussi P., Puybasset, Louis, Rădoi, Andreea, Ragauskas, Arminas, Raj, Rahul, Rambadagalla, Malinka, Rehorčíková, Veronika, Helmrich, Isabel Retel, Rhodes, Jonathan, Richter, Sophie, Rocka, Saulius, Roe, Cecilie, Roise, Olav, Rosenfeld, Jeffrey, Rosenlund, Christina, Rosenthal, Guy, Rossaint, Rolf, Rossi, Sandra, Rueckert, Daniel, Rusnák, Martin, Sahuquillo, Juan, Sakowitz, Oliver, Sanchez-Porras, Renan, Sandor, Janos, Schäfer, Nadine, Schmidt, Silke, Schoechl, Herbert, Schoonman, Guus, Schou, Rico Frederik, Schwendenwein, Elisabeth, Sewalt, Charlie, Singh, Ranjit D., Skandsen, Toril, Smielewski, Peter, Sorinola, Abayomi, Stamatakis, Emmanuel, Stanworth, Simon, Stevens, Robert, Stewart, William, Stocchetti, Nino, Sundström, Nina, Takala, Riikka, Tamás, Viktória, Tamosuitis, Tomas, Taylor, Mark Steven, Te Ao, Braden, Tenovuo, Olli, Theadom, Alice, Thibaut, Aurore, Thomas, Matt, Tibboel, Dick, Timmers, Marjolijn, Tolias, Christos, Trapani, Tony, Tudora, Cristina Maria, Unterberg, Andreas, Vajkoczy, Peter, Valeinis, Egils, Vallance, Shirley, Vámos, Zoltán, van der Jagt, Mathieu, van der Naalt, Joukje, Van der Steen, Gregory, van Dijck, Jeroen T.J.M., van Erp, Inge A., van Essen, Thomas A., Van Hecke, Wim, van Heugten, Caroline, Van Praag, Dominique, van Veen, Ernest, van Wijk, Roel, Vyvere, Thijs Vande, Vargiolu, Alessia, Vega, Emmanuel, Velt, Kimberley, Verheyden, Jan, Vespa, Paul M., Vik, Anne, Vilcinis, Rimantas, Volovici, Victor, von Steinbüchel, Nicole, Voormolen, Daphne, Vulekovic, Peter, Whitehouse, Daniel, Wiegers, Eveline, Williams, Guy, Wolf, Stefan, Yang, Zhihui, Ylén, Peter, Younsi, Alexander, Zeiler, Frederick A., Ziverte, Agate, Zoerle, Tommaso, Adeoye, Opeolu, Badjatia, Neeraj, Barber, Jason, Bergin, Michael, Boase, Kim, Bodien, Yelena, Chesnut, Randall, Corrigan, John, Crawford, Karen, Diaz-Arrastia, Ramon, Dikmen, Sureyya, Duhaime, Ann-Christine, Ellenbogen, Richard, Feeser, Venkata, Ferguson, Adam R., Foreman, Brandon, Gaudette, Etienne, Giacino, Joseph, Gonzalez, Luis, Gopinath, Shankar, Grandhi, Ramesh, Gullapalli, Rao, Hemphill, Claude, Hotz, Gillian, Huie, Russell, Jha, Ruchira, Keene, Dirk C., Kitagawa, Ryan, Korley, Frederick, Kramer, Joel, Kreitzer, Natalie, Levin, Harvey, Lindsell, Chris, Machamer, Joan, Madden, Christopher, Martin, Alastair, McAllister, Thomas, McCrea, Michael, Merchant, Randall, Mukherjee, Pratik, Nelson, Lindsay, Ngwenya, Laura B., Noel, Florence, Nolan, Amber, Okonkwo, David, Palacios, Eva, Perl, Daniel, Puccio, Ava, Rabinowitz, Miri, Robertson, Claudia, Ben Rodgers, Richard, Rosenthal, Eric, Sander, Angelle, Sandsmark, Danielle, Schneider, Andrea, Schnyer, David, Seabury, Seth, Sherer, Mark, Sugar, Gabriella, Temkin, Nancy, Toga, Arthur, Torres-Espin, Abel, Valadka, Alex, Vassar, Mary, Wang, Kevin, Wang, Vincent, Yue, John K., Yuh, Esther, Zafonte, Ross, Kals, Mart, Wilson, Lindsay, Levey, Daniel F., Parodi, Livia, Steyerberg, Ewout W., Richardson, Sylvia, He, Feng, Sun, Xiaoying, Jain, Sonia, Palotie, Aarno, Ripatti, Samuli, Rosand, Jonathan, Manley, Geoff T., Maas, Andrew I.R., Stein, Murray B., and Menon, David K.

Published
2024
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2. A genome-wide association study of outcome from traumatic brain injury

Author

Kals, Mart, Kunzmann, Kevin, Parodi, Livia, Radmanesh, Farid, Wilson, Lindsay, Izzy, Saef, Anderson, Christopher D, Puccio, Ava M, Okonkwo, David O, Temkin, Nancy, Steyerberg, Ewout W, Stein, Murray B, Manley, Geoff T, Maas, Andrew IR, Richardson, Sylvia, Diaz-Arrastia, Ramon, Palotie, Aarno, Ripatti, Samuli, Rosand, Jonathan, Menon, David K, Åkerlund, Cecilia, Amrein, Krisztina, Andelic, Nada, Andreassen, Lasse, Anke, Audny, Antoni, Anna, Audibert, Gérard, Azouvi, Philippe, Azzolini, Maria Luisa, Bartels, Ronald, Barzó, Pál, Beauvais, Romuald, Beer, Ronny, Bellander, Bo-Michael, Belli, Antonio, Benali, Habib, Berardino, Maurizio, Beretta, Luigi, Blaabjerg, Morten, Bragge, Peter, Brazinova, Alexandra, Brinck, Vibeke, Brooker, Joanne, Brorsson, Camilla, Buki, Andras, Bullinger, Monika, Cabeleira, Manuel, Caccioppola, Alessio, Calappi, Emiliana, Calvi, Maria Rosa, Cameron, Peter, Lozano, Guillermo Carbayo, Carbonara, Marco, Cavallo, Simona, Chevallard, Giorgio, Chieregato, Arturo, Citerio, Giuseppe, Clusmann, Hans, Coburn, Mark, Coles, Jonathan P, Cooper, Jamie D, Correia, Marta, Čović, Amra, Curry, Nicola, Czeiter, Endre, Czosnyka, Marek, DahyotFizelier, Claire, Dark, Paul, Dawes, Helen, De Keyser, Véronique, Degos, Vincent, Corte, Francesco Della, Boogert, Hugo den, Depreitere, Bart, Đilvesi, Đula, Dixit, Abhishek, Donoghue, Emma, Dreier, Jens, Dulière, GuyLoup, Ercole, Ari, Esser, Patrick, Ezer, Erzsébet, Fabricius, Martin, Feigin, Valery L, Foks, Kelly, Frisvold, Shirin, Furmanov, Alex, Gagliardo, Pablo, Galanaud, Damien, Gantner, Dashiell, Gao, Guoyi, George, Pradeep, Ghuysen, Alexandre, Giga, Lelde, Glocker, Ben, Golubovic, Jagoš, Gomez, Pedro A, Gratz, Johannes, Gravesteijn, Benjamin, and Grossi, Francesca

Subjects
Epidemiology, Health Sciences, Traumatic Head and Spine Injury, Genetics, Physical Injury - Accidents and Adverse Effects, Neurosciences, Brain Disorders, Human Genome, Traumatic Brain Injury (TBI), Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Brain Injuries, Traumatic, Genome-Wide Association Study, Humans, Mannose-Binding Lectin, Prospective Studies, Transcriptome, Traumatic brain injury, Genome-Wide association study, Outcome, Recovery, Consortia, Genetic Associations In Neurotrauma (GAIN) Consortium, Clinical Sciences, Public Health and Health Services, Clinical sciences
Abstract

BackgroundFactors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias.MethodsWe performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography.FindingsThe estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10-8), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10-5). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10-4).InterpretationWhile multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Published
2022

3. FAIR Data Reuse in Traumatic Brain Injury: Exploring Inflammation and Age as Moderators of Recovery in the TRACK-TBI Pilot

Author

Huie, J Russell, Chou, Austin, Torres-Espin, Abel, Nielson, Jessica L, Yuh, Esther L, Gardner, Raquel C, Diaz-Arrastia, Ramon, Manley, Geoff T, Ferguson, Adam R, and Investigators, The TRACK-TBI

Subjects
Neurosciences, Brain Disorders, Traumatic Head and Spine Injury, Traumatic Brain Injury (TBI), Physical Injury - Accidents and Adverse Effects, Rehabilitation, Aging, Inflammatory and immune system, Injuries and accidents, leveraging data science for traumatic brain injury prevention, evidence based healthcare, precision medicine, data sharing, aging, inflammation, proteomics, outcomes, TRACK-TBI Investigators, Clinical Sciences, Psychology
Abstract

The guiding principle for data stewardship dictates that data be FAIR: findable, accessible, interoperable, and reusable. Data reuse allows researchers to probe data that may have been originally collected for other scientific purposes in order to gain novel insights. The current study reuses the Transforming Research and Clinical Knowledge for Traumatic Brain Injury (TRACK-TBI) Pilot dataset to build upon prior findings and ask new scientific questions. Specifically, we have previously used a multivariate analytics approach to multianalyte serum protein data from the TRACK-TBI Pilot dataset to show that an inflammatory ensemble of biomarkers can predict functional outcome at 3 and 6 months post-TBI. We and others have shown that there are quantitative and qualitative changes in inflammation that come with age, but little is known about how this interaction affects recovery from TBI. Here we replicate the prior proteomics findings with improved missing value analyses and non-linear principal component analysis and then expand upon this work to determine whether age moderates the effect of inflammation on recovery. We show that increased age correlates with worse functional recovery on the Glasgow Outcome Scale-Extended (GOS-E) as well as increased inflammatory signature. We then explore the interaction between age and inflammation on recovery, which suggests that inflammation has a more detrimental effect on recovery for older TBI patients.

Published
2021

4. A genome-wide association study of outcome from traumatic brain injury

Author

Åkerlund, Cecilia, Amrein, Krisztina, Andelic, Nada, Andreassen, Lasse, Anke, Audny, Antoni, Anna, Audibert, Gérard, Azouvi, Philippe, Azzolini, Maria Luisa, Bartels, Ronald, Barzó, Pál, Beauvais, Romuald, Beer, Ronny, Bellander, Bo-Michael, Belli, Antonio, Benali, Habib, Berardino, Maurizio, Beretta, Luigi, Blaabjerg, Morten, Bragge, Peter, Brazinova, Alexandra, Brinck, Vibeke, Brooker, Joanne, Brorsson, Camilla, Buki, Andras, Bullinger, Monika, Cabeleira, Manuel, Caccioppola, Alessio, Calappi, Emiliana, Calvi, Maria Rosa, Cameron, Peter, Lozano, Guillermo Carbayo, Carbonara, Marco, Cavallo, Simona, Chevallard, Giorgio, Chieregato, Arturo, Citerio, Giuseppe, Clusmann, Hans, Coburn, Mark, Coles, Jonathan P., Cooper, Jamie D., Correia, Marta, Čović, Amra, Curry, Nicola, Czeiter, Endre, Czosnyka, Marek, DahyotFizelier, Claire, Dark, Paul, Dawes, Helen, De Keyser, Véronique, Degos, Vincent, Corte, Francesco Della, Boogert, Hugo den, Depreitere, Bart, Đilvesi, Đula, Dixit, Abhishek, Donoghue, Emma, Dreier, Jens, Dulière, GuyLoup, Ercole, Ari, Esser, Patrick, Ezer, Erzsébet, Fabricius, Martin, Feigin, Valery L., Foks, Kelly, Frisvold, Shirin, Furmanov, Alex, Gagliardo, Pablo, Galanaud, Damien, Gantner, Dashiell, Gao, Guoyi, George, Pradeep, Ghuysen, Alexandre, Giga, Lelde, Glocker, Ben, Golubovic, Jagoš, Gomez, Pedro A., Gratz, Johannes, Gravesteijn, Benjamin, Grossi, Francesca, Gruen, Russell L., Gupta, Deepak, Haagsma, Juanita A., Haitsma, Iain, Helbok, Raimund, Helseth, Eirik, Horton, Lindsay, Huijben, Jilske, Hutchinson, Peter J.A., Jacobs, Bram, Jankowski, Stefan, Jarrett, Mike, Jiang, Jiyao, Johnson, Faye, Jones, Kelly, Karan, Mladen, Kolias, Angelos G., Kompanje, Erwin, Kondziella, Daniel, Kornaropoulos, Evgenios, Koskinen, LarsOwe, Kovács, Noémi, Kowark, Ana, Lagares, Alfonso, Lanyon, Linda, Laureys, Steven, Lecky, Fiona, Ledoux, Didier, Lefering, Rolf, Legrand, Valerie, Lejeune, Aurelie, Levi, Leon, Lightfoot, Roger, Lingsma, Hester, Maas, Andrew I.R., CastañoLeón, Ana M., Maegele, Marc, Majdan, Marek, Manara, Alex, Martino, Costanza, Maréchal, Hugues, Mattern, Julia, McMahon, Catherine, Melegh, Béla, Menon, David K., Menovsky, Tomas, Mikolic, Ana, Misset, Benoit, Muraleedharan, Visakh, Murray, Lynnette, Negru, Ancuta, Nelson, David, Newcombe, Virginia F.J., Nieboer, Daan, Nyirádi, József, Olubukola, Otesile, Oresic, Matej, Ortolano, Fabrizio, Palotie, Aarno, Parizel, Paul M., Payen, JeanFrançois, Perera, Natascha, Perlbarg, Vincent, Persona, Paolo, Peul, Wilco, Piippo-Karjalainen, Anna, Pirinen, Matti, Pisica, Dana, Ples, Horia, Polinder, Suzanne, Pomposo, Inigo, Posti, Jussi P., Puybasset, Louis, Radoi, Andreea, Ragauskas, Arminas, Raj, Rahul, Rambadagalla, Malinka, Helmrich, Isabel Retel, Rhodes, Jonathan, Richardson, Sylvia, Richter, Sophie, Ripatti, Samuli, Rocka, Saulius, Roe, Cecilie, Roise, Olav, Rosenfeld, Jeffrey V., Rosenlund, Christina, Rosenthal, Guy, Rossaint, Rolf, Rossi, Sandra, Rueckert, Daniel, Rusnák, Martin, Sahuquillo, Juan, Sakowitz, Oliver, SanchezPorras, Renan, Sandor, Janos, Schäfer, Nadine, Schmidt, Silke, Schoechl, Herbert, Schoonman, Guus, Schou, Rico Frederik, Schwendenwein, Elisabeth, Sewalt, Charlie, Skandsen, Toril, Smielewski, Peter, Sorinola, Abayomi, Stamatakis, Emmanuel, Stanworth, Simon, Stevens, Robert, Stewart, William, Steyerberg, Ewout W., Stocchetti, Nino, Sundström, Nina, Takala, Riikka, Tamás, Viktória, Tamosuitis, Tomas, Taylor, Mark Steven, Ao, Braden Te, Tenovuo, Olli, Theadom, Alice, Thomas, Matt, Tibboel, Dick, Timmers, Marjolein, Tolias, Christos, Trapani, Tony, Tudora, Cristina Maria, Unterberg, Andreas, Vajkoczy, Peter, Vallance, Shirley, Valeinis, Egils, Vámos, Zoltán, van der Jagt, Mathieu, van der Steen, Gregory, van der Naalt, Joukje, van Dijck, Jeroen T.J.M., van Essen, Thomas A., Van Hecke, Wim, van Heugten, Caroline, Van Praag, Dominique, van Veen, Ernest, Vyvere, Thijs Vande, van Wijk, Roel P.J., Vargiolu, Alessia, Vega, Emmanuel, Velt, Kimberley, Verheyden, Jan, Vespa, Paul M., Vik, Anne, Vilcinis, Rimantas, Volovici, Victor, von Steinbüchel, Nicole, Voormolen, Daphne, Vulekovic, Petar, Wang, Kevin K.W., Wiegers, Eveline, Williams, Guy, Wilson, Lindsay, Winzeck, Stefan, Wolf, Stefan, Yang, Zhihui, Ylén, Peter, Younsi, Alexander, Zeiler, Frederick A., Zelinkova, Veronika, Ziverte, Agate, Zoerle, Tommaso, Izzy, Saef, Radmanesh, Farid, Frantzén, Janek, Katila, Ari, Maanpää, Henna-Rikka, Tallus, Jussi, Adeoye, Opeolu, Badjatia, Neeraj, Boase, Kim, Barber, Jason, Bodien, Yelena, Chesnut, Randall, Corrigan, John D., Crawford, Karen, Diaz-Arrastia, Ramon, Dikmen, Sureyya, Duhaime, Ann-Christine, Ellenbogen, Richard, Feeser, Ramana, Ferguson, Adam R., Foreman, Brandon, Gardner, Raquel, Gaudette, Etienne, Giacino, Joseph, Goldman, Dana, Gonzalez, Luis, Gopinath, Shankar, Gullapalli, Rao, Hemphill, Claude, Hotz, Gillian, Jain, Sonia, Keene, Dirk, Korley, Frederick K., Kramer, Joel, Kreitzer, Natalie, Levin, Harvey, Lindsell, Chris, Machamer, Joan, Madden, Christopher, Manley, Geoffrey T., Martin, Alastair, McAllister, Thomas, McCrea, Michael, Merchant, Randall, Mukherjee, Pratik, Nelson, Lindsay, Ngwenya, Laura B, Noel, Florence, Nolan, Amber, Okonkwo, David, Palacios, Eva, Perl, Daniel, Puccio, Ava, Rabinowitz, Miri, Robertson, Claudia, Rosand, Jonathan, Sander, Angelle, Satris, Gabriella, Schnyer, David, Seabury, Seth, Sherer, Mark, Stein, Murray, Taylor, Sabrina, Temkin, Nancy, Toga, Arthur, Valadka, Alex, Vassar, Mary, Yue, John K., Yuh, Esther, Zafonte, Ross, Kals, Mart, Kunzmann, Kevin, Parodi, Livia, Anderson, Christopher D., Puccio, Ava M., Okonkwo, David O., Stein, Murray B., and Manley, Geoff T.

Published
2022
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5. An update on diagnostic and prognostic biomarkers for traumatic brain injury

Author

Wang, Kevin K, Yang, Zhihui, Zhu, Tian, Shi, Yuan, Rubenstein, Richard, Tyndall, J Adrian, and Manley, Geoff T

Subjects
Autoimmune Disease, Physical Injury - Accidents and Adverse Effects, Neurodegenerative, Brain Disorders, Dementia, Neurosciences, Traumatic Brain Injury (TBI), Acquired Cognitive Impairment, Clinical Research, Traumatic Head and Spine Injury, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Injuries and accidents, Neurological, Good Health and Well Being, Biomarkers, Brain Injuries, Traumatic, Humans, Liquid Biopsy, Neuroimaging, Prognosis, Severity of Illness Index, traumatic brain injury, diagnostics, theranostics, neurotrauma, Clinical Sciences
Abstract

IntroductionTraumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome. Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, including protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (αII-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The authors discuss biomarker evidence in TBI diagnosis, outcome prognosis and possible identification of post-TBI neurodegernative diseases (e.g. chronic traumatic encephalopathy and Alzheimer's disease), and as theranostic tools in pre-clinical and clinical settings. Expert commentary: A spectrum of biomarkers is now at or near the stage of formal clinical validation of their diagnostic and prognostic utilities in the management of TBI of varied severities including concussions. TBI biomarkers could serve as a theranostic tool in facilitating drug development and treatment monitoring.

Published
2018

6. Prehospital Intubation is Associated with Favorable Outcomes and Lower Mortality in ProTECT III

Author

Denninghoff, Kurt R, Nuño, Tomas, Pauls, Qi, Yeatts, Sharon D, Silbergleit, Robert, Palesch, Yuko Y, Merck, Lisa H, Manley, Geoff T, and Wright, David W

Subjects
Clinical Trials and Supportive Activities, Clinical Research, Physical Injury - Accidents and Adverse Effects, Good Health and Well Being, Adolescent, Adult, Aged, Aged, 80 and over, Brain Injuries, Traumatic, Double-Blind Method, Emergency Medical Services, Female, Humans, Intubation, Intratracheal, Male, Middle Aged, Progesterone, Prognosis, Prospective Studies, Transportation of Patients, Treatment Outcome, United States, Young Adult, prehospital intubation, traumatic brain injury, TBI, air ambulance, ground transport, outcomes, Clinical Sciences, Nursing, Public Health and Health Services, Emergency & Critical Care Medicine
Abstract

ObjectiveTraumatic brain injury (TBI) causes more than 2.5 million emergency department visits, hospitalizations, or deaths annually. Prehospital endotracheal intubation has been associated with poor outcomes in patients with TBI in several retrospective observational studies. We evaluated the relationship between prehospital intubation, functional outcomes, and mortality using high quality data on clinical practice collected prospectively during a randomized multicenter clinical trial.MethodsProTECT III was a multicenter randomized, double-blind, placebo-controlled trial of early administration of progesterone in 882 patients with acute moderate to severe nonpenetrating TBI. Patients were excluded if they had an index GCS of 3 and nonreactive pupils, those with withdrawal of life support on arrival, and if they had documented prolonged hypotension and/or hypoxia. Prehospital intubation was performed as per local clinical protocol in each participating EMS system. Models for favorable outcome and mortality included prehospital intubation, method of transport, index GCS, age, race, and ethnicity as independent variables. Significance was set at α = 0.05. Favorable outcome was defined by a stratified dichotomy of the GOS-E scores in which the definition of favorable outcome depended on the severity of the initial injury.ResultsFavorable outcome was more frequent in the 349 subjects with prehospital intubation (57.3%) than in the other 533 patients (46.0%, p = 0.003). Mortality was also lower in the prehospital intubation group (13.8% v. 19.5%, p = 0.03). Logistic regression analysis of prehospital intubation and mortality, adjusted for index GCS, showed that odds of dying for those with prehospital intubation were 47% lower than for those that were not intubated (OR = 0.53, 95% CI = 0.36-0.78). 279 patients with prehospital intubation were transported by air. Modeling transport method and mortality, adjusted for index GCS, showed increased odds of dying in those transported by ground compared to those transported by air (OR = 2.10, 95% CI = 1.40-3.15). Decreased odds of dying trended among those with prehospital intubation adjusted for transport method, index GCS score at randomization, age, and race/ethnicity (OR = 0.70, 95% CI = 0.37-1.31).ConclusionsIn this study that excluded moribund patients, prehospital intubation was performed primarily in patients transported by air. Prehospital intubation and air medical transport together were associated with favorable outcomes and lower mortality. Prehospital intubation was not associated with increased morbidity or mortality regardless of transport method or severity of injury.

Published
2017

10. A genome-wide association study of outcome from traumatic brain injury

Author

Kals, Mart, primary, Kunzmann, Kevin, additional, Parodi, Livia, additional, Radmanesh, Farid, additional, Wilson, Lindsay, additional, Izzy, Saef, additional, Anderson, Christopher D., additional, Puccio, Ava M., additional, Okonkwo, David O., additional, Temkin, Nancy, additional, Steyerberg, Ewout W., additional, Stein, Murray B., additional, Manley, Geoff T., additional, Maas, Andrew I.R., additional, Richardson, Sylvia, additional, Diaz-Arrastia, Ramon, additional, Palotie, Aarno, additional, Ripatti, Samuli, additional, Rosand, Jonathan, additional, Menon, David K., additional, Åkerlund, Cecilia, additional, Amrein, Krisztina, additional, Andelic, Nada, additional, Andreassen, Lasse, additional, Anke, Audny, additional, Antoni, Anna, additional, Audibert, Gérard, additional, Azouvi, Philippe, additional, Azzolini, Maria Luisa, additional, Bartels, Ronald, additional, Barzó, Pál, additional, Beauvais, Romuald, additional, Beer, Ronny, additional, Bellander, Bo-Michael, additional, Belli, Antonio, additional, Benali, Habib, additional, Berardino, Maurizio, additional, Beretta, Luigi, additional, Blaabjerg, Morten, additional, Bragge, Peter, additional, Brazinova, Alexandra, additional, Brinck, Vibeke, additional, Brooker, Joanne, additional, Brorsson, Camilla, additional, Buki, Andras, additional, Bullinger, Monika, additional, Cabeleira, Manuel, additional, Caccioppola, Alessio, additional, Calappi, Emiliana, additional, Calvi, Maria Rosa, additional, Cameron, Peter, additional, Lozano, Guillermo Carbayo, additional, Carbonara, Marco, additional, Cavallo, Simona, additional, Chevallard, Giorgio, additional, Chieregato, Arturo, additional, Citerio, Giuseppe, additional, Clusmann, Hans, additional, Coburn, Mark, additional, Coles, Jonathan P., additional, Cooper, Jamie D., additional, Correia, Marta, additional, Čović, Amra, additional, Curry, Nicola, additional, Czeiter, Endre, additional, Czosnyka, Marek, additional, DahyotFizelier, Claire, additional, Dark, Paul, additional, Dawes, Helen, additional, De Keyser, Véronique, additional, Degos, Vincent, additional, Corte, Francesco Della, additional, Boogert, Hugo den, additional, Depreitere, Bart, additional, Đilvesi, Đula, additional, Dixit, Abhishek, additional, Donoghue, Emma, additional, Dreier, Jens, additional, Dulière, GuyLoup, additional, Ercole, Ari, additional, Esser, Patrick, additional, Ezer, Erzsébet, additional, Fabricius, Martin, additional, Feigin, Valery L., additional, Foks, Kelly, additional, Frisvold, Shirin, additional, Furmanov, Alex, additional, Gagliardo, Pablo, additional, Galanaud, Damien, additional, Gantner, Dashiell, additional, Gao, Guoyi, additional, George, Pradeep, additional, Ghuysen, Alexandre, additional, Giga, Lelde, additional, Glocker, Ben, additional, Golubovic, Jagoš, additional, Gomez, Pedro A., additional, Gratz, Johannes, additional, Gravesteijn, Benjamin, additional, Grossi, Francesca, additional, Gruen, Russell L., additional, Gupta, Deepak, additional, Haagsma, Juanita A., additional, Haitsma, Iain, additional, Helbok, Raimund, additional, Helseth, Eirik, additional, Horton, Lindsay, additional, Huijben, Jilske, additional, Hutchinson, Peter J.A., additional, Jacobs, Bram, additional, Jankowski, Stefan, additional, Jarrett, Mike, additional, Jiang, Jiyao, additional, Johnson, Faye, additional, Jones, Kelly, additional, Karan, Mladen, additional, Kolias, Angelos G., additional, Kompanje, Erwin, additional, Kondziella, Daniel, additional, Kornaropoulos, Evgenios, additional, Koskinen, LarsOwe, additional, Kovács, Noémi, additional, Kowark, Ana, additional, Lagares, Alfonso, additional, Lanyon, Linda, additional, Laureys, Steven, additional, Lecky, Fiona, additional, Ledoux, Didier, additional, Lefering, Rolf, additional, Legrand, Valerie, additional, Lejeune, Aurelie, additional, Levi, Leon, additional, Lightfoot, Roger, additional, Lingsma, Hester, additional, CastañoLeón, Ana M., additional, Maegele, Marc, additional, Majdan, Marek, additional, Manara, Alex, additional, Martino, Costanza, additional, Maréchal, Hugues, additional, Mattern, Julia, additional, McMahon, Catherine, additional, Melegh, Béla, additional, Menovsky, Tomas, additional, Mikolic, Ana, additional, Misset, Benoit, additional, Muraleedharan, Visakh, additional, Murray, Lynnette, additional, Negru, Ancuta, additional, Nelson, David, additional, Newcombe, Virginia F.J., additional, Nieboer, Daan, additional, Nyirádi, József, additional, Olubukola, Otesile, additional, Oresic, Matej, additional, Ortolano, Fabrizio, additional, Parizel, Paul M., additional, Payen, JeanFrançois, additional, Perera, Natascha, additional, Perlbarg, Vincent, additional, Persona, Paolo, additional, Peul, Wilco, additional, Piippo-Karjalainen, Anna, additional, Pirinen, Matti, additional, Pisica, Dana, additional, Ples, Horia, additional, Polinder, Suzanne, additional, Pomposo, Inigo, additional, Posti, Jussi P., additional, Puybasset, Louis, additional, Radoi, Andreea, additional, Ragauskas, Arminas, additional, Raj, Rahul, additional, Rambadagalla, Malinka, additional, Helmrich, Isabel Retel, additional, Rhodes, Jonathan, additional, Richter, Sophie, additional, Rocka, Saulius, additional, Roe, Cecilie, additional, Roise, Olav, additional, Rosenfeld, Jeffrey V., additional, Rosenlund, Christina, additional, Rosenthal, Guy, additional, Rossaint, Rolf, additional, Rossi, Sandra, additional, Rueckert, Daniel, additional, Rusnák, Martin, additional, Sahuquillo, Juan, additional, Sakowitz, Oliver, additional, SanchezPorras, Renan, additional, Sandor, Janos, additional, Schäfer, Nadine, additional, Schmidt, Silke, additional, Schoechl, Herbert, additional, Schoonman, Guus, additional, Schou, Rico Frederik, additional, Schwendenwein, Elisabeth, additional, Sewalt, Charlie, additional, Skandsen, Toril, additional, Smielewski, Peter, additional, Sorinola, Abayomi, additional, Stamatakis, Emmanuel, additional, Stanworth, Simon, additional, Stevens, Robert, additional, Stewart, William, additional, Stocchetti, Nino, additional, Sundström, Nina, additional, Takala, Riikka, additional, Tamás, Viktória, additional, Tamosuitis, Tomas, additional, Taylor, Mark Steven, additional, Ao, Braden Te, additional, Tenovuo, Olli, additional, Theadom, Alice, additional, Thomas, Matt, additional, Tibboel, Dick, additional, Timmers, Marjolein, additional, Tolias, Christos, additional, Trapani, Tony, additional, Tudora, Cristina Maria, additional, Unterberg, Andreas, additional, Vajkoczy, Peter, additional, Vallance, Shirley, additional, Valeinis, Egils, additional, Vámos, Zoltán, additional, van der Jagt, Mathieu, additional, van der Steen, Gregory, additional, van der Naalt, Joukje, additional, van Dijck, Jeroen T.J.M., additional, van Essen, Thomas A., additional, Van Hecke, Wim, additional, van Heugten, Caroline, additional, Van Praag, Dominique, additional, van Veen, Ernest, additional, Vyvere, Thijs Vande, additional, van Wijk, Roel P.J., additional, Vargiolu, Alessia, additional, Vega, Emmanuel, additional, Velt, Kimberley, additional, Verheyden, Jan, additional, Vespa, Paul M., additional, Vik, Anne, additional, Vilcinis, Rimantas, additional, Volovici, Victor, additional, von Steinbüchel, Nicole, additional, Voormolen, Daphne, additional, Vulekovic, Petar, additional, Wang, Kevin K.W., additional, Wiegers, Eveline, additional, Williams, Guy, additional, Winzeck, Stefan, additional, Wolf, Stefan, additional, Yang, Zhihui, additional, Ylén, Peter, additional, Younsi, Alexander, additional, Zeiler, Frederick A., additional, Zelinkova, Veronika, additional, Ziverte, Agate, additional, Zoerle, Tommaso, additional, Frantzén, Janek, additional, Katila, Ari, additional, Maanpää, Henna-Rikka, additional, Tallus, Jussi, additional, Adeoye, Opeolu, additional, Badjatia, Neeraj, additional, Boase, Kim, additional, Barber, Jason, additional, Bodien, Yelena, additional, Chesnut, Randall, additional, Corrigan, John D., additional, Crawford, Karen, additional, Dikmen, Sureyya, additional, Duhaime, Ann-Christine, additional, Ellenbogen, Richard, additional, Feeser, Ramana, additional, Ferguson, Adam R., additional, Foreman, Brandon, additional, Gardner, Raquel, additional, Gaudette, Etienne, additional, Giacino, Joseph, additional, Goldman, Dana, additional, Gonzalez, Luis, additional, Gopinath, Shankar, additional, Gullapalli, Rao, additional, Hemphill, Claude, additional, Hotz, Gillian, additional, Jain, Sonia, additional, Keene, Dirk, additional, Korley, Frederick K., additional, Kramer, Joel, additional, Kreitzer, Natalie, additional, Levin, Harvey, additional, Lindsell, Chris, additional, Machamer, Joan, additional, Madden, Christopher, additional, Manley, Geoffrey T., additional, Martin, Alastair, additional, McAllister, Thomas, additional, McCrea, Michael, additional, Merchant, Randall, additional, Mukherjee, Pratik, additional, Nelson, Lindsay, additional, Ngwenya, Laura B, additional, Noel, Florence, additional, Nolan, Amber, additional, Okonkwo, David, additional, Palacios, Eva, additional, Perl, Daniel, additional, Puccio, Ava, additional, Rabinowitz, Miri, additional, Robertson, Claudia, additional, Sander, Angelle, additional, Satris, Gabriella, additional, Schnyer, David, additional, Seabury, Seth, additional, Sherer, Mark, additional, Stein, Murray, additional, Taylor, Sabrina, additional, Toga, Arthur, additional, Valadka, Alex, additional, Vassar, Mary, additional, Yue, John K., additional, Yuh, Esther, additional, and Zafonte, Ross, additional

Published
2022
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11. Association Between TBI-Related Hearing Impairment and Cognition: A TRACK-TBI Study.

Author

Hwang, Phillip H., Nelson, Lindsay D., Sharon, Jeffrey D., McCrea, Michael A., Dikmen, Sureyya S., Markowitz, Amy J., Manley, Geoff T., and Temkin, Nancy R.

Abstract

Objective: To examine the association between hearing impairment and cognitive function after traumatic brain injury (TBI). Setting: A total of 18 level I trauma centers throughout the United States in the T ransforming R esearch a nd C linical K nowledge in TBI (TRACK-TBI) study. Participants: From February 2014 to June 2018, a total of 2697 participants with TBI were enrolled in TRACK-TBI. Key eligibility criteria included external force trauma to the head, presentation to a participating level I trauma center, and receipt of a clinically indicated head computed tomographic (CT) scan within 24 hours of injury. A total of 1267 participants were evaluated in the study, with 216 participants with hearing impairment and 1051 participants without hearing impairment. Those with missing or unknown hearing status or cognitive assessment were excluded from analysis. Design: Prospective, observational cohort study. Main Measures: Hearing impairment at 2 weeks post-TBI was based on self-report. Participants who indicated worse hearing in one or both ears were defined as having hearing impairment, whereas those who denied worse hearing in either ear were defined as not having hearing impairment and served as the reference group. Cognitive outcomes at 6 months post-TBI included executive functioning and processing speed, as measured by the Trail Making Test (TMT) B/A and the Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index subscale (WAIS-IV PSI), respectively. Results: TBI-related hearing impairment had a small but significantly greater TMT B/A ratio than without TBI-related hearing impairment: mean difference (B) = 0.25; 95% CI, 0.07 to 0.43; P =.005. No significant mean differences on WAIS-IV PSI scores were found between participants with and without TBI-related hearing impairment: B = 0.36; 95% CI, −2.07 to 2.60; P =.825. Conclusion: We conclude that TBI-related hearing impairment at 6 months postinjury was significantly associated with worse executive functioning but not cognitive processing speed. [ABSTRACT FROM AUTHOR]

Published
2022
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13. FAIR Data Reuse in Traumatic Brain Injury: Exploring Inflammation and Age as Moderators of Recovery in the TRACK-TBI Pilot.

Author

Huie, J. Russell, Chou, Austin, Torres-Espin, Abel, Nielson, Jessica L., Yuh, Esther L., Gardner, Raquel C., Diaz-Arrastia, Ramon, Manley, Geoff T., and Ferguson, Adam R.

Subjects
BRAIN injuries, PRINCIPAL components analysis, MEDICAL research, INFLAMMATION, BLOOD proteins
Abstract

The guiding principle for data stewardship dictates that data be FAIR: findable, accessible, interoperable, and reusable. Data reuse allows researchers to probe data that may have been originally collected for other scientific purposes in order to gain novel insights. The current study reuses the Transforming Research and Clinical Knowledge for Traumatic Brain Injury (TRACK-TBI) Pilot dataset to build upon prior findings and ask new scientific questions. Specifically, we have previously used a multivariate analytics approach to multianalyte serum protein data from the TRACK-TBI Pilot dataset to show that an inflammatory ensemble of biomarkers can predict functional outcome at 3 and 6 months post-TBI. We and others have shown that there are quantitative and qualitative changes in inflammation that come with age, but little is known about how this interaction affects recovery from TBI. Here we replicate the prior proteomics findings with improved missing value analyses and non-linear principal component analysis and then expand upon this work to determine whether age moderates the effect of inflammation on recovery. We show that increased age correlates with worse functional recovery on the Glasgow Outcome Scale-Extended (GOS-E) as well as increased inflammatory signature. We then explore the interaction between age and inflammation on recovery, which suggests that inflammation has a more detrimental effect on recovery for older TBI patients. [ABSTRACT FROM AUTHOR]

Published
2021
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14. Consensus statement on concussion in sport—the 5 th international conference on concussion in sport held in Berlin, October 2016

Author

Manley, Geoff T, Tator, Charles H, Echemendia, Ruben J, Nagahiro, Shinji, Aubry, Mark, McCrea, Michael, Engebretsen, Lars, Makdissi, Michael, Davis, Gavin A, Patricios, Jon, Sills, Allen, Bailes, Julian, Cassidy, David, Castellani, Rudy J, Iverson, Grant L, Feddermann-Demont, Nina, Cantu, Robert C, Meeuwisse, Willem, Broglio, Steven, Maddocks, David, Kutcher, Jeffrey, Emery, Carolyn, Herring, Stanley, Putukian, Margot, Guskiewicz, Kevin M, Leddy, John J, Meehan, William P, McCrory, Paul, Dvořák, Jiří, Vos, Pieter E, Giza, Christopher C, Johnston, Karen M, Kissick, James, Schneider, Kathryn J, Turner, Michael, and Ellenbogen, Richard

Abstract

The 2017 Concussion in Sport Group (CISG) consensus statement is designed to build on the principles outlined in the previous statements1–4 and to develop further conceptual understanding of sport-related concussion (SRC) using an expert consensus-based approach. This document is developed for physicians and healthcare providers who are involved in athlete care, whether at a recreational, elite or professional level. While agreement exists on the principal messages conveyed by this document, the authors acknowledge that the science of SRC is evolving and therefore individual management and return-to-play decisions remain in the realm of clinical judgement. This consensus document reflects the current state of knowledge and will need to be modified as new knowledge develops. It provides an overview of issues that may be of importance to healthcare providers involved in the management of SRC. This paper should be read in conjunction with the systematic reviews and methodology paper that accompany it. First and foremost, this document is intended to guide clinical practice; however, the authors feel that it can also help form the agenda for future research relevant to SRC by identifying knowledge gaps.

Published
2017
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16. Consensus statement on concussion in sport—the 5thinternational conference on concussion in sport held in Berlin, October 2016

Author

McCrory, Paul, primary, Meeuwisse, Willem, additional, Dvorak, Jiří, additional, Aubry, Mark, additional, Bailes, Julian, additional, Broglio, Steven, additional, Cantu, Robert C, additional, Cassidy, David, additional, Echemendia, Ruben J, additional, Castellani, Rudy J, additional, Davis, Gavin A, additional, Ellenbogen, Richard, additional, Emery, Carolyn, additional, Engebretsen, Lars, additional, Feddermann-Demont, Nina, additional, Giza, Christopher C, additional, Guskiewicz, Kevin M, additional, Herring, Stanley, additional, Iverson, Grant L, additional, Johnston, Karen M, additional, Kissick, James, additional, Kutcher, Jeffrey, additional, Leddy, John J, additional, Maddocks, David, additional, Makdissi, Michael, additional, Manley, Geoff T, additional, McCrea, Michael, additional, Meehan, William P, additional, Nagahiro, Sinji, additional, Patricios, Jon, additional, Putukian, Margot, additional, Schneider, Kathryn J, additional, Sills, Allen, additional, Tator, Charles H, additional, Turner, Michael, additional, and Vos, Pieter E, additional

Published
2017
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17. The diagnostic values of UCH-L1 in traumatic brain injury: A meta-analysis.

Author

Shahjouei, Shima, Sadeghi-Naini, Mohsen, Yang, Zhihui, Kobeissy, Firas, Rathore, Disa, Shokraneh, Farhad, Blackburn, Spiros, Manley, Geoff T, and Wang, Kevin K.W.

Subjects
BRAIN injuries, BIOMARKERS, COMPUTED tomography, DIAGNOSIS, MEDICAL information storage & retrieval systems, MEDLINE, META-analysis, SYSTEMATIC reviews
Abstract

Traumatic brain injury (TBI) is a major health concern. The purpose of this study is to identify the diagnostic accuracy of ubiquitin C-terminal hydrolase-L1 (UCH-L1)—a protein biomarker—in comparison with CT-scan findings post-TBI. Accordingly, we conducted a systematic review of eligible studies and assessed the risk of bias according to the QUADAS-2 checklist. A total of 13 reports from 10 original studies were included. Based on our analysis, serum UCH-L1 has a high accuracy in predicting CT findings in mild to moderate TBI. Based on the QUADAS-2 checklist, this result has a high risk of bias affecting its applicability. The plasma level of UCH-L1 has moderate accuracy in predicting CT findings when assessed in all GCS levels. This result has a low risk of bias and low concerns regarding applicability. Pooled analysis suggests that the plasma/serum UCH-L1 level has high accuracy in predicting CT findings in a wide range of GCS in patients with TBI. This result has a high risk of bias and high concern about its applicability. The heterogeneity in approaching TBI biomarker interferes with drawing a definitive conclusion. Therefore, although UCH-L1 is a promising blood-based diagnostic biomarker for TBI, but due to differences in reported diagnostic accuracy, further studies are needed to recommend UCH-L1 as an alternative to CT scanning. [ABSTRACT FROM PUBLISHER]

Published
2018
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20. Consensus statement on concussion in sport-the 5 th international conference on concussion in sport held in Berlin, October 2016.

Author

McCrory P, Meeuwisse W, Dvořák J, Aubry M, Bailes J, Broglio S, Cantu RC, Cassidy D, Echemendia RJ, Castellani RJ, Davis GA, Ellenbogen R, Emery C, Engebretsen L, Feddermann-Demont N, Giza CC, Guskiewicz KM, Herring S, Iverson GL, Johnston KM, Kissick J, Kutcher J, Leddy JJ, Maddocks D, Makdissi M, Manley GT, McCrea M, Meehan WP, Nagahiro S, Patricios J, Putukian M, Schneider KJ, Sills A, Tator CH, Turner M, and Vos PE

Subjects
Berlin, Consensus, Humans, Sports, Athletic Injuries diagnosis, Athletic Injuries therapy, Brain Concussion diagnosis, Brain Concussion therapy
Abstract

Competing Interests: Competing interests: For full author disclosures and competing interests see the online supplementary folder ICMJE forms on the BJSM website (http://dx.doi.org/10.1136/bjsports-2017-097699).

Published
2017
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