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      Serum biomarkers in patients suspected of transient ischaemic attack in primary care: a diagnostic accuracy study

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          Abstract

          Objective

          The diagnosis of transient ischaemic attack (TIA) based on symptoms and signs can be challenging and would greatly benefit from a rapid serum biomarker of brain ischaemia. We aimed to quantify the added diagnostic value of serum biomarkers in patients suspected of TIA beyond symptoms and signs.

          Methods

          This is a cross-sectional diagnostic accuracy study with a 6-month follow-up period. Participants were patients suspected of TIA by the general practitioner (GP) in whom a blood sample could be collected within 72 hours from symptom onset. A research nurse visited the participant for the blood sample and a standardised interview. The GP referred participants to the regional TIA service. An expert panel of three neurologists classified cases as TIA, minor stroke or any other diagnosis, based on all available diagnostic information including the GP’s and neurologist’s correspondence and the follow-up period. We used multivariable logistic regression analyses to quantify the diagnostic accuracy of clinical predictors and the improvement of accuracy by seven biomarkers (NR2, NR2 antibodies, PARK7, NDKA, UFD1, B-FABP and H-FABP).

          Results

          206 patients suspected of TIA participated, of whom 126 (61.2%) were diagnosed with TIA (n=104) or minor stroke (n=22) by the expert panel. The median time from symptom onset to the blood sample collection was 48.0 (IQR 28.3–56.8) hours. None of the seven biomarkers had discriminative value in the diagnosis of TIA, with C-statistics ranging from 0.45 to 0.58. The final multivariable model (C-statistic 0.83 (0.78–0.89)) consisted of eight clinical predictors of TIA/minor stroke: increasing age, a history of coronary artery disease, sudden onset of symptoms, occurrence of symptoms in full intensity, dysarthria, no history of migraine, absence of loss of consciousness and absence of headache. Addition of the individual biomarkers did not further increase the C-statistics.

          Conclusions

          Currently available blood biomarkers have no added diagnostic value in suspected TIA.

          Trial registration number

          NCT01954329

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          Most cited references18

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          Regression modelling strategies for improved prognostic prediction.

          Regression models such as the Cox proportional hazards model have had increasing use in modelling and estimating the prognosis of patients with a variety of diseases. Many applications involve a large number of variables to be modelled using a relatively small patient sample. Problems of overfitting and of identifying important covariates are exacerbated in analysing prognosis because the accuracy of a model is more a function of the number of events than of the sample size. We used a general index of predictive discrimination to measure the ability of a model developed on training samples of varying sizes to predict survival in an independent test sample of patients suspected of having coronary artery disease. We compared three methods of model fitting: (1) standard 'step-up' variable selection, (2) incomplete principal components regression, and (3) Cox model regression after developing clinical indices from variable clusters. We found regression using principal components to offer superior predictions in the test sample, whereas regression using indices offers easily interpretable models nearly as good as the principal components models. Standard variable selection has a number of deficiencies.
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            Transient Ischemic Attack versus Transient Ischemic Attack Mimics: Frequency, Clinical Characteristics and Outcome

            Background: There is insufficient evidence regarding which clinical features are best suited to distinguish between transient ischemic attack (TIA) and disorders mimicking TIA (TIA mimics). Methods: We compared the frequency, clinical characteristics and outcome of patients with TIA and TIA mimics in a prospective, single-center emergency department cohort over 2 years. Results: Of 303 patients, 248 (81.8%) had a TIA and 55 (18.2%) had TIA mimics. Epileptic seizures (26/55; 43.7%) and migraine attacks (13/55; 23.6%) were the most common TIA mimics. In patients presenting with unilateral paresis, TIA mimics were less likely than in patients without unilateral paresis [odds ratio (OR) 0.35, 95% confidence interval (CI) 0.17–0.68]. Memory loss (OR 9.17, 95% CI 2.89–32.50), headache (OR 3.71, 95% CI 1.07–12.78) and blurred vision (OR 2.48, 95% CI 0.90–6.59) increased the odds of TIA mimics. Once these clinical features were taken into account, neither aphasia, dysarthria, sensory loss, blood pressure values nor the duration of symptoms were found to improve explanation of the underlying status. At 3 months, stroke, recurrent TIA and myocardial infarction were absent in patients with TIA mimics but occurred in 13 (5.2%), 20 (8.1%) and 3 (1.2%) TIA patients, respectively. Conclusions: About 1 in every 5 patients with suspected TIA had a TIA mimic. Paresis suggested TIA, while other clinical variables used in risk assessment scores after TIA were not shown to distinguish between the two entities. Patients with TIA mimics had a better short-term prognosis.
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              PARK7 and nucleoside diphosphate kinase A as plasma markers for the early diagnosis of stroke.

              Plasma markers for stroke could be useful in diagnosis and prognosis and in prediction of response of stroke patients to therapy. PARK7 and nucleoside diphosphate kinase A (NDKA) are increased in human postmortem cerebrospinal fluid (CSF), a model of global brain insult, suggesting that measurement in CSF and, more importantly, in plasma may be useful as a biomarker of stroke. We used ELISA to measure PARK7 and NDKA in plasma in 3 independent European and North American retrospective studies encompassing a total of 622 stroke patients and 165 control individuals. Increases in both biomarkers were highly significant, with sensitivities of 54%-91% for PARK7 and 70%-90% for NDKA and specificities of 80%-97% for PARK7 and 90%-97% for NDKA. The concentrations of both biomarkers increased within 3 h of stroke onset. PARK7 and NDKA may be useful plasma biomarkers for the early diagnosis of stroke. In addition, this study demonstrated the utility of analysis of postmortem CSF proteins as a first step in the discovery of plasma markers of ischemic brain injury.
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2019
                17 October 2019
                : 9
                : 10
                : e031774
                Affiliations
                [1 ] departmentJulius Center for Health Sciences and Primary Care , University Medical Center Utrecht, Utrecht University , Utrecht, The Netherlands
                [2 ] departmentDepartment of Neurology , Donders Centre for Neuroscience, Radboud University Medical Center , Nijmegen, The Netherlands
                [3 ] departmentDepartment of Neurology , Amsterdam University Medical Center , Amsterdam, The Netherlands
                [4 ] departmentDepartment of Neurology , University Medical Center Utrecht, Utrecht University , Utrecht, The Netherlands
                Author notes
                [Correspondence to ] Dr Louis Servaas Dolmans; l.s.dolmans@ 123456umcutrecht.nl
                Author information
                http://orcid.org/0000-0001-5255-3852
                Article
                bmjopen-2019-031774
                10.1136/bmjopen-2019-031774
                6803126
                31628130
                119b81cc-f1b5-4408-a2e1-a51212b1b00b
                © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 17 May 2019
                : 18 September 2019
                : 19 September 2019
                Funding
                Funded by: Dutch foundation 'Stoffels-Hornstra';
                Award ID: na
                Funded by: 'Stichting Beroepsopleiding Huisartsen (SBOH)', Dutch employee of GP trainees;
                Award ID: na
                Categories
                Neurology
                Original Research
                1506
                1713
                Custom metadata
                unlocked

                Medicine
                biomarker,tia,minor stroke,diagnostic accuracy,panel
                Medicine
                biomarker, tia, minor stroke, diagnostic accuracy, panel

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