Sensitive Troponin I Assay in Early Diagnosis of Acute Myocardial Infarction

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Sensitive Troponin I Assay in Early Diagnosis
of Acute Myocardial Infarction

• Journal Club
• Mohammed AlShamsi
• R4

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OUTLINES

• Receiver-Operating-Characteristic Curves (ROC).
• Introduction.
• Methods.
• Statistical Analysis.
• Results.
• Critical appraisal.

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Receiver Operating Characteristic Curve (ROC)

• The name "Receiver Operating Characteristic" came
  from "Signal Detection Theory" developed during
  World War II for the analysis of radar images.
• Radar operators had to decide whether a blip on
  the screen represented an enemy target, a
  friendly ship, or just noise.
• Signal detection theory measures the ability of
  radar receiver operators to make these important
  distinctions. Their ability to do so was called
  the Receiver Operating Characteristics.

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• ROC curves were developed in the 1950's as a
  by-product of research into making sense of radio
  signals contaminated by noise.
• During 1970's that signal detection theory was
  recognized as useful for interpreting medical
  test results.
• More recently it's become clear that they are
  remarkably useful in medical decision-making

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• ROC curves plot the sensitivity of a test versus
  its false positive rate for various points
• ROC analysis has wide applicability in radiology
  research for comparing observers, modalities, and
  tests.

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T4 value Hypothyroid Euthyroid
5 or less 18 1
5.1 - 7 7 17
7.1 - 9 4 36
9 or more 3 39
Totals 32 93
T4 value Hypothyroid Euthyroid
5 or less 18 1
gt 5 14 92
Totals 32 93
T4 value Hypothyroid Euthyroid
7 or less 25 18
gt 7 7 75
Totals 32 93
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Cutoff Level Sensitivity Specificity
5 0.563 0.989
7 0.781 0.806
9 0.906 0.419
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• The sensitivity and specificity of a diagnostic
  test depends on more than just the "quality" of
  the test.
• They also depend on the definition of what
  constitutes an abnormal test.
• No test distinguish normal from disease with
  100 accuracy.
• The area of overlap indicates where the test
  cannot distinguish normal from disease.

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• This graph shows three ROC curves representing
  excellent, good, and worthless tests plotted on
  the same graph.
• The accuracy of the test depends on how well the
  test separates the group being tested into those
  with and without the disease in question.
• Accuracy is measured by the area under the ROC
  curve. An area of 1 represents a perfect test an
  area of .5 represents a worthless test.
• A rough guide for classifying the accuracy of a
  diagnostic test is the traditional academic point
  system
• 0.90 1.00 excellent
• 0.80 - 0.90 good
• 0.70 - 0.80 fair
• 0.60 - 0.70 poor

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Introduction

• Cardiac troponin testing is central to the
  diagnosis of acute myocardial infarction
• An early diagnosis of AMI facilitates rapid
  decision making and treatment and therefore
  improves the outcome in patients presenting with
  chest pain.
• Introduction of cardiac markers is a milestone in
  cardiology.
• The sensitivity of the available cardiac markers
  is weak within the first hours after the onset of
  chest pain

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• ????????
• Is Sensitive trop sensitive enough?

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MethodsStudy Population.

• They enrolled 1818 consecutive patients
  presenting with new-onset chest pain at
  chest-pain units at three German study centers
  between January 2007 and December 2008
• Study was approved by local ethics committees
• All patients provided written informed consent

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• Inclusion
• Age between 18 to 85 years
• Angina pectoris or equivalent
• Exclusion criteria
• Major surgery or trauma within the previous 4
  weeks
• Pregnancy
• IV drug abuse
• Hemoglobin level lt10 g/dL.

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• Blood was drawn for routine blood work and
  sample storage at admission, 3 and 6 hours after
  
• Concordantly, a 12-lead ECG was obtained.
• All patients were followed up 30 days after
  initial hospitalization
• Additionally , the local civil registry office
  provided information about death.
• Follow-up information was available in 98 of
  the population.

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• Outcome measures
• composite of death.
• MI.
• Stroke.
• Hospital admission because of cardio-vascular
  reasons .
• Need for unplanned coronary intervention

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• Chest pain onset time was carefully assessed by
  independent research staff.
• Troponin I Ultra was purchased from Siemens
  Healthcare Diagnostics, which had no role in the
  design of the study or analysis of the results.

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In-house troponin

• TropT (Roche Diagnostics, Germany) or
• Trop I (Siemens Healthcare Diagnostics).
• Detection limits are 0.01 ng/mL (Troponin T) and
  0.04 ng/mL (Troponin I) with assay ranges of
  0.01-25 ng/mL (Troponin T) and 0.04-40 ng/mL
  (Troponin I), respectively.
• Reference limits based on the 99th percentile for
  a healthy population are 0.01 ng/mL (Troponin T)
  and 0.07 ng/mL (Troponin I) with 10 CV cut-offs
  of 0.03 ng/mL (Troponin T) and 0.14 ng/mL
  (Troponin I), respectively.

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Laboratory Methods

• Investigational troponin
• Investigational troponin I was measured with the
  TnI-Ultra assay on an ADVIA Centaur XP system
  (Siemens Healthcare Diagnostics, Germany).
• The assay range is 0.006-50 ng/mL.
• The reference limit based on the 99th percentile
  for a healthy population is 0.04 ng/mL

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Adjudication of the Final Diagnosis

• Based on all available clinical, laboratory, and
  imaging findings
• Adjudicated by an expert committee of two
  independent cardiologists who were unaware of the
  results of the troponin I assays

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Diagnosis Based on Conventional Troponin Assays

• Primary diagnosis of AMI was adjudicated
  according to current guidelines .
• Evidence of myocardial necrosis
  that was consistent with
• myocardial ischemia,
  together with clinical symptoms
• of
  ischemia
• 
  or
• ECG changes indicative of new
  ischemia (new ST-segment or T-wave
• changes or
  new LBBB)
• 
  or
• Imaging evidence of new loss of
  viable myocardium
• 
  or
• Detection of a culprit lesion on
  coronary angiography

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Diagnosis Based on Sensitive Troponin I Assay

• They used the concentration of 0.04 ng per mL
  as the upper reference limit and established the
  diagnosis of myocardial infarction if one value
  of more than 0.04 ng per mL was documented,
• combined with a rise or fall in the value of
  30 or more within 6 hours after admission.

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Statistical Analysis

• Skewed variables were described by median and
  interquartile range.
• Normally distributed variables were characterized
  by their arithmetic mean and standard deviation.
  
• They calculated ROC curves on the basis of the
  continuously measured biomarker levels by taking
  every measured biomarker level as a cutoff value
  and then deriving sensitivity and specificity
  values from the resulting two-by-two tables for
  each cutoff value.
• The diagnosis variable used for the two by two
  tables contrasted non-coronary chest pain against
  acute myocardial infarction.

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• P values are based on the Wald z-test statistic
• All statistical analyses were performed with the
  use of R software (version 2.8.1) and SAS
  software (version 9.2).

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Results
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Low or Moderate Troponin I Levels
585 pts
86 pts
0-006-0.04
6H
Moder. Elevated. (gt0.04 ) without rise or fall
(lt30)in repeated testing.
115 pt gt 0.04
30 pts diagnosed as AMI according to trop T
62 had a distinct non-coronary diagnosis
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Short-Term Outcome

• A troponin I level of more than 0.04 ng per
  milliliter was independently associated with an
  increased risk of an adverse outcome at 30 days
  (hazard ratio, 1.96 95 confidence interval,
  1.27 to 3.05 P0.003).

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Assessment of validity
Was there an independent, blind comparison with a reference standard (gold standard) of diagnosis?
Was the diagnostic test evaluated in an appropriate spectrum of patients?
Were all patients analyzed in the groups to which they were randomized (intention to treat analysis)?
Was the test, or group of tests, validated in a second, independent group of patients?
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Assessment of importance of the results

• Are likelihood ratios or data necessary for their
  calculation provided for the diagnostic test?

Target Disorder Target Disorder Totals
Present Absent Totals
Diagnostic Test Result Positive a b ab
Diagnostic Test Result Negative c d cd
Totals Totals ac bd abcd
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Sensitivity a/(ac)
Specificity d/(bd)
Likelihood ratio for a positive test result LR sens/(1-spec)
Likelihood ratio for a negative test result LR - (1-sens)/spec
Positive Predictive Value a/(ab)
Negative Predictive Value d/(cd)
Pre-test probability (prevalence) (ac)/(abcd)
Post-test oddsprevalence/(1-prevlance) x LR
Post-test probability post-test odds/(post-test odds 1)
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Assessment of Utility
Will the reproducibility of the test result and its interpretation be satisfactory in my setting?
Are the results applicable to my patient?
Will the results change my management?
Will patients be better off as a result of the test?