Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee...
-
Upload
griffin-bradley -
Category
Documents
-
view
215 -
download
0
Transcript of Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee...
![Page 1: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/1.jpg)
Management of Neonatal Hyperbilirubinemia
Methods of the AHRQ Evidence Report
FDA Advisory Committee MeetingJune 11, 2003
Joseph Lau, MD
Tufts-New England Medical Center EPC
![Page 2: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/2.jpg)
INVESTIGATORS
Stanley Ip, MD
Mei Chung, MPH
Stephan Glicken, MD
John Kulig, MD
Rebecca O’Brien, MD
Robert Sege, MD, PhD
Joseph Lau, MD
![Page 3: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/3.jpg)
Evidence report process
• Rigorous, comprehensive syntheses and analyses of relevant scientific literature
• Explicit and detailed documentation of methods, rationale, and assumptions
• Scientific syntheses may include meta-analyses and cost analyses
• Broad range of experts is included in the development process
• Reports do NOT make clinical recommendations
![Page 4: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/4.jpg)
Systematic review process
• Formulate well focused study questions
• Establish evidence review protocol (inclusion and exclusion criteria)
• Perform comprehensive literature search
• Screen abstracts and full articles
• Abstract data and perform critical appraisal
• Perform analyses, summarize and interpret results
![Page 5: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/5.jpg)
Key questionsAssociation of neonatal hyperbilirubinemia with
neurodevelopmental outcomes
1. What is the relationship between peak bilirubin levels and/or duration of hyperbilirubinemia and developmental outcome?
2. What is the evidence for effect modification of the results in question 1, by gestational age, hemolysis, serum albumin, and other factors?
![Page 6: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/6.jpg)
Key questions (cont.)Treatments for neonatal hyperbilirubinemia
3. What are the quantitative estimates of efficacy of treatment for:
1. reducing peak bilirubin levels (e.g., number-needed-to-treat (NNT) at 20 mg/dl to keep total serum bilirubin (TSB) from rising);
2. reducing the duration of hyperbilirubinemia (e.g., average number of hours by which time TSB greater than 20 mg/dl may be shortened by treatment); and
3. improving neurodevelopmental outcomes.
![Page 7: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/7.jpg)
Key questions (cont.)Diagnosis of neonatal hyperbilirubinemia
4. What is the efficacy of various strategies for predicting hyperbilirubinemia, including hour-specific bilirubin percentiles?
5. What is the accuracy of transcutaneous bilirubin measurements?
![Page 8: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/8.jpg)
Literature search
• Medline and Premedline databases searched September 2001, yielding 4,325 citations
• Consulted domain experts and reviewed bibliography of relevant review articles for potential additional studies
• Supplemental search for case reports of kernicterus was also performed
![Page 9: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/9.jpg)
General inclusion criteria
• English language human studies• Newborns between birth and one-month • Healthy, full-term infants 34 weeks EGA or 2,500 grams 10 subjects per arm (5 for Q1 and Q2)
• Additional criteria were applied to specific question
![Page 10: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/10.jpg)
Literature search results
• Total citations screened = 4,325• Full articles retrieved = 663• Studies included in report = 138*
– Q1/Q2 = 37 + 28 kernicterus case reports– Q3 = 21– Q4 = 10– Q5 = 46
* Total of counts of individual questions exceeds 138 due to overlapping coverage
![Page 11: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/11.jpg)
Summarizing and grading of evidence
![Page 12: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/12.jpg)
Important parameters to sum up
• Methodological quality (internal validity, design, conduct, and reporting of the study)
• Applicability (generalizability, external validity, population, setting)
• Study size (weight, precision)• Effect (results, associations, test
performance)
![Page 13: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/13.jpg)
Methodological quality
Refers to the design, conduct, and reporting of the clinical study. Because studies may be from a variety of types of design, the following three-level classification of study quality may be used to apply to each type of design.– Least potential bias (Grade A)– Susceptible to some bias, but not sufficient
to invalidate the results (Grade B)– Significant bias that may invalidate the
result (Grade C)
![Page 14: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/14.jpg)
Applicability Category 1: Sample is representative of the target
population, or if results are definitely applicable to general population irrespective of study sample.
Category 2: Sample is representative of a relevant sub-group of the target population.
Category 3: Sample is representative of a narrow subgroup of patients only, and not well generalizable to other subgroups.
![Page 15: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/15.jpg)
Quantitative methods used in evidence report
![Page 16: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/16.jpg)
Question 3: NNT
What are the quantitative estimates of efficacy of treatment for: reducing peak bilirubin levels (e.g., number-needed-to-treat (NNT) at 20 mg/dl to keep total serum bilirubin (TSB) from rising)?
![Page 17: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/17.jpg)
Hypothetical example of treating bilirubin at 15 mg/dl to prevent it from rising
Treat at 15 mg/dl
Not treat
Rise 10 pts 20
Not rise 90 80
Total 100 100
Risk Difference = 10/100 – 20/100 = -10/100 = -0.1
NNT = 1 / Risk Difference = 1/10 = 10
![Page 18: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/18.jpg)
Methods to assess agreement between two testing methods reported in studies
• Correlation (r value)– Meta-analyses performed in evidence
report when data available
• Bland and Altman method (difference of results of two testing methods plotted against their mean value)– Preferred method
![Page 19: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/19.jpg)
Accuracy of BilicheckTM
Bhutani et al., Pediatrics 2000
![Page 20: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/20.jpg)
Limitations of correlation coefficient to assess agreement
(hypothetical data - all have correlation coefficient of 1)
0
5
10
15
20
25
30
35
40
45
0 5 10 15 20 25 30 35 40 45
HPLC bilirubin(reference standard)
Ne
w m
ea
su
rin
g d
ev
ice
![Page 21: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/21.jpg)
Limitations of correlation coefficients in assessing agreement between two testing methods
• Correlation coefficient provides a measure of the strength and directionality of the association, but NOT agreement
• Correlation measures ignore bias• Correlation coefficient does not provide
information as to clinical utility of diagnostic test• Correlation coefficient (r) is dependent on
distribution of serum bilirubin• Measures relative rather than absolute
agreement• High correlation coefficient is a necessary but
not a sufficient condition to assess agreement
![Page 22: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/22.jpg)
Bland and Altman method
• True value is unknown• Takes the average of the paired measurements
as the best estimate• Plot for each pair of measurements, the
difference in results between devices against the average results
• Removes statistical artifact of plotting the difference against either of the measurement (built-in correlation)
• The magnitude of bias can be estimated as well as the standard deviation of the differences
![Page 23: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/23.jpg)
Error distribution paired HPLC TSB and TcBBhutani et al., Pediatrics 2000
![Page 24: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/24.jpg)
Common methods to summarize diagnostic test performance
• Combining sensitivity and specificity independently
• Combining diagnostic odds ratios across studies
• Summary ROC curve
![Page 25: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/25.jpg)
Summary ROC methodMoses LE, Shapiro D, Littenberg B. Combining independent studies of a diagnostic test into a summary ROC curve: Data-analytic approaches and some additional considerations. Stat Med 1993; 12:1293-1316.
• Assumption: studies results differ because of different thresholds
• Solution: fit a curve in the ROC space that best describes the data
• Problem: sensitivity and specificity are correlated
• Solution: regress the difference of the logits onto the sum of logits and transform back to ROC space
![Page 26: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/26.jpg)
1 - specificity
a
b
d
c
1 - specificity
sen
sitiv
ity
a
b
d
c
ROC curve constructed from multiple test thresholds
Diseased
Notdiseased
Multiple thresholds evaluated in test
b c da
![Page 27: Management of Neonatal Hyperbilirubinemia Methods of the AHRQ Evidence Report FDA Advisory Committee Meeting June 11, 2003 Joseph Lau, MD Tufts-New England.](https://reader030.fdocuments.net/reader030/viewer/2022032709/56649ec45503460f94bcf323/html5/thumbnails/27.jpg)
Examples of SROC curves and pooled sensitivity and specificity