JAMA Pediatrics Journal Club Slides Effect of Laboratory

JAMA Pediatrics Journal Club Slides: Effect of Laboratory Calibration of Neonatal Bilirubin Kuzniewicz MW, Greene DN, Walsh EM, Mc. Culloch CE, Newman TB. Association between laboratory calibration of a serum bilirubin assay, neonatal bilirubin levels, and phototherapy use. JAMA Pediatr. Published online April 11, 2016. doi: 10. 1001/jamapediatrics. 2015. 4944. Copyright restrictions may apply

Introduction Background • The Vitros Bu. Bc Neonatal Bilirubin assay (Ortho Clinical Diagnostics) is a widely used reflectance spectrophotometry assay for measuring serum bilirubin. • On May 21, 2012, Ortho Clinical Diagnostics notified customers that it had “received customer complaints of positively biased results using Vitros. . . Bu. Bc Slides. ” • Based on customer input and an internal investigation, the company adjusted the calibrator values for the Vitros Bu. Bc Slides. Study Objective • To investigate the clinical effect of recalibration on maximum total serum bilirubin (TSB) levels and phototherapy use in Kaiser Permanente Northern California (KPNC), a large, integrated health care delivery system. Copyright restrictions may apply

Methods Study Design • Descriptive study comparing TSB levels and phototherapy use before and after recalibration. Setting • KPNC, a large, integrated health care delivery system. Intervention • The hospital laboratories implemented the manufacturer-adjusted calibrators between May 24, 2012, and June 13, 2012. Patients • All live births ≥ 35 weeks’ gestation at 12 KPNC facilities that used universal bilirubin screening with a TSB. • Prerecalibration cohort (January 1, 2010, through April 30, 2012): n = 61 677 • Postrecalibration cohort (July 1, 2012, through December 31, 2013): n = 42 571. Copyright restrictions may apply

Methods Outcomes • TSB ≥ 15 mg/d. L (to convert to micromoles per liter, multiply by 17. 104) and TSB ≥American Academy of Pediatrics (AAP) phototherapy threshold. – All TSB values from each infant’s first month after birth were obtained. – Each TSB value was compared with the 2004 AAP phototherapy guideline, based on hour-specific TSB value, gestational age, and direct antiglobulin testing result. • Phototherapy during the birth hospitalization and readmissions. • An admission with either of the following: – An International Classification of Diseases, Ninth Revision code for phototherapy (99. 83) and an order for phototherapy in the electronic medical record. – An electronic medical record flowsheet entry for phototherapy. Statistical Analysis • Outcomes were compared between the 2 cohorts using an autoregressive integrated moving average (ARIMA) time-series model. Copyright restrictions may apply

Results • Infants in the 2 periods were similar in terms of birth weight and percentage born before 37 weeks’ gestation. • The mean maximum TSB in the postrecalibration period was 1. 25 mg/d. L lower (95% CI, 1. 19 -1. 31; P <. 001) than in the prerecalibration period. • In the ARIMA models, the postrecalibration period was associated with the following: – 8. 0% (95% CI, 7. 1%-8. 8%) absolute reduction in infants with a TSB level ≥ 15 mg/d. L. – 4. 8% (95% CI, 4. 1%-5. 4%) absolute reduction in infants with a TSB level ≥AAP phototherapy threshold. – 5. 5% (95% CI, 5. 1%-6. 0%) absolute reduction in infants receiving phototherapy during the birth hospitalization. – 2. 0% (95% CI, 1. 7%-2. 3%) absolute reduction in phototherapy readmissions. Copyright restrictions may apply

Results Monthly Rates of Phototherapy Administration and Hyperbilirubinemia Copyright restrictions may apply

Results TSB Levels and Phototherapy Rates Copyright restrictions may apply

Comment • Modest systematic reductions in TSB values resulted in a major reduction in the percentage of infants with clinically significant hyperbilirubinemia. • Recalibration led to a significant reduction in use. – For every 10 000 deliveries, recalibration resulted in a reduction of 1300 patient-days/year and 4500 fewer TSB tests/year. – Recalibration saved $1. 4 million for every 10 000 deliveries (estimating an inpatient hospitalization day at $1000 and the cost of a TSB test and blood draw at $30). • Approximately 380 laboratories across the United States were enrolled in College of American Pathologists proficiency testing for neonatal total bilirubin using the Vitros assay. – KPNC hospital laboratories represented about 6% of those enrolled. • The overall health care resources lost to analytical inaccuracy far exceed what was calculated for the KPNC health care system. Copyright restrictions may apply

Comment • Calibration shifts in laboratory assays can have major clinical implications. • While theoretical models can predict these effects, it is rare to capture the consequential extent of the changes. • This study provides a powerful example of how small changes in measurement methods can lead to large changes in diagnosis and treatment. • The data from the Vitros Bu. Bc assay recalibration highlight the following needs: – Increased integration of laboratory expertise into clinical guidelines. – Support of international initiatives to standardize laboratory measurements. Copyright restrictions may apply

Contact Information • If you have questions, please contact the corresponding author: – Michael W. Kuzniewicz, MD, MPH, Division of Research, Kaiser Permanente Northern California, 2000 Broadway Ave, Oakland, CA 94612 (michael. w. kuzniewicz@kp. org). Funding/Support • This project was supported by grant R 01 HS 020618 from the Agency of Healthcare Research and Quality. Conflict of Interest Disclosures • None reported. Copyright restrictions may apply