PPT Presentation demonstration

Dr. Johannes Michiel LuteijnProf. Joan Morris BINOCAR Scientific Meeting Swansea, October 7th, 2014Thanks to:Lolkje de Jong-van den BergHelen DolkEster GarneJoanne GivenMaria Loane

EUROCAT Post-marketing surveillance for congenital anomaliesNames? The abstract only mentioned Joan. Explain EUROmediCAT, daughter project of EUROCAT Organisation1Two studies estimated 57-79% of pregnant women in Northern Europe are exposed to prescription drugs during pregnancy.1,2Little is known about the safety of drugs in pregnancy, partly due to pregnant women not being involved in pre-marketing studies.

1 Bakker, M. K., Jentink, J., Vroom, F., Van Den Berg, P. B., De Walle, H. E., & De Jong-Van Den Berg, L. T. (2006). Drug prescription patterns before, during and after pregnancy for chronic, occasional and pregnancy-related drugs in the netherlands. BJOG : An International Journal of Obstetrics and Gynaecology, 113(5), 559-5682 Engeland, A., Bramness, J. G., Daltveit, A. K., Ronning, M., Skurtveit, S., & Furu, K. (2008). Prescription drug use among fathers and mothers before and during pregnancy. A population-based cohort study of 106,000 pregnancies in norway 2004-2006. British Journal of Clinical Pharmacology, 65(5), 653-660Drug use in pregnancyMention chronic drugs2Aim: To develop a method of signal detection to be used as a routine analysis tool.

EUROmediCAT signal detection3Dataset15 EUROCAT registries in EUROmediCATBirths from 1995-2011

14,950 registrations of congenital anomaly with at least a single exposure to a drug (ATC-code 5-digit+) Folic acid, minerals and vitamins not included as exposures

ExclusionsAnomalies with 1-4 digit ATC-code exposures only (n=1,288)Anomalies with no clear 1st trimester exposure (n=13,377)Infants with a chromosomal anomaly

Recent data loss. Explain coding. ~83% of Polish and ~20% of Dutch data lost. The loss of data due to data cleaning was a major concern; close to half the data was lost due to some registries collecting exposures outside of the 1st trimester/no certain 1st trimester exposure. 4

DatasetDrug exposure5- and 7-digit ATC codes (n = 272, n = 505)Exposure collected mainly prospective to birth by healthcare professionals.

CasesEUROCAT coding committee identified 59 subgroups of non-chromosomal congenital anomaly

3 Teratogenic mechanisms of medical drugs. Van Gelder MM, van Rooij IA, Miller RK, Zielhuis GA, de Jong-van den Berg LTW, Roeleveld N. Hum Reprod. Update. 2010 Jul-Aug;16(4):378-94Potential drug-congenital anomaly signals must have at least 3 exposed cases 5 and 7-digit ATC codes should appear at least 3 times in the EUROmediCAT dataset. 6Analysis of drug-CA combinationsAnalysis by Fishers exact test

A total of 59 congenital anomalies x 836 drug-codes.

49,324 analyses performed.19,529 5-digit ATC-code analyses29,795 7-digit ATC-code analyses

Drug AAll other drugs excluding AAnomaly abAll other anomaliescdMention false discovery rate; do not elaborate as only 10 minute presentation and peoples minds will just go blank7Fishers exact results for 7-digit ATC anomaly combinations

Observed Odds RatioP-value0.05Multiple testing issuesP ValuesGiven there is no association - P = probability observed or more extreme result would occurP = 0.05 means that 5% of Fishers exact tests where there is no association will be statistically significantIe 5% of 5,000 tests are likely to be false positives

False Discovery Rate: Proportion of significant results that are expected to be false positivesFDR of 5% means 5% of the significant results are likely to be false positivesIe 5% of significant results are likely to be false positives

Denominator is changed from 5% of analyses to 5% of results. 9False Discovery RatePossible test results (Z-score)DensityDistribution of test statistics if there are no associationsBFalse Discovery RatePossible test results (Z-score)DensityDistribution of test statistics if there are no associationsObserved distribution of test statisticsAB

False Discovery Rate0.05Observed Odds RatioP-value0.05FDR = 5%

False Discovery Rate0.05Observed Odds RatioP-value0.05FDR = 5%May exclude true associationsFalse Discovery RateObserved Odds RatioP-value0.05

FDR = 50%FDR = 5%May exclude true associationsFalse Discovery RateObserved Odds RatioP-value0.05

FDR = 5%May exclude true associationsFDR = 50%May include too many false associations49,324 drug-CA combinations

19,529 5-digit drug combinations(including aggregate drug groups)

29,795 7-digit drug combinations

97 potential signals at (FDR= 0.5 ; p < 0.003)31 potential signals at (FDR = 0.5 ; p < 0.0005)128 potential signals

Flowchart of analysesMultiple testing procedure(649 p-value < 0.05)

Multiple testing procedure(886 p-value < 0.05)

P value just to show very stringent selection of signals. This is result of multiple testing procedure. 16Preliminary Results Association treeExample Spina bifida and N03AG01 (valproic acid)Congenital AnomalyExposureExposedCasesOdds RatioNeural Tube DefectsN03AG304.1 (2.6 - 6.0)Spina BifidaN03AG297.4 (4.7 - 11.2)Neural Tube DefectsN03AG01294.0 (2.6 - 6.0)Spina BifidaN03AG01287.3 (4.6 - 11.0)Cases not yet verified by registryDisentangle is key word1749,324 drug-CA combinations

128 potential signals

115 potential signals

47,789 FDR > 0.5

13 Less than 3 exposed cases

77 Independent signalsSubject to detailed follow-up

20 5-digit ATC code of 7-digit ATC associated with the same CA6 Aggregate CA of a more specific CA associated with the same exposure12 Protective associationsExclusionsFlowchart of analysesP value just to show very stringent selection of signals. This is result of multiple testing procedure. 18Validation of methodologySpina bifida and valproic acid OR 7.25 (4.61-11.02)28 Exposed cases

Congenital heart defects and human insulin OR 2.46 (1.81-3.35)102 Exposed cases

Cases not yet verified by registryThe WHO-Uppsala Monitoring Centre receives reports of adverse drug reactions from all over the world. 66,000 reports of CA-related adverse drug reactions since 200070% American/CanadianValuable independent dataset for testing signals

Future workAdded in few examples to make presentation more interesting for clinical oriented people. Let me know what you think.20