The Many Lives of the Newborn Screening Dried Blood Spot (the LIFE CYCLE of a Blood Spot)

Transcription

1 The Many Lives of the Newborn Screening Dried Blood Spot (the LIFE CYCLE of a Blood Spot) Piero Rinaldo, MD, PhD Professor of Laboratory Medicine T. Denny Sanford Professor of Pediatrics Mayo Clinic College of Medicine Practice Test development Research September 23 rd, 2009

2 The Life Cycle of Blood Spots Collection Primary testing Quality control, quality assurance Second tier testing Confirmatory testing Education Metabolic autopsy Test development IRB-approved research

3 The Life Cycle of Blood Spots Collection Primary testing Quality control, quality assurance

4 Quality Control, Quality Assurance Batch repeats QC failure (batch rejection) Equipment failure Verification of abnormal results Resolution of discrepancies Internal proficiency testing Educational sample exchange

5 The Life Cycle of Blood Spots Collection Primary testing Quality control, quality assurance Second tier testing

6 2 nd Tier Tests A cost effective mean to implement clinically defined cutoffs when normal population and disease range overlap (poor specificity) Performed in 1-2 batches weekly (except CAH) Same specimen, no additional patient contact Normal result overrules primary screening Reporting of primary screening is not delayed

7 Impact of 2 nd tier Test for CAH Volume Period Cutoff Abnormal (1 st ) Abnormal (2 nd ) True positives FPR PPV Detection rate 312,874 Jun 04 Aug 08 3 tiers (BW) 2,346 (0.75%) % 7.1% 1:20,858

8 Effectiveness of CAH Screening (Cost Savings Per Year, ~72,000 births) w/o 2 nd Tier False positives False (+) rate 0.97% 0.06% Cost clinical F/U $847 per case Cost 2 nd tier test $35 per test w/ 2 nd Tier Cost clinical F/U $601,370 $38,115 Cost 2 nd tier test $0 $24,850 Total F/U cost $601,370 $62,965 Cost difference (savings) (89.5%)

9 The Life Cycle of Blood Spots Collection Primary testing Quality control, quality assurance Second tier testing Confirmatory testing Education (quality improvement) Does California (550,000 births/year) need any education?

10 How Many Conditions has CA NOT Picked Up by NBS (yet)? A. None (seen all 42 ) B. 2 C. 5 D. 7 E. 10

11 How Many Conditions has CA NOT Picked Up by NBS (yet)? X X X X A. None (seen all 42 ) B. 2 C. 5 D. 7 E. 10

12 Education (Sample Exchange) Anonimized punches of extremely rare disorders are shared with other public health laboratories to self-evaluate their preparedness to diagnose them Thanks guys! They were all positive, which begs the question why aren't there any in California? I'm guessing it's that Caucasian thing again - know anything about ethnic differences? As you'll see one was below our C5-OH cutoff of 1.2 but all were positive for C5:1 MS/MS test results for Beta-ketothiolase (BKT) at GDL, Richmond, CA Sample ID C5-OH C5:1 umol/l B B B B B B B B CA cutoffs

13 The Life Cycle of Blood Spots Collection Primary testing Quality control, quality assurance Second tier testing Confirmatory testing Education Metabolic autopsy (the last hope)

14 Science 2001;254:2272

15 Our Our four month old daughter died suddenly and unexpectedly Luckily we had a connection to the Mayo Clinic, and shortly after Nora s death we found out that she had died of a Fatty acid oxidation Deficiency (FOD) We had never heard of such a thing..

16 Once in a Million? % Intensity +Precursor (85): Expt. 3, 0.73 min (26 scans) from Retrospective analysis of original NBS sample 4.14e3 cps LCHAD m/z, amu +Precursor (85): Expt. 3, 0.73 min (26 scans) from e3 cps 80 Control % Intensity m/z, amu

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18 + P r e c ( ) : E x p 3, t o m in f r o m S a m p le 1 ( A L V A R A D O O L ) o f S N S A L V A... M a x c p s % 9 5 % 9 0 % 8 5 % 8 0 % 7 5 % 7 0 % 6 5 % 6 0 % 5 5 % 5 0 % 4 5 % 4 0 % 3 5 % 3 0 % 2 5 % 2 0 % 1 5 % 1 0 % 5 % Retrospective Analysis of 10 YR OLD Original Newborn Screening Sample What is the diagnosis? m / z, a m u + P r e c ( ) : E x p 3, t o m in f r o m S a m p le 4 ( W H E A T L E Y ) o f S N S w if f ( T u... M a x c p s % 9 5 % 9 0 % 8 5 % 8 0 % 7 5 % 7 0 % 6 5 % 6 0 % 5 5 % 5 0 % 4 5 % 4 0 % 3 5 % 3 0 % 2 5 % 2 0 % 1 5 % 1 0 % 5 % Normal control m / z, a m u

19 Maria Crandall died at 15 months of age, most likely due to an undiagnosed (and unscreened) FAO disorder No conclusive postmortem diagnosis was possible because there were no available specimens The NBS card had been discarded before her death

20 Ryan Stallings died at 9 months of age, due to undiagnosed (and unscreened) Methylmalonic acidemia His mother was charged with first degree murder (antifreeze) At trial she was found guilty and sentenced to life in jail without possibility of parole She spent 14 months in jail The NBS card had been discarded before Ryan s death

21 The Life Cycle of Blood Spots Collection Primary testing Quality control, quality assurance Second tier testing Confirmatory testing Education Metabolic autopsy Test development

22 The Many Lives of the Newborn Screening Dried Blood Spot (the LIFE CYCLE of a Blood Spot) Practice Test development Research Why do we need access to stored specimens?

23 Partial List of Candidate Conditions for Expansion of Uniform Panel ALD (X-linked) CDG Ib CMV Creatine defects Duchenne G6PD Gaucher (LSD) HIV MPS I/II/IIIa/VI (LSD) Fabry (LSD) (in alphabetical order) Fam. Hypercholesterol. Fragile X Friedreich ataxia Krabbe (LSD) Niemann-Pick (LSD) Pompe (LSD) SCID SLO SMA Wilson disease

24 New Test Development, Validation, and Implementation at Mayo Clinic ALD (X-linked) CDG Ib CMV Creatine defects Duchenne G6PD Gaucher (LSD) HIV MPS I/II/IIIa/VI (LSD) Fabry (LSD) Fam. Hypercholesterol. Fragile X Friedreich ataxia Krabbe (LSD) Niemann-Pick (LSD) Pompe (LSD) SCID SLO SMA Wilson disease

25 Acid Maltase Deficiency (Pompe Disease)

26 How to Nominate a Condition

27 Screening Test Screening test(s) to be used High volume method, platform Modality of screening DBS, physical or physiologic assessment, other Clinical validation Location, duration, size, preliminary results of past/ongoing pilot study for clinical validation Performance metrics Sensitivity, specificity, detection rate, PPV, FPR Confirmatory testing Reliability, availability Wall Risks Street False positives, carrier detection, invasiveness Journal of method Detection of other disorders , D1

28 Screening Test (Pompe) Screening test(s) to be used Three alternative methods under evaluation Modality of screening Dried blood spots (DBS) Clinical validation Pilot study in Taiwan, no active screening in US Performance metrics Preliminary evidence of high false positive rate Confirmatory testing Available at several US Institutions Risks Interference by neutral maltase

29 Newborn Screening for Pompe Disease Pilot Study in Taiwan 132,538 Newborns tested 1,101 Newborns retested (2 nd sample) FPR = 0.83% PPV = 0.4% 121 Newborns recalled 4 True positives (no false negatives)

30 What Does a FPR of 0.83% Mean? Births/ Year 177,417 87,942 54, ,585 70, ,481 69,014 FPR PPV State Illinois Indiana Kentucky Michigan Minnesota Ohio Wisconsin 0.83% 0.4% No. of FP/WEEK

31 Mayo s Plan to Mitigate Risk of High FPR for LSDs Implement all assays available for testing of DBS for LSDs

32 Screening Strategy at Mayo Pompe Disease

33 Mayo s Plan to Mitigate Risk of High FPR for LSDs Implement all assays available for testing of DBS for LSDs Conduct an IRB-approved, prospective pilot study of 100,000 anonimized newborn screening blood spots with the goal to identify the most effective and efficient testing approach

34 The Reality of Where We Live Minneapolis Star Tribune, November 11, 2007, A1

35 Why Do We Need Access To Stored Specimens? To better serve the public and to be financially responsible, future expansions of NBS programs will demand FROM THE BEGINNING a significant improvement of performance Analytical validation is possible under current regulations by IRBapproved random use of anonimized recent specimens CLINICAL validation could take DECADES without collaborative, IRBapproved, informed access to historical specimens There is no reason to seek informed consent a priori from hundreds of thousands when it would be applicable only to 5-10 cases per year The most ethical, cost effective, and productive approach is to seek informed parental consent for access to stored specimens of cases diagnosed clinically. Parents overwhelmingly support this effort

36 Process for RETROACTIVE Access IRB protocol submitted and approved (Institution, others) Patient/family support group asked to circulate letter to registered families, asking to contact investigator if willing to participate Families initiate contact. Investigator provides information of the testing to be performed and answer questions If approval is granted, families are provided a template letter Letter is submitted to the state NBS lab requesting the release of the residual specimen in storage to the investigator for the purpose of clinical validation of a new NBS test After completion of the testing, the specimen is returned either to the state lab or to a NIH-funded repository (family s choice)

37 1 newborn 1 day 1 week

38 1 week (~1,500) 1 month (~6,000) Why do we need so many? 1 year (~75,000) 5 years (~300,000)

39 WD ALD LSD LSD FA MTHFR LSD WD ALD LSD Nothing in the last 2 years (TOO SOON!)

40 California has stored NBS cards for 24 years (>12,000,000)

41 Conclusions Stored blood spots can contribute in many ways to improving public health but also patient care, even many years after the primary testing Access to stored samples is vital to ensure timely implementation of robust new tests after adequate clinical validation Test development and validation is different from research, and it constitutes the predominant reason behind the need for long term storage

42 Thank You for Your Attention Of all cooperative enterprises, public health is the most important The needs of the patient come first and gives the greatest return William J. Mayo, MD