E U R O P E A N R E S E A R C H N E T W O R K F O R E V A L U A T I O N A N D

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1 uropean esearch etwork for evaluation and improvement of screening, Diagnosis and treatment of Inherited disorders of Metabolism B nnual eport 217 DIM dmin. ffice Manchester entre for Genomic Medicine, 6th floor, t Mary s Hospital xford oad Manchester, M13 9W, K el: Fax: mail: admin@erndim.org P H W K F V I D I M P V M F I G, D I G I D M F I H I D D I D F M B I M

2 P G 2 hair s Introduction It is a pleasure to present to you the first DIM nnual eport. his 217 report provides an overview of DIM activities as well as finance information. DIM is an international organisation aiming at consensus between uropean Biochemical Genetics entres on reliable and standardised procedures for diagnosis, treatment and monitoring of inherited metabolic diseases. his is achieved through provision of quality control schemes operated according to accepted norms and on a global scale. We also provide education through meetings and provision of relevant documentation such as recommended operating procedures and annual reports of schemes on the internet. In addition, we supply control and reference materials in conjunction with our partner organisation, M laboratory. he DIM Foundation was formally registered on eptember 5th 1994, at the Dutch hamber of ommerce in Maastricht, and Q schemes were operated for Quantitative mino cids, rganic cids and pecial Metabolite ssays, in addition to an interpretative scheme for rganic cids. ince Dr George uijter, hair, xecutive ommittee these early years much progress has been made and DIM has evolved into an organisation with professional governance and strong increases in the number of Q schemes, and number of participating laboratories. DIM an organisation with professional governance & strong increases in the number of Q schemes, and number of participating laboratories ctivities DIM continues to grow and in 217 we saw an increase in both the number of laboratories registering with us and the number of Q schemes that we offer. lthough the Foundation maintains a strong uropean basis with 61% of participating laboratories in 217 being uropean, a significant number of participating laboratories now also come from sia, orth merica, ceania, outh merica and frica. wo pilot schemes were implemented in 217. hese are fully funded by DIM during the pilot phase, i.e. free to participants. urveys have shown that there is sufficient interest worldwide to make the schemes viable although these are for rare metabolites and the assays are often undertaken by only one laboratory in any country. he 217 pilots were: ognitive mino cids and pecial ssays in DB.. merica; 54; 14% ceania; 18; 5% sia; 68; 17% We held an extended DIM Participant meeting in Manchester, nited Kingdom, in ovember 217. he meeting was well attended and received very positive feedback. DIM was also represented at the IIM 217 in io and the IPM 217 in Durban. he presentations from the 217 DIM Participant meeting and the DIM session at. merica; 9; 2% frica; 5; 1% Figure 1: umber of registered laboratories in 217, by continent the IIM 217 can be found on the DIM website ( under Meetings. DIM collaborated with the ducation and raining ommittee () of IM to provide the 217 cademy training course which was held in pril in yon, France. In ugust 217, the urope; 243; 61% (ontinued on page 3) D I M P 2 1 7

3 D I M P P G ctivities (continued) (ontinued from page 2) dministration ffice welcomed Jenny Barrett as the new cientific dministrator in a post funded by IM. he appointment of Jenny doubled the full time staff in the dministration ffice! DIM is extremely grateful to IM for this funding which will help to speed up our slow, but steady, progress towards applying for accreditation. Finance ummary dmin; 8% Meetings; 7% Websites; 1% Figure 2: umber of participants per country Figures 3 and 4 are summaries of our 217 income and expenditure. he main source of our income was the Q scheme fees paid by participants however, we also receive significant support from IM for staff costs (included in the dmin in Figure 3) and website developments. he Meetings income was due to sponsorship and registration fees for the 217 DIM Participant Meeting which was held as a separate meeting in urope due to IIM 217 being held in io. s would be expected our major expense is the provision of the Q schemes, which in 217 made up 62% of our expenditure; while dministration (staff costs, office consumables etc.) and Meetings, respectively, accounted for 23% and 12% of our expenditure. Meetings; 12% Finance; 2% Websites; 1% DIM our major expense is the provision of the Q schemes... dmin; 23% Q schemes; 83% Q schemes, pilots & support; 62% Figure 3: ummary of 217 income plans Q alendar hanges were made to the Q scheme calendar to allow the scheme results to be finalised within the scheme year. he aim of this change is to allow the publication of the 218 certificates of participation in the first quarter of the next year, which we know would be welcomed by many participants. ample Dispatch he cylcarnitines in DB scheme moved to centralised dispatch by Q in 218. In 219 we are hoping to combine the dispatch of the DP and Qualitative rganic cids samples. esults websites nline submission for the Qualitative rganic cids and Figure 4: ummary of 217 expenditure cylcarnitines in DB schemes launched for the first 218, submission rounds. he aim is to launch online submission for the DG scheme later in 218. Pilot schemes he ognitive mino cids and pecial ssays in DB pilot schemes have both continued in 218.

4 BGI HI MBI I YP DMK GYP ID VI B IHI XMBG MXI M PKI PHIIPPI P. F IGP BI VI I K. F M GY BZI I G HGY JP WY Q I KI I KIGD. F DI BI KWI MYI W ZD H FI WD IW GI VKI I FID PD PG WIZD ZH PBI IDI BGIM I HI D HD PI KY IY GMY F K umber of scheme registrations % increase on previous year P G 4 DIM Q schemes 397 labs 6 countries 1752 registrations Q egistrations In laboratories, from 6 countries participated in the 15 Q schemes that we offered, with 1752 individual scheme registrations. DIM received 621 registrations for qualitative schemes in 217 and 1131 registrations for quantitative schemes. verall, registrations were slightly increased compared to 216 (Figure 5) with nine of the fifteen Q schemes having an increase in registrations compared to 216 (see able 1). here were 2 new Q able 1: 217 egistrations per scheme Q chemes o. of 217 registrations otal egistrations Figure 5: otal Q scheme registrations by year (and % increase compared to previous year) Difference to 216 o. % DB % * DG % WB % DP % FB % F % P** PP 51.% Q % Q 266.% Q % % % MP % % (minus & P) % schemes in 217: the and P schemes. aboratories from 6 countries registered for the 217 Q schemes (Figure 6). For just over half these countries (31/6) only 1-2 laboratories were registered with DIM. While over 38% of participants came from one of 4 countries (K, France, and Germany). Pilot chemes Year In 217 there were 2 pilot schemes running: ognitive mino cids (, 32 participants from 5 countries) and pecial ssays in DB (DB, 15 participants from 33 countries). For the pilot all participants were uropean laboratories while for the DB pilot 48.5% of participating laboratories were from outside of urope. = see ppendix (page 8) for full Q scheme names; * = 1 st year as a full Q scheme, (previously acylcarnitines were part of the scheme); ** = 1 st year as a full Q scheme, (ran as a pilot in , number of pilot registrations in 216 was 27) r a e y s u io v re p n o se a re c in % 45 o of participants per country I G B I H I I K B P D M Y I I G V P Y M G I B H B D M I X I X M I I P P K IP M P I G H I P F I B P I B I Y K I V M Z I G B F Figure 6: umber of participants per country I Y Y G P W G J Q H I I I D K I f o M D G I K I W K I D Y I I I F D I K IW W M Z H V G W D I F D P D G I I M I B D I I G P Z B P I W H Z I H D D I Y Y Y P K I M H G K F D I M P 2 1 7

5 D I M P Q amples cross all the 217 Q schemes we used 152 different Q samples and over 14,6 aliquots were prepared by the scheme organisers. he main source of materials used for the 217 Q schemes were samples of patient urine collected by the cientific dvisor/scheme organiser (42/152 samples). total of 16 samples used in the 217 schemes were donated by participating laboratories (9 samples used in the DP scheme and 3 samples used in the MP scheme) and a patient organisation (3 samples used in the DP scheme). We would like to thank all the individual laboratories that donated patient samples and also the Dutch Patient ssociation, VK for their help. Information on the types of donated samples that are useful to DIM can be found on under Q schemes. Discounts on scheme fees are offered to participating labs that donate samples; for more information contact admin@erndim.org. If your laboratory has a sample you think might be useful to one of the DIM Q schemes please contact admin@erndim.org. P G 5 DIM different Q samples and over 14,6 aliquots were prepared... o of samples WB spiked with analytes ultured fibroblasts spiked with analytes rine spiked with analytes erum spiked Plasma/serum with analytes xtra sample requests We received 72 requests for extra material for the 217 schemes, from 54 laboratories (11.5% of all labs). he main reasons for the requests were: the sample parcel not being received (24 requests; 6.% of all labs); labs wishing to test/validate a new method (18 requests, 4.5% of all labs); vials broken/ leaked in transit (16 requests; 4.% of all labs); and labs requesting extra material to reanalyse (11 requests; 2.8% of all labs), which together made up over 95% of all requests for extra material. It should be noted that a quarter of all requests were for samples to help with testing or validating a new method. Where this leads to a publication, labs should ask DIM for consent (admin@erndim.org) for the use of the data from DIM samples and DIM should be acknowledged in the publication. Full details For the DG and MP schemes, some laboratories require a larger sample volume due to their analysis method. For the DG scheme, 21 labs (32% of scheme participants) requested extra sample volume due to their analysis method and were sent a total of 26 extra set of samples at a reduced fee. For the rine MP scheme 1 lab (1% rine collected by / rine donated rine donated Whole blood by labs by patient organisation samples collected by / Figure 7: Materials used as Q materials in 217 schemes [ = cientific dvisor; = cheme rganiser] able 2: equests for extra 217 Q samples Q chemes Human F/artificial F spiked with analytes o. of extra materials requests DB 9 7.3% % of labs registered 2 2.3% DG.% WB % DP % FB 3 4.% F.% P 2 3.9% PP 2 6.7% Q 7 3.2% Q % Q 4 3.1% 1 4.% 7 4.1% MP 5 4.8% ll requests % = see ppendix (page 8) for full Q scheme names of scheme participants) requested extra sample volume and was sent 1 extra set of samples at a reduced fee.

6 P G 6 eporting ompliance ates verall reporting compliance rates in 217 were good, with 94% of results being submitted on time (able 3), 1.7% of results were submitted after the submission deadlines (compared to 1.2% in 216) & 4.4% of results were not submitted at all (compared to 5.9% in 216). he percentage of results submitted on time was 9% or above for 13 schemes. he lowest reporting compliance rates were for the DB (82.4%) and DG (84.6%) schemes, which were the only schemes in 217 which did not have online submission available. able 3: eporting compliance rates for 217 Q schemes Q chemes o of registered labs % esults submitted on time Q chemes o of registered labs % esults submitted on time HM % P 3 9.% DB % PP % % Q % DIM % of results were submitted on time... DG % Q % WB % Q % DP % % FB % % F % MP % = see ppendix (page 8) for full Q scheme names Participations on- & Partial ubmitters: 32 labs (8.9%) participated in all the schemes they registered for, with an additional 67 labs (16.9%) labs participating in at least one scheme. While 9 labs (2.3%) did not participate in any schemes they registered for (7 labs = 1 schemes; 1 lab = 2 schemes; 1 lab = 3 schemes); ll non- and partial submitters are sent a letter asking for the reason for the non-submission of results and offering advice and support if needed. ducational Participants 1 labs registered as ducational Participants * (P). 7 labs were Ps in 1 scheme each, 2 labs were Ps in 2 schemes and 1 lab was an P in 3 schemes. abs that registered as an P for only some of the analytes in a Quantitative scheme (= 4 labs) are not included in Figure 8 as their performance was assessed for the remaining analytes. Withdrawn labs ix labs withdrew from one or more 217 Q schemes (= 8 Q registrations,.5% of all registrations): 3 labs were no longer offering a service, 1 lab had technical issues, and 2 labs did not receive their DB samples parcels so were allowed to withdraw from the scheme. * = abs can only apply for ducational Participation if they are not offering a clinical service for the relevant analyte or test and acceptance is dependent on the approval of the appropriate cientific dvisor, % F GID B on submitters Partial submitters ducational Participants Withdrew DB DG WB DP FB F PP P Q Q Q MP Figure 8: on-submitters etc. per Q scheme [ see ppendix (page 8) for full Q scheme names and full scheme results] D I M P 2 1 7

7 D I M P Performance Performances in all the DIM Q schemes are reviewed and agreed at meetings of the cientific dvisory Board (B) which includes the cientific dvisors for all the full Q and pilot schemes. he full results for all the Q schemes are given in able 5 (page 8) but a summary is given in Figure 9 below. Poor Performance f the 387 labs that participated in one or more 217 Q schemes, 66 labs (17.1% of participating labs) were classed as a poor performer for score and/or critical error in one or more of the Q schemes they participated in. ight critical errors were agreed by the B for the 217 schemes, which resulted in 9 additional instances of poor performance (i.e. poor performance for critical error only, see able 5, page 8). he details of the agreed critical errors can be found on under eports. atisfactory Performance 82.9% of participating labs (= 321/387) obtained satisfactory performance in all of the Q schemes they participated in (compared to 8.8% in the 216 schemes). he level of satisfactory performance in the 217 schemes ranged from 85.7% (P ) to 98.5% (FB ) with the overall level of satisfactory performance for all schemes being 95.3% (see able 5, page 8) compared to 93.9% in 216. P G 7 DIM % of participating labs obtained satisfactory performance in all of the Q schemes they participated in % F PIIPIG B only PP for score D PP for score only atisfactory performers DB DG WB DP FB F PP P Q Q Q MP Figure 9: Performance per Q scheme [ see ppendix (page 8) for full Q scheme names and full scheme results] Global Poor Performance Global Poor Performance (GPP) is poor performance in more than one Q scheme in one year. In 217, ten labs had poor performance in more than one Q scheme (= 2.6% of participating labs). his is lower Persistent Poor Performance Persistent Poor Performance (PPP) is defined as at least 2 years with poor performance in an Q scheme in 3 participating years. For the period , 2 labs were classed as persistent poor performers (= 5.2% of participating labs) compared with 19 labs (5.1% of participating labs) for the period than the rate of GPP in 216 when 3.8% of participating labs had GPP (= 14/372). he 1 labs with GPP in 217 were all poor performers in 2 separate Q schemes. Fifteen labs with PPP for also had PPP for f these 15, 8 labs had poor performance in both 215 & 216 but were good performers in the 217 schemes. wo of the labs with PPP in were PPP in 2 separate Q schemes and the remaining 18 labs only had PPP in one Q scheme. ppeals We received 7 appeals against classification as a poor performer in the 217 schemes, compared to 1 appeal for the 216. schemes. hree 217 appeals were upheld (FB = 2; Q = 1) and the labs performances were updated. he outcomes of the successful appeals are included in the performance results in Figure 9 & able 5 (page 8). hange equests equests for scores to be adjusted which would not result in a change to a lab s performance are classed as hange equests. In 217, 8 change requests were received. even of these were upheld, all of which related to the DG or DB nnual reports.

8 ppendix able 4: Full Q chemes and scheme codes cheme ode DB DG WB DP FB F PP P Q Q Q MP Q cheme ame cylcarnitines in DB cylcarnitines in serum ongenital Disorders of Glycosylation (plasma/serum) ystine in WB Diagnostic Proficiency esting (urine) ysosomal nzymes in fibroblasts eurotransmitters in F Purines & Pyrimidines (urine) Pterins in urine Qualitative rganic cids (urine) Quantitative mino cids (serum) Quantitative rganic cids (urine) pecial ssays in serum pecial ssays in urine rine Mucopolysaccharides able 5: ummary of all 217 participations and performance results Q egistered onsubmitters Partial Withdrawn ducational Participating PP 1 for score PP 1 for score PP 1 for 2 atisfactory cheme labs submitters labs Participants labs only D 2 only performers DB % 5 4.1% 2 1.6% 1.8% % 3 2.7%.% 1.9% % % 2 2.3%.% 1 1.1% 8 9.9% 2 2.5% % DG %.%.%.% % 1 1.6%.% 1 1.6% % WB 37.% 3 8.1%.%.% % 3 8.8%.%.% % DP 19.% 2 1.8%.% % 1.9% 1.9% 5 4.7% % FB 72.% 5 6.9%.%.% % 1 1.5% % F %.%.%.% % 2 7.4% % PP % 1 2.%.% 1 2.% % 5 1.6% % P % 1 3.3%.%.% % %.%.% % Q %.% 1.5% 1.5% % 3 1.4% 2.9% 2.9% % Q % % 3 1.1%.% % % % Q % 4 3.2%.% 1.8% % 3 2.6% % % % 1.4%.% % 8 3.6% % % 2 1.2%.%.% % 4 2.4% % MP % 2 2.% 1 1.% 6 5.9% % 7 7.6%.%.% % HM % 5 2.9% 8.5% 11.6% % 64 4.% 3.2% 9.6% % = see able 4 for full Q scheme names; 1 = Poor Performance; 2 = ritical rror; 3 = ducational Participation does not apply to the DP scheme; 4 = does not apply to these schemes Working towards a consensus between Biochemical Genetics entres on reliable and standardised procedures for diagnosis, treatment and monitoring of inherited metabolic diseases DIM dmin. ffice Manchester entre for Genomic Medicine, 6th floor, t Mary s Hospital xford oad Manchester, M13 9W, K el: Fax: mail: admin@erndim.org DIM fficers hair of the xecutive ommittee: George uijter, otterdam, he etherlands reasurer: Jörgen Bierau, Maastricht, he etherlands ecretary: Viktor Kožich, Prague, he zech epublic hair of the cientific dvisory Board: hristine Vianey-aban, yon, France