Medical Training4
Medical Training
Medical Training 2
Laboratory Analysis
Medical Training
Diagnosis and Analysis3
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EXAM NO. |
RESULT |
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E17207 |
PASS |
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E17208 |
PASS |
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E17209 |
PASS |
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E17210 |
FAIL |
Candidates who failed in written exam cannot proceed further in Fellowship Assessment in 2017.
Passed candidates can proceed further in Fellowship Assessment in 2017.
Volume 2, Issue 1 (click here to download the full pdf version)
Message from the President
Pathology is a medical specialty integrating personal experience and cutting-edge techniques. As a professional body committed to the upkeep and assurance of high-quality pathology practices, our College is dedicated to equipping our fellows with the ability to meet the challenges of evolving advancement in techniques and increasing expectation of the community. Concurring with the initiative by Hong Kong Academy of Medicine to promote training in genetics and genomics in several specialties, our College has been working on establishing a post-specialty fellowship in Genetic and Genomic Pathology under a special task force led by Dr Michael CHAN involving Specialty Board Chairpersons, Chief Examiners and representatives from various pathology specialties. Continued input of opinions from fellows and trainees is important.
We are encouraged by the success of the International Pathology Day Workshops targeted at high school students. The success is attributed to the hard work of a team of young fellows and trainees from various pathology specialties under the leadership of Dr Leon LAI. This year, such a workshop will be conducted again at around 15 November 2017. We shall continue to count on selfless support from fellows and trainees.
The College will continue to enhance communication with overseas and local professional bodies. There are representatives of our College in advisory groups in local administrations, and regular meetings with sister colleges overseas will continue.
The future of the profession and the College lies with our young fellows. The Academy is forming a Young Fellows Chapter for better engagement in the Academy’s activities. Each college is asked to nominate one fellow who has been conferred fellowship within the past 10 years. Dr MAK Siu Ming has been nominated to serve the first term (one year) of this Chapter.
The time of succession has also come. Nomination for Office Bearers and Councillors will be open soon. Your active participation is crucial for the success and prosperity of the pathology profession.
Professor CHEUNG Nga Yin, Annie May 2017
Volume 12, Issue 1 January 2017 (download full article in pdf)
In this topical update, Dr Rock Leung reviews the testing strategy and quality assurance issues on laboratory testing for direct oral anticoagulant (DOACs). We welcome any feedback or suggestions. Please direct them to Dr Rock Leung (e-mail: leungyyr.ha.org.hk) of Education Committee, the Hong Kong College of Pathologists. Opinions expressed are those of the authors or named individuals, and are not necessarily those of the Hong Kong College of Pathologists.
Dr. Rock LEUNG
Associate Consultant, Division of Haematology, Department of Pathology and Clinical Biochemistry
Queen Mary Hospital, Hong Kong
Abbreviations
| DOACs | Direct oral anticoagulants |
| FIIa | Thrombin |
| PK | Pharmacokinetics |
| PD | Pharmacodynamics |
| PT | Prothromhin time |
| APTT | Activated partial thromboplastin time |
| TT | Thrombin time |
| dTT | Diluted thrombin time |
| ECT | Ecarin clotting time |
| DRVVT | Diluted Russell’s viper venom time |
The newly available Food and Drug Administration (FDA) -approved oral anticoagulants, namely dabigatran extexilate, rivaroxaban, apixaban and edoxaban, have been more commonly used nowadays for treatment and prophylaxis of venous thromboembolism, as well as for prevention of stroke in non-valvular atrial fibrillation. This new class of anticoagulants has been referred as novel oral anticoagulants (NOACs), target-specific oral anticoagulants (TOACs), or direct oral anticoagulants (DOACs). For the sake of standardization, the International Society for Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SCC) for the control of anticoagulation recommends the term DOACs. DOACs have been shown to be at least as effective as warfarin in various clinical trials. Moreover, there was reduced incidence of intracranial haemorrhage reported in some studies when compared with warfarin [1]. Unlike warfarin, DOACs do not need routine therapeutic monitoring given their predictable pharmacokinetics (PK), pharmacodynamics (PD) and wide therapeutic windows. There are, however, clinical conditions that measurement of anticoagulation activity of DOACs is necessary or potentially useful, e.g. before invasive procedures, during adverse events like break-through bleeding or thrombosis, and pre- and post-administration of reversal therapy for patients with DOACs overdose. Thus, there is a role for laboratory, by testing for DOACs, to help clinicians on patient management. In addition, it is the responsibility of the laboratory to acknowledge the interferences of DOACs on conventional and special coagulation tests as part of the laboratory quality assurance in the era of gaining popularity of DOACs usage.
In contrast with heparin that can only inhibit free protease, DOACs are rapidly-acting, target-specific anticoagulants that inhibit both the free and bound activated serine protease [2]. The fact that DOACs can inactivate bound serine protease explains their more robust action than warfarin or heparin. Dabigatran is a direct thrombin (IIa) inhibitor while rivaroxaban, apixaban and edoxaban are direct inhibitors of activated factor X (Xa). Most of the DOACs are cleared by liver and kidney, with the exception of dabigatran being almost exclusively excreted by kidney. DOACs reach peak plasma levels within approximately two hours and plasma trough levels within 12 hours or 24 hours depending on their frequency of administration [3]. The DOACs can be withhold a few days before elective surgery or invasive procedures due to their short half-lives and favourable pharmacokinetics.
Routine monitoring of DOACs is not required. Testing on patients on DOACs is generally indicated in certain clinical circumstances, including acute bleeding, suspected DOACs overdose, drug interaction, in patients with impaired renal function, before surgery or invasive procedure in patients who have taken the drug beyond 24 hours and with creatinine clearance of <50 mL/min or with extreme body weight [4]. Recently, more pharmacokinetics and pharmacodynamics data on indications of clinical testing came up. Currently it is recommended that checking of drug-specific peak and trough levels for DOACs should be performed for patients with body mass index (BMI) of >40 kg m^2 or weighted over 120 kg [5]. There is currently no consensus on when to test for DOACs activities when these drugs are to be used in women with childbearing potential. One should however note that animals studies have shown teratogenic effect of dabigatran, edoxaban and rivaroxaban, these drugs were assigned by the FDA as pregnancy category C, reflecting their potential teratogenicity. Whereas no teratogenicity has been demonstrated in animals for apixaban as of today, it was categorized as pregnancy catergory B by FDA [6]. On the other hand, the use of DOACs is considered an off-label clinical application for paediatric thromboemobolic diseases [7]. It is not unreasonable to obtain information about anticoagulation activity by laboratory assay for this special group of patients, as in the case of low-molecular-weight heparin (LMWH) usage in select paediatric patients.
Given the predictable pharmacokinetics of DOACs, it was proposed that a pharmacokinetic strategy by stopping the drug for a time frame adequate for washout of drug effect is safe before surgery or invasive procedures. This approach can only be applied for planned surgery or invasive procedures, with available information regarding patient’s renal function as well as the dose and timing of the last DOAC administration. For emergent or unplanned procedures in patients with renal insufficiency or unplanned procedures when the timing of the last DOAC administration is uncertain, measurement of residual drug level will be valuable to assist clinical decisions, including the assessment of bleeding risk and the need for antidote for prompt reversal of DOAC effect before surgery. In life-threatening bleeding associated with the use of DOACs, the measurement of drug level can supplement clinical information to determine whether the bleeding is contributed by the anticoagulation effect of DOACs and whether the administration of DOAC-specific antidotes is required. If antidote is applied, laboratory test can monitor the extent of reversal.
The ideal test for DOACs shall be accurate, readily available on a 24-hour basis in order to accommodate emergency clinical situations, and with a reasonably short turnaround time (TAT).
Gold standard method using ultra-performance liquid chromatography – tandem mass spectrometry (UPLI-MS/MS) provides the most accurate information about the drug levels for patients on DOACs. However, the test is not readily available in most of the laboratories.
Routine coagulation screening tests, i.e., prothrombin time (PT), activated partial thromboplastin time (APTT) or thrombin time (TT), have been suggested as screening tests for DOACs. For routine coagulation screening tests to be useful and suitable for testing for DOACs, linearity and adequacy of test response to increasing dosage and amenability to standardization are prerequisites [8]. For dabigatran, TT is readily available in most laboratories and prolongation of clotting time is linearly and dose-dependently related to dabigatran concentrations. However, responsiveness is excessive. Therefore, a normal TT should rule out a dabigatran anticoagulant effect but the degree of prolongation poorly reflects drug concentration. Dilute TT (dTT), i.e., testing of TT on diluted plasma, is adequately responsive to dabigatran and suitable for assessment of dabigatran activity. Ecarin clotting time (ECT), using ecarin for the conversion of FII to meizothrombin, to assess anticoagulant effect of dabigatran was also shown to have satisfactory linearity and responsiveness to increasing dabigatran concentrations. APTT, though being demonstrated to have satisfactory responsiveness to dabigatran, lacks linearity upon increasing drug concentration and there is significant inter-reagent variability [9]. PT is insensitive to dabigatran and not suitable for testing.
Rivaroxaban prolongs the PT in a concentration-dependent manner, but the correlation is generally weak and became weaker with increasing drug concentration. Significant reagent-dependent differences in assay sensitivity are noted in multiple studies, limiting its use for assessment of rivaroxaban activity if the in-house thromboplastin reagent for routine coagulation screening is insensitive to rivaroxaban [10]. APTT is insensitive to rivaroxaban and shall not be used for assessment of rivaroxaban activity. For apixaban, both PT and APTT are insensitive to increasing drug concentrations and for edoxaban, PT performance is similar to that observed for rivaroxaban and APTT is insensitive [11].
Therefore, routine coagulation screening tests PT, APTT and TT cannot provide a reliable measurement of DOAC anticoagulant effect in most circumstances. One exception being a normal TT excludes significant residual effect of dabigatran in patients. Moreover, PT and APTT are either insensitive or show variably sensitivity to the on-therapy range of DOACs and limit their use in determining whether the drug concentration is in subtherapeutic or supratherapeutic ranges. Furthermore, these coagulation screening tests are potentially affected by the presence of lupus anticoagulants and conditions resulting in factor deficiency as in liver disease or dilutional coagulopathy. Thus, the sensitivity & specificity in reflecting the anticoagulant effect of DOACs is limited.
Anti-Xa assay is a chromogenic assay based on the measurement of residual FXa with synthetic substrates upon mixing of plasma with FXa. Although one study showed the feasibility of using of anti-Xa assay for LMWH to assess the presence of rivaroxaban [12], it is recommended to use drug-specific calibrator rather than adopting the anti-Xa assay for measurement of heparin activity due to the following reasons: 1) assays to measure indirect Xa inhibitors, e.g., LMWH, are measured in IU/ml and direct Xa DOACs are measured in ng/mL and there is no direct relationship between these two units of measure, 2) there is significant variability in measured drug concentration, as demonstrated by rivaroxaban, between various anti-Xa kits and 3) the therapeutic range, at least for apixaban and rivaroxaban, far exceeds the typical calibration range for UFH and LMWH (in the 5-9 IU/ml range) and 4) the assay is not specific for anti-Xa DOACs and will detect all anti-Xa anticoagulants2.
Commercially available drug-specific coagulation assays for testing of DOACs use calibrators and controls specific for the DOAC being measured [13-15], enabling the reporting of a drug concentration upon testing of patient’s plasma sample. Multiple calibrators and test plasma dilutions are employed to ensure the test sample responses are within the range of the calibration curve and also to allow for assessment of linearity and parallelism [16]. It was recommended that anti-Xa assay and diluted TT shall be employed when carrying out the drug-specific coagulation assay for anti-Xa inhibitor and anti-IIa inhibitor respectively, given their linear relationship and good correlation with drug concentration as measured by mass spectrometry [11]. Although an ecarin chromogenic assay (ECA) for direct IIa inhibitor and a DRVVT-based assay for both direct IIa and direct Xa inhibitors have been calibrated for testing of DOACs, ECA was shown to have suboptimal accuracy when compared UPLC-MS/MS and DRVVT-based assay would give false positive result in the presence of lupus anticoagulant [17,18]. Studies have shown that various drug-specific coagulation assays differ significantly in quantitation of the DOAC being measured when compared with UPLC-MS/MS in terms of precision and accuracy [17].
Drug-specific assay is by no means a direct measurement of drug concentration for DOACs. Instead it is an extrapolation of drug concentration by its anticoagulation activity measured by clot-based or chromogenic assay.
Therapeutic ranges of DOACs have not been validated by the manufacturing pharmaceutical companies. Moreover, there is no established range of concentrations associated with bleeding. In clinical use, expected trough and peak concentrations as predicated on prescribed dose and frequency are often taken as a reference during result interpretation of drug levels [17] (Table 1).
There is no consensus on whether trough level is superior to peak level when interpreting the findings during monitoring of DOACs. The sample for DOAC level is often collected at a random time during emergency clinical situations. A meaningful interpretation of drug level requires the knowledge of the time of last dose of DOAC, the drug dosage and patient’s renal and liver functions so that the trend of drug concentration over time can be better predicted.
With increasing use of DOAC assay, it is expected that DOAC plasma concentration shall be a standard study parameter in future clinical trials. This will allow the identification of drug concentration threshold associated with bleeding, the establishment of a therapeutic range for different kinds of DOACs and better definition of DOAC-induced bleeding complications.
Non-specific reversal agents like prothrombin complex concentrates, “bypassing agent” like factor eight inhibitor bypass activity (FIBA) and activated FVIIa were used for the correction of DOAC effect. They only had a general antagonizing action on the anticoagulation effect of DOAC without targeting the specific DOACs themselves. Three antidotes for the DOACs are now under various stages of development. Idarucizumab (Praxbind®), the antidote for dabigatran, is now licensed in the United States and recommended for licensing by the European Medicines Agency. Andexanet alfa, the antidote for the oral anti-Xa inhibitors, is undergoing phase III study. Ciraparantag (PER977), an agent reported to reverse the anticoagulant effects of all of the DOACs is at an earlier stage of development [19]. In life-threatening bleeding, administration of antidote or reversal agent before emergency operations shall not be delayed until the availability of test results. Otherwise, the decision on whether antidote is indicated can be guided by suitable laboratory assay as mentioned in the previous section. Drug-specific assay is considered the most suitable candidate given its superior sensitivity and probably better specificity than conventional coagulation assay and better accessibility and faster turnaround compared with mass spectrometry. Measurement of drug activity shall guide the antidote treatment and allow more effective use of this costly medicine. The importance is highlighted by one study on idaruxizumab for dabigatran reversal in which dTT was normal on study entry in nearly one quarter of the study population, indicating little or no circulating anticoagulant in this group of patients, whom benefit from the administration of idaruxizuman was minimal [20]. Although DOAC concentrations warranting the administration of antidote were recommended (e.g., a drug concentration over 50 ng/mL in serious bleeding and 30 ng/mL in patients requiring urgent intervention) [19], these actionable limits have not been validated in clinical studies.
Laboratories should develop customized algorithms on DOACs testing strategy for DOACs based on their need. The relative sensitivity of routine coagulation screening test, especially APTT and TT for dabigatran and PT for rivaroxaban, apixaban and edoxaban shall be validated by calibrated materials. Most published algorithms [21, 22] assume patient’s coagulation status is solely under the effect of DOACs and may not be applicable for patients with massive transfusion, disseminated intravascular coagulopathy (DIC) or presence of lupus anticoagulant that may have contributed to the abnormal coagulation screening results. Moreover, it is not practical to change the service PT and APTT reagents solely for DOACs detection.
The set up of clot-based or chromogenic drug-specific assay needs careful literature review on the performances of different commercially available assays. For example, one study reported overestimation of rivaroxaban levels with an anti- Xa assay utilizing exogenous antithrombin [23] and ISTH [4] recommended against its use. Nevertheless, the choice of commercially available assay may be limited by its compatibility with the automated coagulometers in service.
There are currently no standards or guidelines on the validation of drug-specific coagulation assays. Same principles on validation for clot-based or chromogenic coagulation assay shall follow, including testing for accuracy, within-run & between-run precisions and lower limit of quantification (LOQ). The testing of accuracy may be limited by accessibility to mass spectrometry. This can be resolved by testing accuracy against different lot of calibrators. Precision at low drug concentration is important to determine any significant residual DOAC effect in emergency setting. Assay kit with incorporation of low-level calibrators is favored over those with calibrators only covering the usual on-therapy concentration ranges. For the same reason, LOQ validation is important and the report shall report results as “less than” numerical LOQ value (ng/mL). Testing on plasma collected from normal subjects not taking DOACs shall be carried out to determine the intrinsic anti-Xa or anti-IIa activity from natural anticoagulant, e.g., antithrombin, which may also affect the lowest reportable limit of the assay.
As part of the quality assurance, PT, APTT, TT and fibrinogen activity shall be assessed for samples sent for quantitation of DOACs. When TT is prolonged, heparin contamination shall be excluded by carrying out protamine neutralization test. Before reporting the drug concentration, linearity of the calibrator curves shall be verified. Calibrator curve shall be acquired for every patient sample instead using stored calibrator curves as a control of lot-to-lot variation of calibrators for this relatively infrequent test. Results shall be reported in ng/mL, and there should be an accompanied comment about the appropriate range of results (peak or trough levels) based on publication. Drug level shall be interpreted in light of the time since last dose of DOAC intake as well as the dosage of DOAC taken. It is critical to have continuous surveillance of test performance over time. This can be achieved through enrollment in External Quality Assurance Programme (EQAP) (e.g., College of American Pathologist).
Drug-specific coagulation assay can be performed by automated coagulometers with pre-set dilution and analysis protocols with a low to moderate level on skill requirement and hence amenable to the organization of a laboratory-wide staff training programme to cater for the development of a routine 24-hour DOAC laboratory testing service. Interval refreshment training shall be organized to upkeep staff competence. Clinical pathologists shall be involved in communication with clinicians during emergency management of patients requiring DOAC testing to ensure efficient delivery of accurate information to facilitate patient management.
It is important for laboratories that carry out special coagulation assay to acknowledge the interferences of DOACs on special coagulation assay. These include clot-based and chromogenic assay. ELISA-based and molecular assays are essentially not affected by DOACs (Table 2) [2, 17].
DOACs are more commonly used nowadays. While clinical indications for laboratory testing are more available, there is a pivotal role of laboratories to formulate a testing strategy for DOACs. Routine coagulation screening tests are not informative in most cases. Development of drug-specific assay for DOACs testing is needed. The interpretation of drug level generated by drug-specific assays needs to be facilitated by more data on the association between drug concentrations and bleeding risks expected in future studies.
| Trough (ng/mL) |
Peak (ng/mL) |
|
| Apixaban 2.5 mg twice daily 10 mg twice daily |
20-94 30-412 |
36-100 122-412 |
| Dabigatran 150 mg twice daily |
31-225 |
64-223 |
| Edoxaban 30 mg once daily 60 mg once daily |
130-174 268-336 |
376-412 388-444 |
| Rivaroxaban 10 mg once daily 20mg once daily |
1-38 4-96 |
91-195 160-360 |
| Assay | Anti-FIIa DOAC | Anti-FXa DOAC |
| Clauss fibriongen | May be falsely decreased | No effect |
| One-stage APTT-based factor assays | May demonstrate false decrease in factor activity | May demonstrate false decrease in factor activity |
| One-stage PT-based factor assays | May demonstrate false decrease in factor activity | May demonstrate false decrease in factor activity |
| Chromogenic FVIII activity | No effect | May demonstrate false decrease in factor activity |
| Bethesda assay | False inhibitor present | False inhibitor present |
| AT activity: thrombin substrate | May demonstrate false increase in AT activity; may mask AT deficiency | No effect |
| AT activity: FXa substrate | No effect | May demonstrate false increase in AT activity; may mask AT deficiency |
| PC activity: clot based | May demonstrate false increase in PC activity; may mask PC deficiency | May demonstrate false increase in PC activity; may mask PC deficiency |
| PC activity: chromogenic | No effect | No effect |
| PS activity: clot-based | May demonstrate false increase in PS activity; may mask PS deficiency | May demonstrate false increase in PS activity; may mask PS deficiency |
| PS activity: chromogenic | No effect | No effect |
| PS activity: ELSA-based or LIA-based | No effect | No effect |
| LA testing | Possible to misclassify as LA present | Possible to misclassify as LA present |
| Activated PC resistance | Falsely increased ratio; possible to misclassify as FV Leiden mutation absent | Falsely increased ratio; possible to misclassify as FV Leiden mutation |
NOTICE is hereby given that the 25th Annual General Meeting (AGM) of The Hong Kong College of Pathologists will be held at the Pao Yue Kong Auditorium, the Hong Kong Academy of Medicine Jockey Club Building, 99 Wong Chuk Hang Road, Aberdeen, Hong Kong on 26 November 2016 at 5:00 p.m. with the following agenda:
Dated the 20th day of October 2016.
By Order of the Council
TANG Wai Lun
Registrar
A member entitled to attend and vote at this Meeting is entitled to appoint a proxy to attend and vote in his or her stead. The proxy need not be a member. The instrument appointing a proxy shall be in writing under the hand of the appointer, and shall be deposited at the office of the College (Room 606, 6/F, the Hong Kong Academy of Medicine Jockey Club Building, 99 Wong Chuk Hang Road, Aberdeen, Hong Kong) not less than 48 hours before the time appointed for holding meeting or adjourned meeting at which the person named in the instrument proposes to vote and in default the instrument of proxy shall not be treated as valid. Only the originals of completed proxy forms received no later than 24 November 2016 5:00 p.m. are considered as valid. For Voting Member (referring to Founder Fellow, Fellow and Founder Member), a proxy form accompanies this Notice.
The Companies Ordinance, Chapter 622 of the Laws of Hong Kong (“New Companies Ordinance”) has replaced the Companies Ordinance, Chapter 32 of the Laws of Hong Kong. As a result, the College considers it appropriate to bring the existing memorandum and articles of association of the College in line with the New Companies Ordinance by adopting the New Articles of Association which incorporate certain key changes under the New Companies Ordinance.
In addition, the Council would like to update the definition of Fellow in the Articles concerning Membership. The Fellow shall be a registered medical practitioner, with deletion of “or registered dentist”. The phrase “full registration” is also deleted.
Attached please find: (1) The existing 2013 Memorandum and Articles (no execution clauses included), (2) The merged and amended 2016 Articles (no execution clauses included, watermarked “Amended” and initialled by the Chairman of the meeting for the purpose of identification “New Articles”) and (3) Marked-up version of 2016 “New Articles” with footnotes for easy comparison.
Download the AGM 2016 Timetable
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1:00 p.m. – 4:30 p.m.
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The 12th Trainee Presentation Session
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5:00 p.m. – 5:45 p.m.
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The 25th Annual General Meeting
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5:45 p.m. – 6:00 p.m.
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Reception
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6:00 p.m. – 6:50 p.m.
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Conferment Ceremony Admission of New Fellows and Members and Presentation of Fellowship and Membership Certificates Conclusion of Conferment Ceremony
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6:50 p.m. – 7:00 p.m.
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Group Photo of Stage Party
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7:00 p.m. – 8:00 p.m.
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The 25th T. B. Teoh Foundation Lecture: Dr. LEE Kam Cheong
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| 8:00 p.m. – 10:00 p.m. | Chinese Banquet Dinner |
After the revamp of the classic website, we need to update the QAP webpage to fit the new system. Below is a brief introduction that may help users transiting to the new platform:
The deadline of submission o f the current round will be 31 October. Sorry for the delay in launching the input form. Further enhancement of the webpage is also in progress.
Webmaster
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Exam No. |
Result |
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E16201 |
PASS |
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E16202 |
PASS |
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E16203 |
FAIL |
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E16204 |
PASS |
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E16205 |
PASS |
|
E16206 |
PASS |
|
E16207 |
FAIL |
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E16208 |
FAIL |
|
E16209 |
PASS |
|
E16210 |
PASS |
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E16211 |
PASS |
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E16212 |
FAIL |
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E16213 |
FAIL |
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E16214 |
PASS |
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Exam No. |
Result |
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E16101 |
FAIL |
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E16102 |
FAIL |
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E16103 |
FAIL |
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E16104 |
PASS |
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E16105 |
PASS |
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E16106 |
FAIL |
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E16107 |
PASS |
|
E16108 |
PASS |
Volume 11, Issue 2 August 2016 (download full article in pdf)
Editorial note:
In this topical update, Dr Chloe Mak reviews the history and development of newborn screening, in particular for Hong Kong. Both benefits and limitations of expanded newborn screening were discussed. The latest pilot screening programme, as stipulated in the Policy Address by Chief Executive, was also illustrated. We welcome any feedback or suggestions. Please direct them to Dr. Sammy Chen (e-mail: chenpls@ha.org.hk) of Education Committee, the Hong Kong College of Pathologists. Opinions expressed are those of the authors or named individuals, and are not necessarily those of the Hong Kong College of Pathologists.
Dr MAK Miu Chloe
Department of Pathology, Princess Margaret Hospital
Newborn screening (NBS) is one of the most successful public health programs in the 20th century. In fact, the idea of mass screening was totally new to the society before 1960’s. When Dr Ivar Asbjørn Følling discovered the disease phenylketonuria (PKU) leading to mental retardation in many children [1] and Dr Robert Guthrie invented a simple and reliable screening test using bacterial inhibition test for blood phenylalanine [2] together with the understanding of disease pathogenesis and effective treatment to prevent mental retardation initiated during early asymptomatic phase [3], the proposal of NBS was
born. However, criticisms were vigorously received over the uncertainties of disease nature, assay validity and long-term treatment effectiveness. To begin with, NBS for PKU was tested as a pilot service in Massachusetts in 1962 [4]. World Health Organization (WHO) issued two landmark reports about population screening: “The Principles and Practice of Screening for Disease” [5] and “The WHO Scientific Group on Screening for Inborn Errors of Metabolism (IEM), Geneva” [6]. The latter report elaborates more on screening for IEM.
After the success of PKU screening in preventing mental retardation, the legislation for mandatory screening was made in 1975 in USA. More disorders were added to the panel, such as congenital hypothyroidism (incidence 1 in 2,200) in 1976, congenital toxoplasmosis (1 in 27,800) in 1986, hemoglobinopathies (1 in 2,900) and congenital adrenal hyperplasia (1 in 19,200) in 1990, biotinidase deficiency (1 in 42,000) in 1992, medium-chain acyl-CoA dehydrogenase deficiency (1 in 21,000) and cystic fibrosis (1 in 2,900) in 1999 in the New England Newborn Screening Program of the University of Massachusetts Medical School [7]. The Centers for Disease Control (CDC) launched the Quality Assurance Program for NBS laboratories since 1978 and now with more than 200 laboratories worldwide participated.
The first wave of NBS started in other countries soon, such as Canada in 1963, Singapore in 1965, Japan in 1967, Australia in 1967, Portugal in 1979, while in other Asian areas NBS was mostly initiated after 1980s: Mainland China, Hong Kong, India, Malaysia and Taiwan in 1980s; Bangladesh, Indonesia, South Korea, Philippines and Thailand in 1990s; Mongolia, Myanmar, Palau, Pakistan, Sri Lanka and Vietnam in 2000s [8-10]. The approach adopted was one-test-one-disease and the panel was limited to a few conditions usually including PKU, congenital hypothyroidism, maple syrup urine disease, homocystinuria, galactosemia, cystic fibrosis and/or congenital adrenal hyperplasia.
IEM is a huge group of clinically and genetically heterogeneous metabolic disorders (Table 1). There are more than 1,000 diseases mainly affecting children. The cumulative incidence was reported up to 1 in 800 [11, 12]. Some IEM are amenable to timely treatment with good prognosis. Traditionally, the diagnosis replies on one or more tests for one disease. However, the advent of tandem mass spectrometry (TMS) applications in amino acids and acylcarnitines detection enables the one-test-many-diseases breakthrough in NBS for IEM [13-15]. TMS accurately identifies analytes by their fingerprint molecular mass-to- charge ratios with commendable specificity and sensitivity. It only requires 0.3 mL whole blood to test for more than 30 diseases in a single dried blood spot. The analytical time takes about two minutes for one sample allowing a high-volume throughput with rapid turnaround time in a NBS setting. Table 2 shows the advantages and disadvantages of TMS applications in NBS.
| Table 1. Classifications of IEM |
|---|
|
1. Disorders of amino acid and peptide metabolism |
|
Table 2 Advantages and Disadvantages of TMS Applications in NBS |
|---|
|
Advantages Disadvantages |
In 1998, the New South Wales Newborn Screening Program was the first center to implement expanded NBS based on electrospray ionization TMS [16]. In the next year, the New England Newborn Screening Program introduced an optional metabolic panel for 19 IEM [7]. Twenty IEM patients were identified after 2.5 years screening of 200,000 newborns [17]. The prospective study showed that screened patients had shorter hospitalization and required less extra parental care. There was no significant difference in parental stress among NBS screened true positive, false positive results and normal control groups. In the same year, Germany started its extended screening with an unrestricted approach and since 2005 streamlined into 10 conditions [18]. Japan piloted TMS-based NBS from 1997 to 2007 with screening of 606,380 babies [19] and 65 IEM patients were identified with overall incidence of 1 in 9,330. Mainland China piloted TMS based NBS in Shanghai from 2003 to 2007 with 116,000 newborns screened [20]. Twenty patients were positive for six IEM with mainly PKU, maple syrup urine disease, methylmalonic acidemia and propionic acidemia. The overall incidence of IEM was 1 in 5,800. There were significant differences in the disease spectrum between northern and southern Chinese [21]. For example, classical PKU with phenylalanine hydroxylase deficiency accounts for the majority of PKU in northern Chinese, whereas, 6-pyruvovyl-tetrahydropterin synthase deficiency was much more common among southern Chinese. There were around 1,300 new cases of PKU screened in China each year. Glucose-6-phosphate dehydrogenase (G6PD) deficiency was very prevalent in Guangzhou with incidence of 1 in 28 but not in Northern Chinese [22]. In addition to expanded NBS in some advanced provinces covering more than 30 IEM, congenital hypothyroidism and PKU are mandatorily screened throughout the whole mainland stipulated in the law of maternal and infant health (launched in 1994) and its action program (launched in 2000) [22].
The International Atomic Energy Agency had devoted a total of $6.7 million USD to assist developing countries developing the infrastructure for NBS, in particular for congenital hypothyroidism [23]. In 2008, the Working Group of the Asia Pacific Society for Human Genetics on Consolidating Newborn Screening Efforts in the Asia Pacific Region was formed with representatives from 11 countries, viz. Bangladesh, China, India, Indonesia, Laos, Mongolia, Pakistan, Palau, Philippines, Sri Lanka and Vietnam. [24].
In 2006, the American College of Medical Genetics (ACMG) announced a consensus statement to standardize the NBS panel and decision matrix with recommendations of a core panel of 29 disorders and 25 additional secondary targets disorders [25]. It also provides the act sheets and confirmatory algorithms on each condition (http://www.ncbi.nlm.nih.gov/books/NBK55827/).
Wilson-Jungner criteria have been recently revisited in the context of genomic and modern medicine. The emphasis has been shifted towards more on the benefits to the affected baby and the family from early diagnosis and the availability of a satisfactory medical system for subsequent patient management [26]. Whether curative treatment is available or not, this is not a mandatory pre-requisite for NBS implementation.
In Hong Kong, two metabolic conditions have been screened on a population basis namely congenital hypothyroidism and G6PD deficiency since March 1984 under the Neonatal Screening Unit of Clinical Genetic Service, Department of Health. The local incidence of CH is about 1 in 2,500, while that of G6PD deficiency is 4.5% in male and 0.3% in female newborn [27]. The program significantly lowered the mortality and morbidity. Apart from antenatal education through the Maternity and Child Health Centers, the Department of Health also provides follow-up and counseling to affected families.
The third was neonatal hearing screening. Language development is significantly improved if the hearing loss is treated before the age of 6 months. A local feasibility study was performed in 1999 screening 1,064 infants with an incidence of permanent deafness 1 in 355 [28]. A two-stage program was implemented in all Hospital Authority hospitals with maternity service since 2007 [29].
In 2008, a Coroner inquest was called into the acute death of a 14-year-old boy with a postmortem genetic diagnosis of glutaric acidemia type II (multiple acyl-CoA dehydrogenase deficiency) [30]. The Coroner’s report recommended that “the Department of Health, the Hospital Authority, the Faculty of Medicine of various universities and others concerned should carry out a feasibility study to see whether universal check may be carried out on all newborn babies for congenital metabolism defect” (http://www.judiciary.gov.hk/en/publications/coro ner_report_july08.pdf).
In 2012, the University of Hong Kong conducted the first territory-wide pilot study funded by the SK Yee Medical Fund Foundation (http://hub.hku.hk/cris/project/hkugrant107939). The study tested the feasibility of expanded NBS in public hospitals with an OPathPed model [31]. In 2013, a private NBS for IEM service commenced in the Chinese University of Hong Kong, sponsored by Joshua Hellmann Foundation for Orphan Disease (http://www.obg.cuhk.edu.hk/fetal-medicine/fetal- medicine-services/jhf-newborn-metabolic- screening-program/).
In 2015, the Policy Address by the Chief Executive announced that a working group was established between the Department of Health and Hospital Authority to study the feasibility and logistics of expanded NBS for IEM in the public healthcare system (http://www.info.gov.hk/gia/general/20150 1/14/P201501140477.htm).
The feasibility study in the form of a pilot study was officially initiated on 1 October 2015 and lasts for 18 months, testing in two public hospitals with the collaboration between the Department of Health and the Hospital Authority. The aim of this pilot study is to demonstrate the feasibility of implementing NBS for IEM while developing and optimising education on IEM to public and healthcare professional, the screening tests, laboratory algorithms, clinical management and follow-up algorithms and programme evaluation. Twenty four conditions are included (Table 3). Educational materials were distributed to public and healthcare professionals (figure 1). A video was broadcasted in antenatal clinics and postnatal wards (Cantonese, Mandarin and English version).
|
Table 3 Screening Panel of Government-initiated Pilot Study |
|---|
|
Disorders of Amino Acids Maple syrup urine disease Citrullinemia type I Citrullinemia type II Tyrosinemia Type I Homocystinuria Disorders of Organic Acids Multiple carboxylase deficiency Glutaric acidemia type I Methylmalonic acidemia Propionic acidemia Isovaleric acidemia 3-hydroxy-3-methylglutaryl-CoA lyase deficiency Beta-ketothiolase deficiency Disorders of Fatty Acid Oxidation Carnitine uptake deficiency Others Congenital adrenal hyperplasia Biotinidase deficiency |
NBS for IEM enables early diagnosis and treatment, prevents morbidity and mortality, avoids unnecessary investigations, alleviates family’s anxiety, predicts prognosis and provides valuable information for family planning and genetic counseling. In addition, some maternal diseases with treatment implications can also be detected during NBS, such as primary carnitine deficiency, PKU and vitamin B12 deficiency. The storage of DBS on a population scale can be a valuable asset in quality assurance, biomedical researches and forensic investigations.
NBS is shown to be cost- effective. Although randomized clinical trial on clinical utility and cost-effectiveness is difficult due to the rarity of individual IEM, cost- effectiveness in PKU [32-34], congenital hypothyroidism [35-37] and MCADD [34, 38, 39] were well documented. Table 4 shows some examples of studies on the outcome comparison between screened and unscreened patients.
There are also limitations in expanded NBS. First, because of the short history of expanded NBS developed only in the last two decades, long-term evaluation is still lacking. Recently, the Southeastern Newborn Screening Genetics Collaborative and the Public Health Informatics Institute collaborated to address the long-term issue through international effort. Second, patients with early symptom onset before release of NBS result would not benefit. False negative can happen to patients with mild or atypical presentation or use of non-standardized cutoff values and testing strategies. Third, since TMS allows one-test-multiple-diseases, some diseases which are not required by the program would also be unraveled. Conditions which are benign or with doubtful pathological significance may be identified, for examples, 3-methylcrotonyl-CoA carboxylase deficiency and short-chain acyl-CoA dehydrogenase deficiency. Detection and disclosure of carrier status such as in sickle cell disease and cystic fibrosis may create confusion to the parents [40, 41]. Fourth, although screening is available and even mandatory in some countries, treatment is not and not all screened positive children received proper treatment. Some treatments require special drugs and milk formulae. The clinical follow-up system may not be as well established as the screening program. Fifth, NBS results can be false positive or inconclusive. The overall sensitivity and
specificity of TMS-based NBS is already commendable more than 99% with false positive rate from 0.07% to 0.33%, positive predictive values from 8% to 18% [20, 42-46]. False positive may lead to unnecessary hospitalizations and parental anxiety [47]. Measures such as better education and communication, algorithmic interpretation rules and two-tier testing system, can be implemented to reduce false positive rates andpotentialadverseeffects.
NBS represents the highest volume of genetic testing. It is more than a test and it requires a comprehensive healthcare system from pre- analytical, analytical to post-analytical phase involving expertise from public health, healthcare management, clinical, pathology and information technology. The field of NBS and IEM is still expanding. More disorders are under evaluation and covered such as severe combined immunodeficiency [48, 49] and X-linked adrenoleucodystrophy [50]. Various different or new technologies are applied to enhance the diagnostic performance, increase throughput, allow more automation and decrease costs [51-54]. Although a genomic approach for NBS is technically feasible, it entails a lot of difficult technical, clinical, social and ethical issues with hazards more than good [55]. On the other hand, using SNP array approach to detect a large panel of well-known pathogenic mutations on a wide spectrum of disorders would be more pragmatic. Expanded NBS is shown to be economically valid with significant reduction in critical care and chronic medical care expenditures. Last but not the least, NBS saves lives.
Table 4 Outcome comparison between screened and unscreened IEM patients
| Reference | Study | Results |
|---|---|---|
| Wilcken et al. [56] | Screening more than two million babies | The handicap rate 1 in 74,074 in the clinical group versus 1 in 232,558 in NBS group |
| Boneh et al. [57] | Six babies with glutaric acidemia type I detected by NBS | These patients benefited from mild protein restriction and carnitine supplement. All patients except one had normal cognitive and gross motor development, versus in unscreened patients with glutaric acidemia type I leads to acute encephalopathy and debilitating dyskinetic dystonia. |
| Klose et al. [58] | 57 patients clinically diagnosed with organic acidemias and fatty acid oxidation defects | Sixty-three percent of these patients presented within the first year of life and 54% suffered from acute metabolic crises with eight deaths. Majority of these metabolic crises (93.5%) and death (87.5%) could have been prevented by expanded NBS and early treatment. |
| Schulze et al. [44] | 250,000 neonates for 23 metabolic diseases and 106 patients with positive screening results followed for 42 months | Seventy patients received proper treatment and remained asymptomatic. Six patients developed symptoms and three died. Nine patients presented earlier than the availability of screening results. Overall, 1 in 4,100 babies benefited from the early screening and subsequent treatment. |
| Cipriano et al. [59] | Decision-analytic model analyzing 21 diseases taking into account of the disease severity, analytical sensitivity and specificity, need of confirmatory tests, specialist management, start-up and operating costs, hospital-related costs and potential deflation of future costs and benefits. | Bundling PKU together with 14 diseases was the most cost-effective strategy with $70,000 Canadian dollars per life-year gain. |
| Seymour et al. [60] | Systemic reviews published by the Health Technology Assessment in United Kingdom | Recommended screening for PKU, biotinidase deficiency, congenital adrenal hyperplasia, MCADD and glutaric acidemia type I |
| Pollitt et al [61] | Systemic reviews published by the Health Technology Assessment in United Kingdom | Considered screening as many conditions as possible with the emphasis on the benefits of early diagnosis to the patients and the family. The availability of effective treatment was not a compulsory pre- requisite. |
| Filiano et al. [62] | Cost-benefit study | The lifetime costs for one cerebral palsy patient from infancy to 65 years old were $167,000 to $1 million USD as at 1998. The costs included medical charges, developmental services, special education and lost wages. Projected yearly savings of $36,600,000 (USD as at 1998) could be achieved through expanded NBS. The saving was twice of the incremental cost for NBS. |
| Couce et al. [63] | 10-year clinical follow-up of 137 IEM patients picked up by expanded NBS | The incidence was 1 in 2,060 newborns. With the long-term management, death rate was only 2.92% and majority of the survivors (95.5%) were asymptomatic after a mean observation of 54 months. |
| Linder et al. [64] | 373 IEM patients detected from a cohort of 1,084,195 newborns studying the efficacy and outcome of 10-year experience in expanded NBS | Presymptomatic diagnosis and treatment of other IEM achieved the same clinical benefits as in PKU. |
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College Written Exam 2016 (Council Meeting 14 July 2016)
Results of College Written Exam in Chemical Pathology and Clinical Microbiology & Infection 2016
| EXAM NO. | RESULT |
| E16206 | PASS |
| E16207 | FAIL |
| E16209 | PASS |
| E16211 | PASS |
Candidates who failed in written exam cannot proceed further in Fellowship Assessment in 2016.
Passed candidates can proceed further in Fellowship Assessment in 2016.
This year is the 25th Anniversary of The Hong Kong College of Pathologists. Since the establishment, the most important mission of our College is to safeguard the quality of training, so as to ensure high standard of pathology service to our patients.
November is the time when new Fellows and Members are admitted to the College. On behalf of the College, I would like to extend my sincere welcome to all new Fellows and Members to the family of The Hong Kong College of Pathologists. This is a moment of celebration for the new milestone. After overcoming years of serious training and prevailing the challenge of examinations, our Fellows are now quali ed specialists in Pathology who are consultants to bedside doctors. This is also a moment of gratitude. Trainers in Hong Kong should be proud of our tradition of sel ess contribution to training. Our trainees and our new Fellows should thank your trainers for their tireless supervision. Of course, you should also thank your family for their unfailing support.
It is now increasingly known that pathologists play a pivotal role in the prevention, diagnosis, and treatment of diseases. The continuously changing clinical scenario and widening scope of knowledge need our vigilant attention to adaptation of training. Due to the increasing use of genetics and genomics in modern pathology, our College is preparing for the establishment of a post-specialty fellowship in Genetic and Genomic Pathology.
To ensure provision of safe service, long term planning of manpower and new services in pathology is important. The Academy and our College will hopefully play a more active role in the future.
To let our community understand our work, the College has been reaching out. With President as representative, our College has expressed views in task forces and specialist panels on health issues. In liaison with the international pathology community on International Pathology Day, a two days’ workshop has been organized in November for the public and secondary school students. With our sincere and persistent e ort, we should be able to break the barrier surrounding our profession and communicate better with the public and health professionals.
Let me express our thanks to Fellows and friends for the continuous support of the College. We sincerely welcome active participation from our new Fellows to strengthen the profession and to better serve the community.
Professor CHEUNG NgaYin,Annie November 2016
We are honoured to stand on the shoulders of giants so that we can continue to enhance the development of pathology based on the achievements of our senior Fellows and colleagues. In this newsletter, tributes are paid to two distinguished pathologists who have contributed tremendously to the development of pathology in Hong Kong. Professor Sir Roddy MACSWEEN and Professor Li Chong CHAN left us in the winter of 2015. This is a personal loss to me, as I have been fortunate enough to have worked with and learnt from them for decades. To express our appreciation and grieve, Professor Faith HO and Professor John NICHOLLS, with the help of Fellows, colleagues and friends, have contributed two articles to pay tributes to these two giants in the eld of pathology.
Indeed, pathology is facing signi cant challenges, from manpower shortage to technological advancement and raised expectations from community. Our College will continue to safeguard the standard of our profession and quality of service to our patients. To achieve this, our College will enhance representation in various local task forces and committees so that our views can be heard. A Task Force on Training for Genetics and Genomics, led by TEC Chairman Dr Michael CHAN, with membership including Chief Examiners and Specialty Board Chairmen, is nalizing the preparation for establishing the post-specialty Fellowship in Genetic and Genomic Pathology.
Introduction of pathology to the general public continues to be enhanced through the International Pathology Day. Last year, we have focused on high school students and a two days’ workshop was conducted with great success. I must thank Dr Michael WONG and the team of young pathologists who made such success possible.
We continue our collaboration with the Hong Kong Academy of Medicine and our sister Colleges. Internationally, I participated in the International Liaison of Pathology Presidents (ILPP) meeting in Melbourne so that knowledge and views can be shared with international pathology professionals.
In 2016, the quinquennial ( ve-yearly) inspection of laboratories for training of the various specialties will be conducted. This is an enormous exercise that demands joint e ort of the large number of inspectors involved. I would like to thank in advance the great contribution from all the Educational Supervisors, inspectors and particularly the Convenors for this inspection exercise.
Professor CHEUNG NgaYin,Annie May 2016
