Comments

Hume-Lee Transplant Center | 03/18/2023

This is a rule that will increase cost, increase demand on labs, possibly decrease organ access. Very poor idea.

DonorConnect | 03/17/2023

DonorConnect strongly opposes the proposal to require duplicate HLA testing for all of the reasons already stated by many of our OPO and Transplant colleagues that oppose this proposal. Because this proposal does not have a sound evidentiary basis, it appears to be a change for the sake of change rather than a change that will truly lead to improvement.

Anonymous | 03/17/2023

As a histocompatibility laboratory director for more than 30 years, I strongly oppose this proposal. As others have stated, the doubled cost, increased time, increased workload, and staffing difficulties would make this untenable. The problem of an incorrect typing is extremely rare and most of the discrepancies seen would not be solved by doing two typings, especially using the same method. This proposal was prompted by a paper that called for duplicate typings using two different methods, which makes sense in theory but in practice the vast majority of labs only have one typing method they use on stat deceased donor typings. The additional cost to labs to bring on another method or validate another vendor's kit for the same method would be burdensome.

Michael Gautreaux | 03/17/2023

This might the be best example of using a cannon to kill a fly that I have ever seen in all of my career in the histocompatibility field. In any human endeavor, errors happen. Errors in donor typings happen for all kinds of reasons and just making labs do the test twice is opening the doors for compounding such errors. In addition, the quality of the test kit from the leading manufacturer of real-time PCR HLA typing kits has seriously eroded. There is change coming from vendors in using next generation sequencing for deceased donor HLA typing. Requiring double typings for NGS will essentially prohibit its use in deceased donor typings. Trust the labs to fix problems with typing without a needless and thoughtless mandate to just do it twice.

At a time when laboratories are having severe difficulties in maintaining laboratory staff who are willing to take call or work overnight shifts, UNOS is proposing doubling their workload for deceased donor typing. In addition, this will impose a burden on OPOs that have to pay for such a confirmatory test or on labs where the OPOs refuse to pay. A double whammy of needless bureaucracy, if ever I've seen one.

Luke Preczewski | 03/16/2023

This proposal is offered with no evidence basis, imposes a monstrous burden, and seems as likely to do harm as help. It is not clear to what degree, if any, it would reduce the already extremely rare errors that have occurred. Meanwhile, it would add hundreds of dollars to the cost of every single transplant. At typical rates for HLA typing multiplied by the total donors each year, the total cost to society appears very likely to exceed $5,000,000. That is a staggering (and I believe conservatively estimated) sum for a proposal so devoid of evidence basis. Not only should this proposal not be adopted, the OPTN should look at the process that allowed it to be proposed without a comprehensive assessment of both costs and benefits. Proposals of this magnitude should not go to public comment without both clear statement of cost and credible estimate of benefit to patients and the system. 

Beyond the huge cost, it creates operational challenges that stand to add delays. Already taxed financially and temporally by runaway attempts to allocate organs greater and greater distances, the last thing the system needs is one more cause of delay and ultimately discards. The bar should be high to further complicate and slow allocation; instead, this is offered with only small and unsure benefit.

UC San Diego Center for Transplantation | 03/15/2023

The UC San Diego Center for Transplantation applauds the Histocompatibility Committee's efforts to improve this important patient safety aspect of transplantation. We agree with the Committee’s benefit/risk analysis of requiring confirmatory HLA typing for all deceased donors, particularly as the Community is increasingly relying on virtual cross-matching for allocation and acceptance of organs. While the incidence of critical HLA typing errors appears to be low, we would argue that acute rejection, graft failure, recipient death and non-utilization of donated organs due to such errors should be never-events particularly considering the simplicity of the solution proposed here.

We would however, recommend one minor administrative change to the proposed language to clarify the requirements around resolving indeterminate or discrepant results. We recognize that HLA labs are required to have these processes in place, but for the sake of clear intent, we would recommend adding the following:

"Prior to reporting any deceased donor HLA typing results to the OPO, the laboratory must review both test results and determine that no critical discrepancies are present.... the laboratory must have a process to address critical discrepancies in their written protocol."

New England Donor Services | 03/15/2023

NEDS opposes the proposed requirement for repeat deceased donor HLA typing. The proposal as outlined does not present compelling evidence that the small number of HLA typing discrepancies when repeated warrants adoption of duplicate HLA typing of all deceased donors. Discrepancies in repeat HLA typing can be a result of transcription errors, resolution of the typing method, and other variables, which are not likely addressed with duplicate HLA typing. The proposal does not specify how many of the reported discrepant HLA typing results were at a resolution level that would impact donor/candidate matching. It also does not appear from the proposal that any patient harm resulted from the small number of HLA typing discrepancies reported in the 5-year period. Mandating duplicate HLA typing of deceased organ donors comes at a significant cost to the donation and transplant system (one estimate as high as $23 million annually). The proposal would also have significant impact lab staffing, resources, materials and quality systems without actual improvement in patient safety. The proposal also requires that duplicate testing be performed only on deceased organ donors, when time is limited, but does not suggest duplicate HLA typing of candidates or living donors despite the abundant time available to perform duplicate HLA typing.

Sierra Donor Services | 03/15/2023

Sierra Donor Services (SDS) strongly opposes the proposal requiring two HLA typings be performed on all deceased donors with samples drawn at two separate times. Patient safety is of utmost importance to SDS and to the transplant community at large however, the policy proposal appears to be a broad solution without evidence that the identified problem will be significantly mitigated. The proposal is an attempt to fix a downstream concern without working to correct the upstream issue, specifically labs mixing up samples. SDS highly recommends the Histocompatibility Committee further study the issue and incorporate the necessary upstream controls to mitigate sample switching at the lab. Additionally, SDS recommends the Histocompatibility Committee study the process and outcomes of labs currently utilizing duplicate testing, to gain more knowledge about comparative rates of incidents, root cause of the incidents, and possible solutions if necessary. Significant additional costs and processing time will be incurred by labs and OPOs and should be weighed against potential benefits and confidence in elimination of errors before implementing any such wide reaching policy change.

NJ Sharing Network | 03/15/2023

NJ Sharing Network recognizes the accuracy of donor HLA typing is critical to the success of transplantation, especially in light of broader organ sharing and the fact that virtual crossmatch is an increasingly common clinical practice for histocompatibility laboratories and transplant programs. However, we STRONGLY OPPOSE the proposal due to the following concerns, about the lack of transparency and clarity of the data presented as well as the data source and analysis:

1. OPO and OPO-affiliated histocompatibility laboratories will be impacted significantly due to increases in workload, testing cost, staffing, and other resource requirements, as well as process complexity.

2. Turnaround time of deceased donor typing and OPO donor case time will increase.

3. 12 cases of a sample switch between 2015-2021 is equivalent to a rate of 0.01% (78,378 deceased donors plus approximately 20% more donors attempted). By the numbers, these are rather rare events. Why would we want to “punish” the entire OPO community and the histocompatibility laboratories by requiring a universal confirmatory typing on two samples (i.e., double the workload) when only a handful of problematic laboratories committed the errors?

4. How did the histocompatibility committee evaluate and come to the hypothesis that the confirmatory HLA typing on a second donor sample, which most likely will be collected minutes after the first sample, will effectively eliminate all of these errors, as opposed to creating more room for errors since the number of samples will essentially double?

5. It is important to note that, at an average cost of $1140 per deceased donor typing, and a STAT fee of $320, this proposal could result in an increased financial burden to the donation and transplant community of over $26,000,000.

6. At roughly 16,500 donors/year nationally (average from 2020-2022, including the actual number of donors and an assumption of 20% more donors attempted), a 0.3% rate of critical HLA discrepancies would be equivalent to 50 reported cases per year. Did the data show that there were, in fact, 50 cases of critical HLA discrepancies identified every year?

7. How were these discrepancies identified? What is the proportion for self-reported events vs. TIEDI via repeat HLA typing by the recipients’ transplant centers?

8. At what stage of the deceased donor evaluation did these errors occur, i.e., errors occurred within the HLA lab during the testing process or by the OPO during sample collection and/or the data entry process?

9. What were the nature of these errors, i.e., sample mislabeling, sample mishandling/switch, transcription, interpretation, allele ambiguity caused by inherent assay limitations, discrepancies between antigen-level resolution reported by the OPO lab and two-field-resolution reported by the transplant center labs, etc.?

10. Did these errors occur only in an isolated group of laboratories, and did any occur more than once in a single laboratory?

11. Did the laboratories/OPO that committed the errors submit appropriate root cause analysis and corrective action and preventive action (CAPA) to UNOS for review? What was the outcome of these events (i.e., issuance of letter of non-compliance, member not in good standing, suspension of OPTN membership, reporting to CMS/CLIA, etc.)? Is there an existing mechanism for their CAPA effectiveness check? Is there any process for ongoing monitoring in these problematic laboratories?

12. What was the involvement of the laboratories’ accrediting organizations (i.e., ASHI or CAP) in any of these critical errors? What was their action, and what were the outcomes? If there was no involvement of accrediting organizations, why not?

Midwest Transplant Network | 03/15/2023

Thank you for the opportunity to submit comments on the Organ Procurement and Transportation Network’s (OPTN’s) policy development process. Midwest Transplant Network and our HLA Laboratory which serves two OPOs and 11 solid organ transplant programs, are Strongly Opposed to the proposal to Require Human Leukocyte Antigen (HLA) Confirmatory Typing for Deceased Donors. We have concerns regarding the data presented including the analysis and source of this data. We offer the following comments for your consideration:

1. OPO and OPO-affiliated histocompatibility laboratories will be impacted significantly due to increase in workload, testing cost, staffing and other resource requirements, as well as process complexity. HLA laboratories are not immune to the issues faced with staffing shortages in healthcare and burnout from excessive overtime and on call responsibilities. 2. Turnaround time of deceased donor typing and OPO donor case time will increase, negatively impacting the ability to place organs, especially those of expedited cases.

3. The proposal is based on multiple sources of data with various inconsistencies and incomplete data collection, leading to concerns regarding the interpretation of the data. The following sources of data were cited in the proposal:

a. Quarterly Discrepant HLA typings report in OPTN Data Service Portal in UNet. This was not updated until mid-2022 to apply the logic of the HLA equivalency tables. The update reduced the discrepancies that were simply due to an increased typing resolution and were not due to a true error in HLA typing. Therefore, data pulled from 2015-2021 is not reflective of corrections addressing the incorrect assignment of these as critical typing discrepancies.

b. TIEDI—TIEDI only flags non-equivalent donor or recipient HLA values for A,B,DR loci for kidney, pancreas, and KP. Review of critical donor HLA discrepancies should be reviewed for all organs and for all HLA loci. As with the Quarterly Discrepant typing report, this report also needs updated logic to address issues categorized as discrepancies due to increased typing resolution of confirmatory laboratories (ex. Donor lab uses qPCR, but confirmatory lab uses NGS).

c. The proposal states that the OPTN Histocompatibility Committee also reviews HLA critical donor discrepancies quarterly. Donor HLA typings are compared from every match run executed, the Donor Histocompatibility Form (DHF), and Recipient Histocompatibility Form (RHF), and therefore will not include discrepancies identified and remedied prior to match run. Between 2015 and 2021, there were 471 critical HLA discrepancies. This review does not include a root cause of the discrepancy communicated by the laboratories involved, but 18 discrepancies involved more than half of the donor’s HLA typing being critically discrepant. In total, 0.2% of HLA typings between 2015 and 2021 were critically discrepant. However, the committee meeting minutes from 03/02/22 indicate that when this data was reviewed, discrepant typings were categorized as:

• “Sample Integrity Issues” (which can represent the incorrect use of a sample)

• technical or transcription errors

• “Split vs. Parent.” “The information indicated that during the last few months the critical error percentage has been hovering between 0.1% and 0.3%, as a total of all donors. The Chair pointed out that this represents a substantial decrease from previous time periods. When looking at critical HLA discrepancies on an annual basis from 2015 through 2021, the largest categories of typing errors occurred as clerical errors/technical/interpretative errors. According to the data provided, DPB1 continues to be somewhat of an issue, but that is partly related to the complexity of DP typing generally.” The committee report also notes that that following the implementation of the HLA double-entry in UNet in early 2020, the percentages regarding critical discrepancies are trending in a positive manner. Essential information regarding root cause analysis of these issues is missing and critical discrepancies due to sample switching was not noted as an area of concern.

d. OPTN Patient Safety Portal 2015-2021—This data is not inclusive of all events that occurred, as reporting these discrepancies to the OPTN Patient Safety Reporting Portal is optional. Of the 94 of the voluntary reported HLA discrepancies, 40 were due to clerical errors, 26 due to other technical/interpretive typing (20 due to assay or software issues), and 12 events that occurred due to samples being switched. Upon review of the Histocompatibility Committee meeting minutes from 03/02/22 regarding the 2015 – 2021 Patient Safety Portal Reports, the committee clarifies that based on the reported data, there were 94 total events from 2015 through 2021 that were HLA-related. Yet only 28 events of the 96 events could be aggregated and reported: 12 were due to incorrect samples/sample switch, one related to Bw4 or Bw6 issues, two due to DRB345 issues, four associated with DR52 Null issues, and nine related to DPB1 errors. The committee held further discussion regarding the more frequent 40 clerical errors and another 26 errors associated with other technical/interpretative typing at this meeting. These errors propose a similar risk to patient safety if incorrectly reported in UNet, yet this proposal does not address those issues. It was noted by the committee that of the 94 events, it was determined that only three patients potentially had adverse events of an immunological origin. UNOS staff reminded the Committee members that it is not possible to determine the exact cause due to the data reporting limitations. This reinforces our concerns about the data used for this proposal.

e. The proposal cites that evidence that exists outside of OPTN reporting channels to support multiple sample collections. In a 2022 research article was published by the Immunogenetics and Transplantation Laboratory Department of Surgery staff at the University of California San Francisco (UCSF), a laboratory whose internal protocols include HLA confirmatory typing. In this article, researchers examined four HLA critical discrepancies from within their lab between 2018 and 2021. However, the author himself has stated in the public comments: “the policy proposal must mandate using two different test methods (e.g., RT-PCR, rSSO, SSP, Nanopore) or methods from two different vendors to type samples drawn at two separate times. Using one method on two separate samples will not resolve the erroneous typing.” Prior to implementing a broad policy, we request that complete and current data be used. Would the OPTN, MPSC, and Histocompatibility Committee consider ways to encourage the self-reporting of issues in the Patient Safety Portal thus allowing for greater collection of data, including more detailed root cause analysis of critical typing discrepancies? Data collection should be inclusive of all organs, all HLA loci, and be reflective of potential sources of error through the entire testing and reporting process, not just for those identified by TIEDI after completion of a match run and allocation. If a discrepancy is caught and reallocation occurs, is this error still captured by the TIEDI system or are the DHF and RHF only reflective of the corrected match run, thus indicating no issue occurred? We should be aware of HLA discrepancies that cause allocation issues even if the risk to patients has been mitigated by reallocation using correct typing. We thank you for the opportunity to submit comments and are Strongly Opposed to this proposal.

LifeShare Transplant Donor Services of Oklahoma | 03/15/2023

Our OPO strongly opposes this requirement for the following reasons:

One, the number of discordant results is VERY low and does not in our opinion justify doubling the testing burden (and cost).

Two, the assumption would appear to be the donor center typing is the one in error when there are discordant results. In fact, it’s reasonable to assume that occasionally the donor center typing is correct and the recipient center is incorrect, especially given the interpretive nature of some of the testing. This further minimizes the theoretical benefit of doubling the donor testing burden.

Three, there still will be discordant results between donor and recipient center typing; verification at the donor end will not eliminate this nor will it eliminate the confirmatory test most centers' labs perform.

Fourth, the policy will double costs to the OPOs, and eventually patients and payers with limited benefit, and is being proposed by representatives of labs that will financially benefit from the requirement.

We strongly oppose mandatory, donor-center confirmatory testing of HLA.

Infinite Legacy | 03/15/2023

As currently required, one test is adequate because the test provides a high rate of accuracy; requiring two tests does not adequately address the root cause of the errors. Any proposal should include requirements and procedures for both OPOs and Transplant centers when discrepant results occur. Requiring the completion of two tests would not change the current practice of transplant center labs choosing to repeat HLA testing at the transplant center HLA lab due to variations in testing and interpretation at each lab. While we appreciate the impact that this has on a very small set of recipients, we would like to see the focus shift towards more training and standardization at the HLA lab. We would also appreciate more guidance on developing best practices for virtual crossmatching.

Mid-America Transplant | 03/15/2023

See attachment.

View attachment from Mid-America Transplant

Region 6 | 03/15/2023

0 strongly support, 2 support, 1 neutral/abstain, 9 oppose, 2 strongly oppose

During the discussion several attendees commented that more data was needed to understand the problem and the impact to Labs/OPOs/Centers related to cost, resources and time. Several attendees commented that this solution may not even solve the problem. One attendee commented that and this should be addressed with individual labs and not mandated for all labs. Another attendee asked for more data about the cases with switched samples and the outcome for the kidneys post-transplant. One attendee commented that if the lab uses the same platform for both samples potentially both typing’s would be incorrect. 

Kevin Burns | 03/15/2023

I appreciate the opportunity to provide feedback on this policy proposal and thank the histocompatibility committee specifically and the general OPTN/UNOS community for working towards making the organ transplant system better. As a histocompatibility laboratory director who has overseen 5 laboratories providing deceased donor typing for 5 OPOs and 9 transplant programs, I strongly OPPOSE this policy proposal. This proposal presents admittedly weak/insufficient data to support the policy change and the proposal completely lacks any type of real impact analysis or modeling while this proposal would surely have significant financial and operational impact on both OPOs and the laboratories that support them. I do agree with a focus on quality and continuous improvement in patient safety and that this solution should be considered in a differential of solutions. However, with inadequate problem evaluation and apparent absence of potential alternative solutions being evaluated we are setup to make greater problems than those we are hoping to fix. After reviewing comments already submitted, including from other laboratory directors in support of this measure, I disagree with the conclusion that this creates significant safety improvements relative to the cost/burden on the system as well as some of their arguments supporting it. Some specific key flaws in the arguments for the proposal are:

1. It is presented in manner that this will correct almost all potential types of errors without data to back that up. However, the obvious target the proposal addresses is the exceedingly rare sample swap. The rate of sample swaps appears to be significantly lower than the statistics presented, when stating that 471 critical discrepancies occurred and 0.2% of typing had critical discrepancies over a 7 year period. This data doesn’t explain the differences between these because 471 is 0.2% of 235,500 which 3x the number of donors between 2015-2021. Since there are basically 2 critical discrepancies possible at each locus tested per donor, at that time there were over 1,235,890 potential data points for critical discrepancies. If we remove 30% of those due to them being liver only donors that may have not been HLA typed (I cannot easily determine how many of the donors are liver only from OPTN), there would still only be a total of 0.05% of typing data points that were critically discrepant. Likewise, if we assumed that there was no overlap in the 12 and 18 potential sample switches reported by voluntary and committee review of discrepancies and that 30% of the 78,378 donors were liver only (again, I’m making this number up due to lack of ability to easily see this on the OPTN data website and hope I’m overestimating the number of liver only donors), this would still yield a sample switch rate of only 0.05%. The data does not tell us where the errors occurred, nor if the original data was incorrect or even if the discrepancies were between different transplant program labs instead of the lab that performed testing for allocation. The references do not clarify the data and in fact also point to the most common critical HLA discrepancy problems being dominantly clerical (and improving with data entry policy updates) and due to complexity of DPB1 assignment and not sample switches.

2. There is no impact analysis and conservatively, if you assume 7.5% increase in donors per year which was the average increase from 2015-2017, 30% liver only donors not typed, 20% typed but not transplanted, 3% inflation and very conservative cost of $600/donor, if implemented Jan 2023 the cost would exceed $72 million for 2023-2029. With a stable rate of 0.05% sample switches (again likely overestimated due to overlap of the reports), there would be 55 sample switches and the cost would be >$1.3 million dollars per sample switch corrected if this was 100% effective and it will not be 100% effective. Reference #11 significantly underestimates the cost of duplicate typing and appears to be top of mind determination rather than actual evaluation. Since this is taxpayer funded, we owe the public for both quality outcomes and fiscally responsible operations. Several HLA technologists and others have rightly commented on the negative impact this will have on their ability to complete the additional testing without this introducing more problems and potentially more errors. We must account for not all laboratories being sufficiently staffed or equipped to taken on this extra burden. Staffing shortages are already significant, and this will make that worse in multiple ways.

3. Many argue that this is equivalent to the repeat ABO typing requirement. This drastically undermines the differences between ABO & HLA typing. As a transfusion medicine physician and former blood bank medical technologist, as well as an HLA director, I assure you that this is not comparable. ABO typing requires 90 minutes. ABO assignment is made by simple agglutination techniques involving a handful of reagents and HLA typing requires numerous DNA primers (and/or probes) with complex software analysis required to interpret results. ABO typing has only 8 potential options inclusive of A1 vs non-A1 subtypes or being unable to subtype A, while HLA genes are the most polymorphic genes known with numerous serotypes documented and numerous other alleles without serological equivalents. HLA typing costs over 2000% more than ABO typing. And clinically, hyperacute rejection is a substantial risk of ABO incompatible transplants, while hyperacute rejection due to HLA incompatibility is uncommon even in transplants across significant DSA. The only thing these 2 tests truly have in common are that they are tests for histocompatibility, but they are not equivalent.

4. No test or process is perfect and so I ask where do we draw the line? Do we require all deceased donor evaluation components to be performed in duplicate such as infectious disease testing, imaging, donor questionnaires, etc. Furthermore, we know that patient testing is at significantly higher chances of being done on incorrect samples. Should we perform duplicate testing on all patients for each test prior to allowing them to be transplanted? No, this is neither reasonable nor feasible.

5. We are still not recovered from supply chain issues that started with the COVID-19 pandemic. Blood collection tubes are still in national shortage, our HLA vendors have had struggled to get supplies needed to manufacture kits and still have been screening orders and needing to underfill order requests. We can not be assured that this increase in testing is feasible.

6. The argument that this is required due to increased utilization of virtual crossmatching is likewise invalid. If our current process and policy for HLA typing of deceased donors lacks sufficient reliability, then transplanting on virtual crossmatches would be unnecessarily risky and the numerous programs transplanting on virtual crossmatches which has been occurring for years would be putting patients at unreasonable risk of harm. I do not believe this to be universally true and clearly the transplant community agrees or the practice of transplanting on virtual crossmatching would be discourage and very limited. Furthermore, as previously stated, sample swaps of patient samples are much more likely and therefore more likely to be the cause of a false negative virtual crossmatch. There is not a policy that requires that patients have their antibody assessments performed more than once prior to transplant.

7. We need to consider measures that will give the data needed to act both precisely and efficiently. Our focus should be on policy to address discrepancy evaluation since the reports/references clearly indicate that the data is unable to be evaluated thoroughly to draw detailed and understandable conclusions for RCA and corrective action effectiveness. From my experience, we have more failures from data entry (although it is purportedly improving from the last policy update), issues with interpretation of data, failures due to technology/random error, limitations of assays for the most polymorphic genes, and either insufficient training/experience or attention to detail. 8. After reviewing all the comments and reported results from the last regional meetings for all regions except for Region 6 that didn’t report yet in the public comments for this proposal. There are 57% of votes in opposition with only 33% in support of this policy. An even more striking difference is that 26% strongly oppose this measure while only 7% strongly support it. As laboratorians providing high complexity tests to support deceased donor transplantation, we must own responsibility together with OPOs and transplant programs to both provide the best quality results for our patients as well as to be good stewards of the funding we receive from taxpayer dollars since this testing is covered by CMS cost reimbursement. If we identify problems in our laboratories and our clients’ processes, it is our responsibility to address them because it is unlikely that all entities will have identical processes and workflows such that this sweeping policy will appropriately address problems that appear to be extremely rare and likely better addressed with targeted approaches.

Region 11 | 03/15/2023

3 strongly support, 5 support, 5 neutral/abstain, 5 oppose, 6 strongly oppose

Multiple members commented that more needs to be known about the cause of the errors because duplicate testing will add time and expense and may not solve for all issues, including sample integrity and transcription errors. Several members commented that regulations for increased training, quality assurance, and quality improvement should be considered rather than duplicate testing which could be susceptible to the same root cause. A member commented that the cost should be secondary to safety and supports the proposal. 

LifeSource | 03/15/2023

LifeSource, the Organ Procurement Organization (OPO) serving Minnesota, North Dakota, South Dakota, and Western Wisconsin, appreciates the opportunity to submit comments in response to the proposal requiring “Human Leukocyte Antigen (HLA) Confirmatory Typing for Deceased Donors.”

LifeSource strongly opposes this proposal which would require duplicate HLA testing to be be performed on all deceased donors with samples drawn at two separate times. We believe the policy is without merit as the proposal does not offer evidence that duplicate testing will solve the root problem. Implementation of this proposal would create a significant increase in the donation process time which has a secondary negative impact on donor family experience and increases cost significantly. Additionally, we are concerned about the volume of blood required to be drawn to run two tests. Has adequate assessment of HLA lab capacity to double the deceased donation workload been adequately assessed across the country? The incidence of errors is extremely low and does not warrant such a wide-reaching policy change. We encourage the Committee to conduct further research to accurately assess the problems so effective solutions can be identified.

Thank you.

Loren Gragert | 03/15/2023

Lacking a root cause analysis, there isn’t enough data provided for us to assess if the proposal will adequately address the problem of HLA typing discrepancies. To address typing errors and discrepancies, the OPTN Histo Committee has made policy and system changes that were implemented over the last several years – (1) locking down data in UNet system to prevent typing from being altered inadvertently, (2) attach raw data from typing software as a PDF, and (3) double data entry. The 0.3% critical discrepancy statistic in the proposal is based on data that goes all the way back to 2015, but system changes to address this issue were implemented as recently as 2019. What are the stats since 2019? This public comment proposal should have included rigorous post-implementation analyses of each of these interventions.

To gain the support of the transplant community, the Histo committee should first strengthen reporting processes to mandate rigorous root case analysis of every discrepancy, including self-reported discrepancies, and provide us with annual summary statistics on the exact nature of the typing discrepancies, by typing kit/methodology.

Complete sample swap is the main type of error that this proposal addresses. No data was provided on the source of sample switch – has it typically been HLA labs, or has it been the OPO that drew and shipped the sample? Alternatively, the committee might explore other measures to improve lab procedures and documentation of chain of custody to avoid sample swaps when extracting samples and HLA typing multiple donors.

UNOS ought to place a high priority on building IT/informatics infrastructure that would capture primary HLA typing data electronically and use it for allocation, which I’d expect would be a more cost effective solution for reducing clerical errors than performing duplicate typing. Better informatics tools are also needed to analyze typing data to identify potential mistypings (e.g. PMID 26546873), as much of this analysis today is done through manual processes.

While I'm not able to support this proposal at this time, I propose that the right timing for implementation of a proposal like this would be when rapid long-read NGS technologies (e.g. Oxford Nanopore) are ready to be adopted operationally by HLA labs for deceased donor HLA typing. When reintroduced there should be a mandate to type by two different methods - an NGS method and a more established non-NGS method.

Association of Organ Procurement Organizations | 03/14/2023

Thank you for the opportunity to submit comments on the Organ Procurement and Transportation Network’s (OPTN’s) policy development process on behalf of the Association of Organ Procurement Organizations (AOPO). AOPO collectively represents 48 federally designated, non-profit Organ Procurement Organizations (OPOs) in the United States, which together serve millions of Americans. As an organization, AOPO is dedicated to providing education, information sharing, research, technical assistance, and collaboration with OPOs, other stakeholders, and federal agencies to continue this nation’s world-leading transplantation rates while consistently improving towards the singular goal of saving as many lives as possible. We offer the following comments for your consideration:

AOPO strongly opposes the proposal requiring two HLA typings be performed on all deceased donors with samples drawn at two separate times. Patient safety is of utmost importance to AOPO and undoubtedly, to our transplant community at large. The proposed policy change appears to be a broad solution without evidence that the identified problem will be significantly mitigated. AOPO recommends the committee further study the issue and data, if possible, from the HLA labs that currently practice duplicate testing to gain more knowledge about comparative rates of incidents, root cause of the incidents, and possible solutions if necessary.

AOPO is concerned the proposed policy change does not address a significant cause of errors - transcription and clerical errors. Significant additional costs and processing time will be incurred by labs and OPOs and should be weighed against potential benefits and confidence in elimination of errors before implementing any such wide reaching policy change.

Additionally, with regard to the Committee’s question about the use of two different testing modalities, AOPO does not support the requirement of using two different testing modalities. Different testing modalities whether it be related to equipment, processes, or test kits, have benefits and challenges.

Donor Network of Arizona | 03/14/2023

Donor Network of Arizona strongly opposes this proposal. The Histocompatibility committee seems to place unilateral responsibility of the transplant process on the OPO side of the equation. Justifying a repeat of every deceased donor HLA typing based on a 0.3% error rate and comparing it to the ABO testing policy in place makes the proposal look shortsighted and misplaced. As a transplant community, patient safety is of utmost importance to all parties involved. We urge the Histocompatibility committee to research deeper into the recipient side of testing to complement their concerns about their confidence surrounding the virtual crossmatch process. Furthermore, HLA labs involved in recipient testing should absolutely confirm HLA typing of the donor on their end and should do so in an appropriate time window to safeguard patients. A recipient HLA lab should never rule out confirmation on their end regardless of the number of times a deceased donor has been typed at the originating OPO. After all, arguments related to sample switches can be made about organs being shipped out for transplants. Further, DNA strongly opposes the proposal of requiring two different testing modalities, as that will result in substantial expense for laboratories and their clients.

Region 7 | 03/14/2023

2 strongly support, 3 support, 2 neutral/abstain, 3 oppose, 5 strongly oppose

The region was generally not supportive of this proposal. There was significant discussion that the increased cost and workload is out of proportion to the problem and that more data and root cause analysis is needed. Members expressed concern that confirmatory testing will not get to the root of the problem and may not prevent or solve the problem of switched samples. There was agreement that safety is important, however, members commented that there could be unintended consequences. One attendee raised the question of what should be done when there are discrepant results in the typing. Another member commented that when continuing to add requirements to OPOs and transplant hospitals, we need to keep in mind the overall collective work requirements and continuously manage the process to prevent organ loss due to administrative processing times. A member in support of the proposal commented that the positive outcomes outweigh the requirements for implementation and highlighted content from the proposal. 

Region 1 | 03/14/2023

0 strongly support, 1 support, 1 neutral/abstain, 7 oppose, 3 strongly oppose

Region 1 generally did not support this proposal. Many attendees expressed serious concern about the cost of this proposal and the potential increase in cold ischemic time, should it become policy.  One member said they did support the proposal, but still were concerned about the cost. A member commented that with virtual crossmatching, this policy is unnecessary. Several attendees expressed that the number of errors was extremely small to warrant this response. Some members commented that the reason for these errors has not yet been identified, so it would be best to do that before proposing a solution. A member remarked that the focus should be on the resolution of the typing.  

Gift of Life Michigan | 03/14/2023

As an OPO laboratory, we currently have a system in place that would comply with the proposal, so instead of requiring a second confirmatory typing, the responsibility should fall upon the laboratory and director on how they would want to handle HLA testing for donors. All laboratories have checks and balances in place to prevent such errors. All laboratories should have a robust quality assurance (QA) program which would include root cause analysis/CAPA for issues that would have clinical implications. These QA plans and metrics are evaluated during a laboratory’s accreditation inspections. If there were issues with the QA plan, the laboratory would be cited and the laboratory would need to submit an appropriate corrective action plan.

Second, there isn’t enough data to support this proposal as it stands. Here are a few additional comments/concerns:

1. It is proposed that this will increase the confidence to utilize virtual crossmatching. However, most transplant centers that use virtual crossmatching are for non-sensitized potential recipients or potential recipients that have a low calculated Percent Reactive Antibody (cPRA). The sensitized recipients with higher cPRAs are still waiting for the results from a physical crossmatch.
2. Some laboratories may not be equipped to run two HLA typings simultaneously. Therefore, increasing turn-around-time for results, which will spill over into the donor case duration.
3. The cost will increase with running two HLA typings and could have major financial implications for some laboratories, i.e. additional equipment, additional reagents, and additional staff.
4. Were the typing discrepancies self-reported, TIEDI or HLA typings repeated by the transplant centers?
5. Where in the testing process did the error occur, during sample collection, sample accessioning, HLA testing, or data entry?
6. What data does the histocompatibility committee have to support that a second sample will eliminate typing errors?

View attachment from Gift of Life Michigan

Center for Organ Recovery and Education | 03/14/2023

As an OPO we recognize the accuracy of HLA typing is critical to the success of transplantation however we do strongly oppose this proposal. This will have an increase in turn around time for donor testing and a negative financial impact on the OPO.

American Society of Transplantation | 03/14/2023

The American Society of Transplantation (AST) opposes the proposal, “Require Human Leukocyte Antigen (HLA) Confirmatory Typing for Deceased Donors,” and offers the following comments for consideration:

•The AST agrees that accurate HLA typing is critical for patient safety; however, the proposal does not present sufficient background on the nature of the problem this proposal is attempting to solve. It is not clear whether the current risks would be reduced through the changes proposed and therefore be justified by the increased expense and testing times that will result from the proposed changes.

•Performing parallel typing on a second sample would decrease - but not eliminate - the chance of mistyping due to sample mix-up or clerical error and would result in increased turnaround time, staffing requirements, cost, and risk of error. Parallel typings also may not impact the risk of typing errors due to misidentified or rare alleles as these tend to be interpretation errors pertinent to laboratory policy.

•The proposal is based on the premise that the donor center typing is the party in error when there are discordant results; however, it’s reasonable to assume that there are situations when the donor typing is correct and the recipient center typing is flawed, which further minimizes the benefit of doubling the donor testing burden because the error is occurring at a different point in the process. •We recommend reviewing the following questions before supporting the proposed requirements:

o What factors are responsible for donor mistyping events?

o Are donor mistypings localized to specific typing labs or geographic regions/OPOs? In other words, is this a systemic problem requiring a systemic solution or is this better addressed by process improvements by individual OPOs/labs?

o Are donor mistypings concentrated within a specific technique or test platform (SSO vs RT-PCR), or reagent lots?

American Society for Histocompatibility and Immunogenetics (ASHI) | 03/14/2023

I was unsure which option to choose. Please see the attachment. Thank you.

View attachment from American Society for Histocompatibility and Immunogenetics (ASHI)

NATCO | 03/14/2023

NATCO appreciates the opportunity to comment on this proposal and applauds the efforts of the OPTN Histocompatibility Committee to promote patient safety. With broader sharing and the continued increase in utilization of virtual crossmatching to determine compatibility for all organ systems, accuracy in HLA typing is undoubtedly critical. However, the extremely high-cost impact on both OPOs and HLA labs associated with double testing on all deceased donors along with both the projected and unanticipated effects on the logistics and overall timing of successful and efficient allocation, recovery, and transplantation must be further scrutinized before this requirement can be made policy. There also needs to be more analysis on the root cause of the rare occurrences of these discrepant typings to establish if this proposal would eliminate the errors. Additionally, it must be considered if doubling the work of many HLA labs already working at maximum capacity would introduce the opportunity for more errors or other logistical challenges. This policy also does not address HLA typing from the transplant candidate perspective. Patient safety is of the utmost importance and all policy proposals looking to improve upon existing systems merit close analysis and consideration. Continued discourse on this topic with alternative solutions or additional enhancements to existing policy should be considered before a policy proposal of this magnitude is implemented.

Region 8 | 03/14/2023

0 strongly support, 1 support, 2 neutral/abstain, 8 oppose, 12 strongly oppose

The majority of Region 8 members opposed this proposal. During the discussion, an attendee explained the proposal must mandate the use of the two different tests, otherwise the discrepancy will not be eliminated. Another attendee believes the proposal will put a strain on staff and needs more information for justification. Some labs won’t have two different test methods, which will be a burden for labs. Members indicated that this proposal could slow down allocation for some donor cases, which could increase organ non-use. A member suggested to update UNET HLA reporting needs before addressing discrepant typing issues, otherwise the data could be incorrect. An attendee said the proposal should be opposed from the clinical side. The member pointed out the risk is 0.3% for potential errors. The final cross-match is the safety net for preventing hyperacute rejection, and this proposal is unhelpful because it does not provide better methodology than cross-match. Several attendees said this proposal would further increase the associated costs with HLA lab personnel and sample supplies. Several members suggested to establish and require API for the elimination of manual entry interpretation errors. An attendee said the data doesn’t support the proposal and that centers are doing confirmatory typing when the organ/blood sample reaches the center. An attendee pointed out that it seemed, from the discussions, that this project is still in development, and there are too many concerns to move forward, as proposed, at this time. An attendee had concern that manual entry would be a problem and that it would put further strain on an already strained system. The member believes this may lead to more errors in general. However, from a patient point of view, patients may feel more comfortable with confirmatory typing, and would have more trust in the system. But, at the same time, the member thinks for the greater good of the patient and donor families, they would understand the limitations of this type of testing.

OPTN Transplant Coordinators Committee | 03/14/2023

The Transplant Coordinators Committee thanks the Histocompatibility Committee for their work on this proposal. 

A member noted the low number of errors and asked if the committee has heard any feedback about less expensive and less burdensome options for OPOs. Another member expressed concerns about requiring additional blood samples from smaller donors. 

A member commented that although the number of cases is low, the results of an error can be very impactful. For example, the associated cost of patient treatment, extended hospital stay, and potentially the need for retransplant. She added that the current policy language does not address what needs to be done in the event of a discrepant typing result other than HLA labs need to follow their existing process for resolving discrepant testing. She recommended using language similar to the ABO policy where in the event of an indeterminate or discrepant testing result, there is an established protocol that needs to be followed by each of the HLA labs.

OPTN Organ Procurement Organization Committee | 03/14/2023

The OPO Committee thanks the Histocompatibility Committee for their work on this proposal and members offers the following comments:

Concern about the ability to draw additional donor blood based on the age and size of the donor.

Concerns about the cost and noted that it could double their HLA lab costs. The member added concern that the HLA labs do not have the resources to handle the increased in testing. She added this could lead to errors because HLA lab staff will be overworked and understaffed. Another member agreed and commented that if transcription errors are the main issue, this proposal doubles the risk for those types of errors.

Concern about the ability to perform confirmatory testing for pediatric or expedited cases when there is only one specimen available.

Suggestion to ensure accurate results, two different individuals and two different testing machines should be used. 

False positive/false negative results are inherent to any clinical assays. What should an OPO do with regards to organ allocation for potential donors with any initially positive test results that are not confirmed by a confirmatory or a confirmatory or a secondary test to prevent the loss of transplantable organs?

The OPO Committee does not support this proposal based on the data (critical HLA discrepancies in 0.3% of deceased donor typing) and the significant increase in costs for testing.

Gift of Life Donor Program | 03/14/2023

Gift of Life Donor Program (PADV) thanks the OPTN HLA Committee for their important work and the opportunity to provide comment on this policy proposal. Gift of Life opposes the policy proposal as currently written. We do not believe the actual problem has been identified and that this policy proposal will minimize errors. According to the data, the errors identified occurred in less than 0.3% of deceased donor HLA typing performed. The data does not show the root cause of the problem or how many were of real clinical significance. This proposal will likely not address errors related to transcription, entry to DonorNet or specimen handling. Given the number of labs performing HLA typing, different techniques and reagents used, the desired outcome may not be achieved if the same lab performs both the initial and confirmatory HLA typing. OPOs routinely encounter instances where an accepting transplant center repeats HLA typing after acceptance or transplant and discovers discrepant typing versus the donor HLA typing used for allocation. In most cases these discrepancies are not resolved and do not impact allocation or transplant. Confirmatory testing will not prevent transplant centers from repeating donor HLA typing after acceptance or transplant and we expect they will continue to discover discrepancies. From a donor testing perspective, the policy is very restrictive and there is no discussion regarding different clinical scenarios. For example, there is no guidance in the policy on: exceptions for when there is only one deceased donor specimen available, the ability to identify HLA using lymph nodes when no blood is available or how to address instances where a discrepancy cannot be resolved. These issues could prolong deceased donor case times and increase risk of organ loss or discard. Finally, the financial impact of this policy proposal cannot be ignored. If implemented as proposed, deceased donor testing will increase by millions of dollars. We encourage the HLA committee to reconsider this policy and start with a pilot study to identify the root cause of the issue, types of errors that result in adverse outcomes and the impact on HLA typing labs, donor case time and allocation. Consideration should also be given to require HLA typing labs to use the same test kits and supplies to ensure consistency in testing and minimize variation in techniques & process. By completing this study and partnering with OPOs and HLA typing labs, alternative ways to further minimize critically discrepant HLA typing is possible.

OPTN Operations & Safety Committee | 03/13/2023

The Operations and Safety Committee thanks the OPTN Histocompatibility Committee for their efforts on the Require Human Leukocyte Antigen (HLA) Confirmatory Typing for Deceased Donors proposal.

The Committee voiced general support of the proposal with some questions and considerations. The Committee suggested a more robust system of verifying or checking in some verification system. 

The Committee voiced concern on costs for HLA testing and that this would potentially increase the time significantly if the tests cannot be run concurrently because the HLA lab does not have the staff or equipment to do this. The Committee commented that it is better to understand this because although it may be a modest dollar amount, the denominator is huge. This may add up to a big cost and there may be some unintended consequences related to logistics of this.

The Committee suggested that as the Histocompatibility Committee develops this proposal, there should be a sense of the costs and unintended logistical consequences, what the underreporting is and other solutions in which the sample handling can be better tracked. It was suggested that there should be some better understanding of the discrepancies by collecting data to provide more insight.

The Committee commented that there may be more buy in if this was positioned being more proactive rather than trying to address the sample mismatches because it is not believed this proposal addresses this.

A member stated that from the transplant center perspective, there would be less opposition than on the OPO side of things. The member continued by agreeing that this is a patient safety issues and is in support of the proposal, but there needs to be better processes in regards to verification. There is going to be a division when looking at when looking from a clinical vs. the OPO side of this proposal.

OPTN Membership & Professional Standards Committee | 03/13/2023

The Membership and Professional Standards Committee (MPSC) thanks the Histocompatibility Committee for the opportunity to review and comment on the Require Human Leukocyte Antigen (HLA) Confirmatory Typing for Deceased Donors proposal. Members expressed concern about the cost-benefit ratio associated with implementing this policy given the lack of data on outcomes for the 3% of cases with errors. Members identified small histocompatibility laboratories as being particularly disadvantaged by the cost of double testing, while also noting that the benefit of this would be minimal. Members considered that the increase in workload could result in additional errors, delays in transplant, and a potential increase in discards. Members commented that sending both results to the OPO would lead to complications and delays as they are not the experts in interpreting the results, therefore the histocompatibility laboratory should only send a single final test. Overall, members did not feel confident that duplicative testing would resolve the issues intended by the proposal.

Brigham & Women's Hospital Tissue Typing Lab | 03/13/2023

We are writing on behalf of the Brigham and Women’s Hospital Tissue Typing Laboratory in response to the proposal that laboratories doing typing for deceased solid organ donors must routinely do duplicate HLA typing. We believe that this stipulation is not warranted at the present time. The authors of this proposal have not presented compelling evidence that the small number of typings which are different when repeated warrant a solution which is inherently flawed. Differences in repeat typings can be a result of transcription errors, level of resolution of the typing method, and other variables which may not actually improve upon duplicate typing. After all, the discrepancy rate is itself measured by duplicate testing. If duplicate testing is done, therefore, and there is a discrepancy between first and second testing, is there necessarily clarity about which typing is the “correct” one? The authors of the recommendation do not specify how many of the discrepant typings were truly errors at the level of resolution necessary to properly allocate an organ. Nor is it clear how many of the fraction of a percent of discrepant typings resulted in an allocation that might have harmed a patient. Mandating prospective duplicate typing of organ donors comes at a price, both in resources and time to issuing test results which can be used in allocation of organs. We fully appreciate and agree on the goal to have perfectly accurate and timely donor HLA typing results. Given the large number of tests routinely performed for donor allocation in the United States, we recommend an unbiased prospective analysis of duplicate donor typings with appropriate sampling of a sufficient number of cases to determine the true cause of any discrepancies, how many are “errors”, and a clear mechanism for deciding the correct typing if there is thought to be a pre-analytic, analytic, or post-analytic problem. This will provide a roadmap to how best to assure the best HLA typing results.

Anonymous | 03/13/2023

The majority of errors cited were clerical errors that have been addressed. Changing policy based on 12 reported events without knowing the impact of the errors seems extreme. Further data is needed to show this change would not increase cold-ischemia time, improve outcomes and be cost-effective.

Anonymous | 03/10/2023

What was the root cause analysis for those low percentage errors? Duplicate testing will only be helpful if the error was because of the limitation of the test, or pre-analytical error. Clerical and typo errors during reporting can be resolved by having an extra layer of verification. Two-person verification should be more than enough to resolve clerical error. This is also part of the reason why HLA typing source document is now required.

Confirmatory typing might work on living donor testing, but won’t work with deceased donor. Additional testing often resulted in delay of TAT, not to mention the potential of increasing cold ischemia time, which affects organs quality.

Cost and staffing are also a big issue. Lab professionals in some of the busiest centers are often overworked, and many of them are already on call very frequently. It’s even harder for smaller labs to provide additional coverage with a small group of staff. Not to mention the increase operational cost associated with additional coverage. Confirmatory testing is not a cost-effective way to resolve this problem, especially when error percentage was so low.

In the end, a deeper analysis is a must, in order to evaluate how effective confirmatory testing will be.

Region 9 | 03/09/2023

0 strongly support, 7 support, 0 neutral/abstain, 7 oppose, 1 strongly oppose

Region 9 had mixed feedback on this proposal. Several members commented 12 errors in six years seems like an extremely low error rate. A few stated that they expected the cost related to requiring two typings, both in money and time spent, would not be justified. A member remarked that the purpose behind the proposal is important, but there needs to be additional discussion around the details. Another attendee suggested that an additional typing on an additional specimen should only be done if there is ambiguity in assigning a specific antigen or allele or if the typing is missing for a locus. A member said that instead of this additional typing, allocation should proceed, with members being informed of the potential risk if the donor is expedited. 

Taba Kheradmand | 03/08/2023

I am a HLA laboratory director for an OPO-affiliated histocompatibility laboratory. My laboratory performs a high number of deceased donor typing with limited staff. I STRONGLY OPPOSE the proposal due to the following concerns with regards to the lack of transparency and clarity of the data presented as well as the data source and analysis:

1. OPO and OPO-affiliated histocompatibility laboratories will be impacted significantly due to increase in workload, testing cost, staffing and other resource requirements, as well as process complexity.

2. Based on an informal analysis of the cost structure from 40 HLA laboratories, at an assumption of 18,000 donors/year (15,000 plus 20% more donors attempted), and an average cost of $1140 per deceased donor typing and a STAT fee of $320, this proposal could dramatically increase the financial burden to the donation and transplant community of over $26,000,000.

In addition, it is common practice for HLA laboratories receiving an out of state organ to confirm HLA typing retrospectively at various resolutions, using the material that accompanies the organ. This means that potentially a donor can be re-types 2-5 times, depending on the number of organs that are exported, which to some extent becomes redundant and costly.

3. Turnaround time of deceased donor typing and OPO donor case time will increase.

4. Modeling a costly, time consuming and labor intensive, high complexity HLA typing assay after an inexpensive, short and simple agglutination assay for ABO, is not realistic and fair comparison.

5. 12 cases of sample switch between 2015-2021 is equivalent to a rate of 0.01% (78378 deceased donors plus 20% more donors attempted). By the numbers, these are rather rare events, statistically speaking. Why would we want to “punish” the entire OPO community and the majority of the histocompatibility laboratories by requiring a universal confirmatory typing on two samples (i.e. double the workload) when only a handful of problematic laboratories committed the errors?

6. How did the histocompatibility committee evaluate and come to the hypothesis that the confirmatory HLA typing on a second donor sample, which most likely will be collected minutes after the first sample, will effectively eliminate all of these errors, as opposed to creating more room for errors since the number of samples will essentially double?

7. At roughly 16,500 donors/year nationally (average from 2020-2022; including the actual number of donors and an assumption of 20% more donors attempted), a 0.3% rate of critical HLA discrepancies would be equivalent to 50 reported cases per year. Did the data show that there were in fact 50 cases of critical HLA discrepancies identified every year? Of these reported events, how many had resulted in adverse or sentinel events (e.g. loss of transplantable organs, graft rejection, or patient death, etc)?

8. How were these discrepancies identified? What is the proportion for self-reported events vs. TIEDI via repeat HLA typing by the recipients’ transplant centers?

9. At what stage of the deceased donor evaluation did these errors occur, i.e. errors occurred within the HLA lab during the testing process, or by the OPO during sample collection and/or the data entry process?

10. What was the nature of these errors, e.g. sample mislabeling, sample mishandling/switch, transcription, interpretation, allele ambiguity caused by inherent assay limitations, discrepancies between antigen-level resolution reported by the OPO lab and two-field-resolution reported by the transplant center labs, etc?

11. Did these errors occur only in an isolated group of laboratories, and did any of these errors occur more than once in a single laboratory?

12. Did the laboratories/OPO that committed the errors submit appropriate root cause analysis and corrective action and preventive action (CAPA) to UNOS for review? What were the outcomes for these events (e.g. issuance of letter of non-compliance, member not in good standing, suspension of OPTN membership, reporting to CMS/CLIA, etc)? Is there an existing mechanism for their CAPA effectiveness check? Is there any process for ongoing monitoring in these problematic laboratories?

13. What was the involvement of the laboratories’ accrediting organizations (i.e. ASHI or CAP) in any of these critical errors? What were their actions and what were the outcomes? If there was no involvement of accrediting organizations, why not?

14. Given the rarity, these CLEARLY appeared to be process and quality issues of individual laboratories, as opposed to systemic problems of the entire OPO and OPO lab operation.

American Nephrology Nurses Association (ANNA) | 03/08/2023

See Attachment

View attachment from American Nephrology Nurses Association (ANNA)

Anonymous | 03/08/2023

This issue requires the involvement of the regulatory authorities ASHI and CAP. Before this drastic measure, this issue deserves a deep analysis to identify if there is a common root cause/s and if possible, develop new standards and guidance to eliminate these HLA typing errors.

Anonymous | 03/08/2023

unnecessary. time consuming. delay organ placement. costly. were the errors made actually typing errors or transcription errors?!

Robert Bray | 03/07/2023

See attachment.

View attachment from Robert Bray

OPTN Kidney Transplantation Committee | 03/07/2023

The Kidney Committee thanks the Histocompatibility Committee for the presentation and the opportunity to provide a public comment on the proposal. A member questioned if the confirmatory typing would need to be done before the match is run or before the transplant occurs, as the latter may relieve some of the timing constraints and provide more flexibility. Another member questioned the duration of time required between lab draws, and further commented the cost for an OPO to send samples individually versus batched should be taken into consideration. Members also commented the proposal’s goal makes sense for the benefit of patient safety, but there are concerns for the cost to the system and time involved with requiring a second test. Members questioned if there was a way to standardize HLA lab costs to help alleviate cost burden. Another member commented a transplant hospital’s quality assurance protocols and root cause analysis may also help address the concerns outlined in the proposal. 

Anonymous | 03/06/2023

As both a transplant professional and a taxpayer, I oppose the proposed requirement for confirmatory typing for deceased donors. The downsides of the very small (0.24%) discrepancy rate coupled with the additional negative consequences (such as time delays and a doubling of costs for labs and OPOs) do not seem to outweigh the potential benefits. If the two typings are not concordant, what will the appropriate action be? For high risk patients (i.e., those with significant antibodies), an actual (wet) crossmatch would be a safer way of predicting poor outcome.

Anonymous | 03/04/2023

I am a HLA laboratory director. My laboratory performs a high number of deceased donor typing. I STRONGLY OPPOSE the proposal due to the following concerns with regards to the lack of transparency and clarity of the data presented as well as the data source and analysis:

1. OPO and OPO-affiliated histocompatibility laboratories will be impacted significantly due to increase in workload, testing cost, staffing and other resource requirements, as well as process complexity.

2. Based on an informal analysis of the cost structure from 40 HLA laboratories, at an assumption of 18,000 donors/year (15,000 plus 20% more donors attempted), and an average cost of $1140 per deceased donor typing and a STAT fee of $320, this proposal could dramatically increase the financial burden to the donation and transplant community of over $26,000,000.

3. Turnaround time of deceased donor typing and OPO donor case time will increase.

4.12 cases of sample switch between 2015-2021 is equivalent to a rate of 0.01% (78378 deceased donors plus 20% more donors attempted). By the numbers, these are rather rare events, statistically speaking. Why would we want to “punish” the entire OPO community and the majority of the histocompatibility laboratories by requiring a universal confirmatory typing on two samples (i.e. double the workload) when only a handful of problematic laboratories committed the errors?

5. How did the histocompatibility committee evaluate and come to the hypothesis that the confirmatory HLA typing on a second donor sample, which most likely will be collected minutes after the first sample, will effectively eliminate all of these errors, as opposed to creating more room for errors since the number of samples will essentially double?

6. At roughly 16,500 donors/year nationally (average from 2020-2022; including the actual number of donors and an assumption of 20% more donors attempted), a 0.3% rate of critical HLA discrepancies would be equivalent to 50 reported cases per year. Did the data show that there were in fact 50 cases of critical HLA discrepancies identified every year?

7. How were these discrepancies identified? What is the proportion for self-reported events vs. TIEDI via repeat HLA typing by the recipients’ transplant centers?

8. At what stage of the deceased donor evaluation did these errors occur, i.e. errors occurred within the HLA lab during the testing process, or by the OPO during sample collection and/or the data entry process?

9. What was the nature of these errors, e.g. sample mislabeling, sample mishandling/switch, transcription, interpretation, allele ambiguity caused by inherent assay limitations, discrepancies between antigen-level resolution reported by the OPO lab and two-field-resolution reported by the transplant center labs, etc?

10. Did these errors occur only in an isolated group of laboratories, and did any of these errors occur more than once in a single laboratory?

11. Did the laboratories/OPO that committed the errors submit appropriate root cause analysis and corrective action and preventive action (CAPA) to UNOS for review? What were the outcomes for these events (e.g. issuance of letter of non-compliance, member not in good standing, suspension of OPTN membership, reporting to CMS/CLIA, etc)? Is there an existing mechanism for their CAPA effectiveness check? Is there any process for ongoing monitoring in these problematic laboratories?

12. What was the involvement of the laboratories’ accrediting organizations (i.e. ASHI or CAP) in any of these critical errors? What were their actions and what were the outcomes? If there was no involvement of accrediting organizations, why not?

13. Given the rarity, these CLEARLY appeared to be process and quality issues of individual laboratories, as opposed to systemic problems of the entire OPO and OPO lab operation.

Sherrell Gay | 03/03/2023

Currently 1 test required and the results are recorded as very high percentage correct. I see no need for aditional tests being done.

Region 5 | 03/03/2023

4 strongly support, 12 support, 2 neutral/abstain, 9 oppose, 5 strongly oppose

Some Region 5 members support this proposal and some Region 5 members oppose this proposal. Some members supported the requirement for additional testing and encouraged doing what is the safest for candidates. However, several members questioned whether the additional time and cost was worth the burden, and if it would solve the root cause of the issue. A member explained that there is resistance, regarding the costs, from the HLA community. A member supported the proposal and suggested the tests be performed simultaneously to minimize the time period for receiving results. In support of the proposal a member stated that this proposal is critically important for centers that have moved to virtual cross-matching. A member pointed out that the majority of errors cited were clerical errors that have been addressed. And the impact of the errors is questionable. The member opined if the proposal creates a greater harm by increasing time required for testing and increasing costs. The member suggested that these additional requirements could reduce the availability of viable organs for transplant. A member explained that patient safety is important; however, the proposal is predicated upon a .24% error rate, of which 12 reported events are related to "sample switching" and it is unclear what the actual adverse impact of these errors resulted in, which leaves this to be a somewhat theoretical problem. The member recommended the committee consider incorporating improved lab standards to limit sample switching. Further, the proposal does not address what an OPO is to do if there are discrepant results (if typed twice), which sample would be the "correct" sample? The member had the following suggestions: consider applying this to living donation; and perform a true cost analysis to determine the financial impact prior to implementation. Several members asked for a cost analysis and additional data before deciding whether additional testing is needed. A member commented that this proposal creates a substantial operational and financial burden for HLA labs (and, subsequently, for OPOs) to address a problem that is not well-documented by data. A members’ institution recommended, instead of this proposal (that will likely add additional delay cost and complexity to organ offer review and the matching process), for the committee to consider a proposal that requires the OPOs to perform high resolution donor typing for kidney deceased donors. The member pointed out that the current technology is cost efficient, accurate, available, and timely. Further, the member explained that this is the standard of care for the largest kidney paired donation program in the country and matching based on the virtual process has been accurate and efficient with rare discordance between visual and physical cross-matches.

Anonymous | 03/01/2023

I understand the need to put patient care first; however, I think this proposal does not address the underlying issue. I think this proposal increases the risk for error, is fiscally irresponsible, and is not the most efficient use of a technologist's shift.

KY Organ Donor Affiliates | 03/01/2023

Kentucky Organ Donor Affiliates supports efforts to address patient safety in all areas of the donation and transplantation process. Unfortunately, this proposal does not address the primary cause of HLA typing errors as shared by the committee - human error, whether in transcription or in sample selection. These errors occur primarily in the lab, no known sample error from an OPO was identified. This proposal, however, puts significant burden for cost and time, for both the additional lab and for ICU care at the donor hospital, on the OPO. KYDA respectfully requests that the committee reconsider if this proposal is actually the best solution for the errors brought forward. KYDA also requests that specifics on the potential risks for the 0.03% error rate be identified and addressed in the proposal.

Region 10 | 02/28/2023

4 strongly support, 2 support, 5 neutral/abstain, 9 oppose, 2 strongly oppose

Members in the region were mostly opposed to the proposal. One attendee expressed their support as it does not seem overly burdensome and hopefully will encourage growing confidence in the use of virtual crossmatches. However, many attendees noted that the discrepancies identified in the proposal were most likely due to clerical errors and requiring additional typing would not address the issue. Many were in support of the committee developing a guidance document to address best practices in HLA typing but are opposed to a policy change. Without a guarantee that the proposal will reduce the number of discrepancies, it only seems to be more burdensome for laboratory staff and increases costs and allocation time. An attendee suggested more emphasis should be placed on the upstream process, like collection of donor material and labeling. Most HLA discrepancies may have to do with training and interpretation of test results, and not mitigated by performing additional testing. Another attendee noted that obtaining two samples could be problematic for unstable donors when timing is limited. Another attendee added that several labs would not be able to type both specimens concurrently and suggested that the first typing be completed and entered into the OPTN computer system for match run purposes. The lab would then immediately complete the second typing within 2-3 hours. In the event that there was a discrepancy, the local OPO would promptly address the issue. That may be more practical from an operations standpoint. Other attendees noted that when there are discrepancies, typing the donor again using the same method would result in the same discrepancy. In order to better address discrepancies, the proposal should require two separate testing methods.  

Region 3 | 02/24/2023

0 strongly support, 3 support, 1 neutral/abstain, 4 oppose, 8 strongly oppose

Region 3 was not in support of this proposal. During the discussion, two attendees commented that within Organ Procurement Organization (OPO) community there are still questions and concerns about the cost associated with this proposal, how discordant results will be resolved and what would happen in expedited cases where you can’t get a confirmatory test. They went on to comment that it is unclear if the proposed solution will solve the problem. Another attendee commented that the .3% discrepancy data goes back to 2015 and there have been changes since 2015 such as double data entry and locking down parts of software to prohibit accidental changes. They went on to comment that we need to understand the error rate in great detail and need to look at more recent data to see how much the changes improved typing. They added that without granular data it’s hard to know what problem we are trying to solve. One recommendation was for the Histocompatibility Committee to consider additional guidelines to ensure labs have gene integrity and a process for resolving ambiguities. One attendee commented that it is not clear if this will resolve the very rare errors, but it will dramatically increase cost and time delays.  There was also a recommendation that the committee needed more data and analysis on the source of the sample switch to determine if the problem is the collection site or the lab. One attendee commented that this solution was cost prohibitive for some labs and recommended looking for more granular data and process improvement methodology to help close the gaps. Several attendees commented that the community needs more information regarding added costs, inefficiencies and unintended consequences.  

Anonymous | 02/22/2023

From a lab prospective, this is not a financially or personally responsible proposal. Doubling the HLA runs needed will not solve transcription/translation errors and rare allele calls or assay limitations. It will increase the burden on technologists already stretched thin by pandemic issues and increasing donor workups (local and import). It will force labs to purchase additional equipment, reagents, kits, consumables, and staff, which may not be feasible for some smaller facilities. It will increase sample mix up, discrepant results and test failures. These costs, both to keep up and to cover the errors, will all be passed to tax payers. It will drive the turn around time up for all testing in the laboratory, who now have to double their work, which will impact opportunities for donation and harm our patients waiting for transplants. I think more effort needs to be directed to automated transfer of results between LIMS systems (to reduce transcription errors) and more comprehensive analysis tools (to ensure the most accurate typing results).

LifeGift | 02/21/2023

While the effort to establish increased patient safety approaches to the HLA process is appreciated, this policy needs much more work to avoid unintended consequences. 1) Please clarify the actual number/volume of patient safety errors and severity as well as cost analysis for OPOs and Labs. 2) Please clarify why double verification on the donor side of the process reduces error rates when NOT verifying candidate HLA. This is reminiscent of the evolution of ABO typing verification. What is the error rate on the candidate side of the process?

Region 2 | 02/21/2023

0 strongly support, 12 support, 3 neutral/abstain, 4 oppose, 6 strongly oppose

Members in the region were split on this proposal. There were a few comments in support of the proposal acknowledging that, although it may increase workload, this will address a potential patient safety issue. The number of identified discrepancies is small, but those discrepancies were important to the patients effected by them. The remaining comments were more critical, identifying pain points with the proposal and offering suggestions for the committee to consider. One attendee commented that patient safety is at the forefront of the community, but the percentage of error is extremely low to implement a policy change that will drastically impact Histocompatibility lab operations and be a cost burden to OPOs, Labs, and Transplant Centers. One attendee commented that the OPTN needs to review the data closer to see if most discrepancies are due to reporting high-resolution vs. low-resolution testing. It would be important to break out the data of the errors to better understand whether they are data entry errors, med tech errors, switched samples, etc. Another attendee identified concerns that the proposal does not address instances where donor management timing does not allow for two typings to be completed. One attendee suggested that in these instances where donor typing cannot be performed twice, transplant programs should be required to do a prospective crossmatch. Several attendees noted that by requiring two HLA samples, it will only lead to more discrepancies, and there needs to be direction on how OPOs address those discrepancies. Additionally, if a discrepancy is found, is a third HLA typing required? Others noted that this proposal will increase the amount of time it takes to allocate and transplant organs, which may result in greater organ non-utilization. One attendee suggested that transplant programs should be able to run a preliminary virtual crossmatch based on the first donor typing results in order to not cause a delay while waiting for confirmatory typing. Another attendee commented that many transplant programs are utilizing virtual crossmatches and the committee should consider developing educational best practices for virtual crossmatches. It was also suggested that the proposal needs to address whether labs are supposed to perform the HLA testing on the same testing kit, or should two kits be used. Finally, several attendees noted that instead of implementing this proposal nationally, the committee should consider doing a pilot study with a handful of OPOs to better understand the effects this may have on the organ allocation process. The Regional Councillor did comment that this proposal should be viewed in a similar fashion to the requirement to dual blood typing for donors and candidates awaiting transplant. The Councillor also noted that for shipped national kidneys allocated to the very broadly sensitized that this proposal might decrease unexpected positive cross matches and thus could be beneficial for allocation and preventing non usage of kidneys.

Region 4 | 02/21/2023

2 strongly support, 7 support, 3 neutral/abstain, 6 oppose, 6 strongly oppose

Region 4 had mixed support for this proposal. Several attendees commented that while the fundamental goal of the proposal is important, the committee has not provided data that this change would correct the small number of cases in which HLA typing issues are reported. Two attendees went on to comment that unless the proposal includes a requirement for a second, unique, vendor or typing method to be utilized in the confirmatory typing, mis-typing due to a reagent issue will likely not be caught. One attendee suggested that it would be more beneficial to use two different vendor kits or two different methods which would not add any cost to the typing. Another attendee commented that a simpler solution may be to require samples be verified by more than one person. One attendee commented that the proposal needed more clarity regarding what would happen when a discrepancy is noted between two typing’s. Several attendees were concerned about the cost of the additional testing commenting that there was very little data about increased cost, or if the extra typing would fix the problem. Several attendees expressed concern about the additional time the extra typing would take adding that it would require labs to increase staff and equipment. Two attendees commented that many accepting centers already re-type for kidneys and having the donor lab do confirmatory typing would double the charge. Another attendee suggested that the committee should focus on the 0.3% of typing’s that have a critical discrepancy.

Anonymous | 02/18/2023

I agree donor's HLA type is a key component of organ allocation. I understand an incorrect donor HLA type could cause problems for a recipient and we should do everything we can to avoid and prevent it. However, an error rate of 0.3% of HLA typing of deceased donor and even much less rate (less than 0.1%) of the HLA typing discrepancy caused by samples switch do not adequately justify that proposed policy. It is also not the best and not practical solution for the prevention of HLA typing error of deceased donors. I believe double check and or multiple check points of donor HLA typing can significantly reduce the clerical or transcriptional errors. Double typing either using two different samples collected by two different persons or by same person at different times (which also possibly creates more unnecessary human error), typed either using same method or two different methods of similar resolution would not resolve the HLA typing discrepancy caused by non-clerical reasons. As a member of the OPO community, I am also concerned about the implementation of this policy could potentially prolong the organ donation process due to the limited qualified oncall HLA technologists of many HLA labs. I believe and agree that the mandatory implementation of that policy may cause more negative impact on deceased donor allocation than is beneficial to organ transplant recipients, even though it is help to minimize the HLA typing error by sample swap.

Anonymous | 02/15/2023

I think it's a good idea to use similar rule for HLA typing as the ABO model, especially for centers who are relying on virtual crossmatch for transplant decisions. Before making this full commitment, it's important to make sure that the labs have sufficient amount of staff to ensure proper testing. Otherwise, we are creating an even more stressful environment for the techs which may lead to more errors and ultimately defeats the purpose of double testing. In addition, it's important to make sure that the HLA labs do not end up absorbing this added extra cost.

Anonymous | 02/14/2023

As a technologist that performs HLA typing regularly on deceased donors, usually multiple donors at a time, doubling the amount of trays increases the opportunity for error. I understand the importance of making sure that deceased donor typings are performed correctly and also reported correctly, but I think giving technologists double the amount of work to do, especially if they work in a busy service area, would be counterproductive to the goal of having no typing mistakes.

Histocompatibility and Immunogenetics Laboratory at Tulane | 02/13/2023

While it is difficult to dispute the intent of this proposal, we are concerned the data was not thoroughly analyzed; a root-cause analysis was not performed. Prior initiatives such as double-entry seem to have decreased typing errors. Is confirmatory typing using separate samples really the best next step to further reduce these errors? Confirmatory typing is a costly intervention and introduces logistical challenges. Furthermore, many details of confirmatory typing are not specified, e.g., different test method and/or technologist, interpreted by a second director or supervisor? If confirmatory typing is not truly the best next step in further reducing typing errors, it should not be done at this time. In the spirit of well designed QI projects, we strongly recommend further analysis of the problem before launching into a potential solution.

Jondavid Menteer | 02/09/2023

Recognizing HLA typing errors is certainly important. HLA typing errors fall into general categories including Clerical errors, Sample switches, and Reagent and technical failures. Errors are estimated to occur with one in 400 results, and the largest proportion of those are clerical errors (and were addressed by duplicate entry system now in place). The remaining errors vary in significance. The threat of hyper acute rejection and major morbidity is only relevant to the most significant mis-typings, and only when the donor organ is being allocated to a presensitized patient. Duplicate testing does not correct failures of technique and reagents since mostly would be done by the same lab by the same batch of reagents and technique, and usually on the same machine. Many labs will not be able to provide different methods for retyping the samples in the same lab, or may become ineligible to type samples for donation if such restrictions were imposed. The duplicate sample testing would help with sample switching errors, which are likely a small number and becoming less common with modern barcoding in 2023 compared with the error rate reported 5 or more years ago. That said, certainly minimizing harm is certainly the goal. Please recognize that the policy is not just expensive and time consuming; it may create harm of its own. Although this policy may reduce a small number of sample switch errors, the reduction In errors this policy generates may be offset by an increase in harm due to delays of transplant, and ultimate non viability of organs due to delays. I would support a policy of duplicate testing in instances where the typing is of critical importance because of prospective virtual crossmatching. Is there a way to FACILITATE duplicate testing without making it mandatory for every donor?

Anonymous | 02/09/2023

This is not a feasible proposal for laboratories that perform a large number of donor HLAs per shift; it will greatly lengthen turn-around-time. There also does not seem to be a high enough occurrence of discrepant HLAs for confirmatory typing to be necessary.

Anonymous | 02/08/2023

I cannot support mandatory confirmatory HLA typing for deceased donors at this time. An error rate of 0.3% is not adequate justification to support this extremely broad and very resource intensive solution. As a member of the OPO community, I am very concerned about the capacity of HLA labs to facilitate this policy change in a manner that does not prolong the organ donation process. Further, more clarification will be needed for potential discrepancies. Overall, patient safety is critically important, but is this the best way to improve the accuracy and integrity of HLA typing?

Anonymous | 02/07/2023

This new policy makes no sense. Can you provide data that would include what type of errors for example was the HLA typing tray unable to unambitiously assign an antigen level call or was it pure clerical error. Was the outcome of any of the critical errors a cause of death? How many centers or should say center(s) making the errors were due to to those targeted centers more consistently than globally? If we are going to go as far as doing something ludacris as this proposal is, then why not implement a second round of psychical crossmatches. Have fresh blood drawn isolate this and do a second round of physical crossmatches. WAIT...... why not have a second set of blood drawn and do a second round of INFECTIOUS DISEASE testing as well? Do you see where this is going. Also why not propose to CMS that the cost of this change will be insurmountable, OPO's etc would have to hire more staff for the workload, and add more instrumentation, reagents and freezers for example. How much more will this cost the tax payers?

UCSF Immunogenetics and Transplantation Laboratory, Director: Rajalingam Raja | 02/07/2023

I am the director of the HLA laboratory at the University of California San Francisco (UCSF), which performs human leukocyte antigen (HLA) typing for ~600 local deceased donors annually. UCSF HLA lab strongly supports this proposal because of the following reasons. However, the proposal must include a condition demanding the use of two different test methods (e.g., RT-PCR, rSSO, SSP, Nanopore) or similar test methods from two different vendors to HLA type samples drawn at two separate times. 1. The HLA genes are incredibly polymorphic, with >35,820 alleles officially recognized per February 2023. Typing deceased donors for ever-increasing alleles of all 11 HLA genes within a short turnaround time by on-call technologists in the middle of the night is particularly challenging. 2. Currently used deceased donor HLA typing methods employ multiplexed PCR amplifications on set thermal cycling conditions designed on the available sequence database, which is well-known for allelic dropouts and ambiguous results yielding erroneous typing. 3. Erroneous HLA typing of deceased organ donors can have profound patient safety implications, such as recipient death and unexpected hyperacute/ accelerated graft rejection. 4. Incorrect HLA typing can also cause inefficiencies in the OPTN/UNOS organ allocation system, such as i) an increased cold ischemia time while HLA types are confirmed by repeat testing, ii) discards of organs shipped to far areas with incorrect HLA typing, and iii) possibly missed transplant opportunities for other candidates who may have been screened off of a match run because of incorrect HLA typing. 5. Comprehensive and precise HLA typing of deceased donors is crucial for precise virtual crossmatching to increase broader organ sharing across greater geographical distances. 6. Adopting a dual typing system for deceased donors will entail additional costs on reagents, but technologist time spent on deceased donor workup will not substantially change. Indeed, double typing will save the technologist time because of the more straightforward crosschecking between two typing assignments and eliminating repeat testing due to failures in certain wells or reflex testing to resolve ambiguities emerging from the single method. Furthermore, the recipient transplant hospital may discontinue repeating HLA typing of the imported donors in their local HLA laboratory if the original typing used for the allocation match run was attained by mandated dual typing. Therefore, the benefits far outweigh the increase in cost, if any. 7. Our recent research on this line concludes that concurrent typing using two independent methods produces accurate HLA typing of deceased donors within a short turnaround time, which is crucial for accurate virtual crossmatching for broader sharing (Reference: Cruz TD, Dames C, Pagaduan L, Cho Y, Kong D, Rajalingam R. Concurrent use of two independent methods prevents erroneous HLA typing of deceased organ donors - An important strategy for patient safety and accurate virtual crossmatching for broader sharing. Hum Immunol. 2022, 83:458-466). In conclusion, we strongly support this proposal. However, the policy proposal must mandate using two different test methods (e.g., RT-PCR, rSSO, SSP, Nanopore) or methods from two different vendors to type samples drawn at two separate times. Using one method on two separate samples will not resolve the erroneous typing.

Anonymous | 02/02/2023

I support this but only if the typing centers are able to do this . Adding an extra typing for deceased donors may require more equipment and staff. Having worked at a typing center and a non-typing center laboratory, there is a huge difference in the amount of work involved when typing is added to a deceased donor workup. We run the risk of laboratories dropping deceased donor typing if they cannot be reimbursed for the material and staffing cost of the confirmatory typing. What is most helpful with Deceased Donor typing is the availability of the Raw Data of the assay and not just a coversheet summary.

Anonymous | 01/27/2023

Most of the HLA typing errors are clerical, which could be avoided if a second set of eyes looks at the results and makes sure that the entry is correct. Also repeating the same typing with the same technology I don’t think solves anything. In the few cases that typing is “wrong” due to technology limitations, you would have the same wrong result twice. No all the labs have more than one molecular technology for HLA typing, and the ones that do, usually used technology that due to timing would not be suitable for deceased donor typing on call. Nanopore is promising but is not easy to do in the middle of the night while doing other HLA typings and crossmatches.

Valia Bravo-Egana | 01/26/2023

Statistics on low incidence of discrepancies on donor HLA typing are important to understand the magnitude of the problem. However, it should not be a justification to accept less than optimal outcomes. Even if only one patient is impacted by this situation, it should be enough to prompt our community to provide a meaningful answer, if available. In this case, implementing confirmatory donor typing as a safeguard to avoid the potential devastating consequences of typing mistakes seems to be reasonable and proportionate to the seriousness of the consequences of not doing it. This seems even more important these days, when organ allocation is not limited to regions but done nationally. Therefore, typing mistakes may have major implications in proper organ allocation. Furthermore, with the everyday increasing rates of usage of virtual immunological assessments, the accuracy of HLA typing becomes vital to provide this service. Finally, I strongly belief that patient safety is never enough. It is our responsibility to improve it and optimize it in an asymptotic manner, where we get closer and closer to the ideal but never get complacent and stop improvement. We own this to our patients and community.

Anonymous | 01/25/2023

This appears to be an rare problem with a disproportionately broad solution. There doesn't appear to be anything preventing a lab from performing an additional typing on another sample currently. It would seem best for each lab to evaluate problem areas and implement solutions accordingly.

Maria Bettinotti | 01/24/2023

The lack of a policy that mandates HLA confirmatory typing of deceased donors constitutes a high risk to the safety of transplant recipients and to the efficient use of organs within the OPTN deceased donor allocation system. The deceased donor's HLA type is a key component of organ allocation:

•Unacceptable antigens are listed in UNet for HLA sensitized candidates on the waiting list so that incompatible candidates are excluded from a match run. An erroneous donor HLA typing may result in the inclusion on the match run of patients highly sensitized against the donor.

•Transplant centers perform virtual crossmatches comparing the HLA antibody profile from the potential recipient with the donor's HLA type to determine whether donor specific antibodies (DSA) are present for specificities not listed as unacceptable antigens. Immunological risk assessment that will guide acceptance or rejection of an organ offer and peri-transplant treatment depends on the accurate determination of candidate/donor mismatches and DSA and therefore on the availability of the correct HLA typing of the deceased donor.

•A transplant program may also specify the maximum number of mismatched antigens it will accept. The OPTN will only offer organs from deceased donors with mismatched antigens equal to or less than the maximum specified. An incorrect HLA typing may result in the OPTN unwittingly offering an organ from a donor with higher level of mismatches than requested.

Currently, the nationwide organ allocation system is based on the deceased donor's HLA typing obtained from one sample and performed only once by a single laboratory. There is no redundancy in the system to safeguard from possible errors such as sample switches, even though an incorrect HLA type in UNet may have devastating consequences. Transplantation of an incompatible imported kidney may be prevented by a physical prospective crossmatch or a confirmatory HLA typing performed by the laboratory supporting the transplant center. However, for imported hearts and lungs, crossmatches and confirmatory typings are usually performed retrospectively due to time limitations. Based on an erroneous HLA typing, an organ may be transplanted to a patient with high levels of circulating donor specific antibodies which can lead to hyperacute or accelerated rejection. Furthermore, even if an error in the deceased donor HLA typing is caught in time to prevent a catastrophic event, it will cause the nation-wide allocation system to be disrupted as organs that have already been shipped to transplant centers may not be used for the intended recipient.

In summary, a single HLA donor typing cannot be guaranteed to be correct. An erroneous donor HLA typing in UNet will disrupt the organ allocation system nationwide and may cause a catastrophic event. Current OPTN policies demand that the OPO must ensure that each deceased donor's blood type is determined by testing at least two donor blood samples prior to the match run. The donor's HLA type is as critical as ABO type to determine patient/ donor compatibility and OPTN policies should contain at least as many safeguards for HLA typing as they do for ABO blood group testing.

Anonymous | 01/23/2023

The proposed policy is far out of proportion to the problem it is trying to address. Although an incorrect donor HLA type could conceivably cause problems for a recipient, it is an extremely rare situation where it would actually help. The background for the policy references a 2022 article from UCSF, which states that they found four typing discrepancies out of 1487 donors, for a 0.27% discrepancy rate. But there were actually only three discrepant typings (the fourth case was just an unusual haplotype), and one of the three discrepancies involved a novel DPB1 allele which would be a problem regardless of whether confirmatory testing was performed (and should be dealt with by epitope analysis anyway when DPB1 types are present that are not on the antibody screening panel). For the two remaining cases, there's a 50% chance the wrong typing would occur in the original typing and a 50% chance the wrong typing would occur in the confirmatory typing. So the real frequency of confirmatory typing helping avoid a match run being executed with a wrong HLA type is 1 in 1487, or 0.07%. Unlike ABO typing discrepancies, where the natural occurrence of anti-A and anti-B antibodies is a substantial concern, the vast majority of recipients would be unaffected by an incorrect donor HLA type as most have no HLA antibodies (77% of transplant recipients in our center have no HLA antibodies). Even for recipients who do have HLA antibodies, an incorrect donor HLA type is unlikely to cross the recipient's HLA antibody specificities (an exact figure is difficult to predict, but a rough guess is that two-thirds of the time the incorrect type wouldn't be an issue).

Anonymous | 01/19/2023

I would not recommend two HLA Typings for the same dononr. Since HLA discrepancies occur in approximately 0.3% of deceased donor typings which is a low percentage, this can be avoided by Histocompatibility labs by adding more check points and improve the process to avoid switching samples which is better than increasing the workload and the price of HLA Typing.

Gerald Morris | 01/19/2023

The increasing reliance on virtual crossmatch for improving access via organ sharing requires high confidence for donor HLA genotyping results. This should be considered similar to ABO blood typing. While documented donor mistypings are a relatively infrequent event, they are potentially high impact events with the potential for requiring re-running the match run or even catastrophic clinical outcomes for multiple recipients. Current methods for donor HLA genotyping are fast, and performing typing on a second sample can be perfomed either simulataneously or in sequence with minimal impact on time to providing HLA typing. The increased costs are minimal when considered as a part of overall cost of transplantation. Implementing this proposal would have a significantly positive impact on patient safety, efficiency of organ allocation, and improving organ sharing.