Alternative Sample Matrices Supporting Remote Sample Collection during the Pandemic and Beyond
Emily L. Gill, Khushbu Patel, Jane A. Dickerson, Matthew C. Dulik, Russell P. Grant, Denise L. Heaney, James W. Rudge · Clinical Chemistry · 2021
The COVID-19 pandemic has changed the landscape of healthcare delivery. It is estimated that 40% of US adults delayed or avoided seeking care during the pandemic and many hospitals saw a 40% to 80% decrease in outpatient visits. According to the CDC, there was a 2.5-fold increase in telehealth visits during the last week of March 2020. Alongside this shift to telemedicine, many laboratories saw a decrease in testing volumes especially in laboratory tests commonly ordered for managing chronic conditions such as diabetes. The traditional model for sample collection requires blood draw by trained professionals, usually in proximity to the testing site, and transport of the specimens in appropriate temperature-controlled conditions. Therefore, alternative matrices that can be collected at home through a simplified collection process, and that are minimally affected by environmental factors such as heat and humidity, are particularly attractive for supporting telemedicine. Alternative matrices that fit these criteria include dried blood spots, microsampling devices, and saliva. Such specimen types have been used prior to the pandemic, mainly for newborn screening programs, research, and recreational testing. In addition to allowing patients and providers to adhere to CDC recommendations for telehealth services during the pandemic, the ease of at-home sample collection opens up access to laboratory testing for underserved populations. Furthermore, the convenience of at-home sample collection has been shown to improve adherence to treatment plans for chronic conditions and retainment of patients in clinical trials. As the pandemic has accelerated technology adoption in many industries, the growing trend in telehealth visits should continue. The regulatory hurdles preventing the adoption of telehealth services have been lifted during the pandemic. It is anticipated that there will be a need for laboratories to support and adapt to these new trends in healthcare. In this Q&A, experts with diverse backgrounds in developing, validating, and operationalizing technologies that aid in remote sample collection offers their views on the current progress and limitations that must be overcome to adopt such technologies at a broader scale. Jane Dickerson: At Seattle Children’s, we developed a remote dried blood spot collection (DBS) program to monitor immunosuppressants and creatinine for pediatric transplant patients. This program has been in place about a decade and is used by approximately 20% of our transplant population. At the beginning of the pandemic, we saw a large increase in DBS test volumes and even received samples from other institutions as care shifted to telehealth. It was during this time that we also received a request from our endocrinology service to offer a similar program for hemoglobin A1c (HbA1c) to monitor patients with diabetes. Within weeks, we validated a HbA1c assay in DBS and developed a process with Endocrinology to roll out the testing to our diabetes patients. As we learned over the years, it is the preanalytical logistics that are the hardest part of implementing a remote collection program! Russell Grant: Our experience is extensive, including pediatric lead testing using dried blood spots (late 1990s onwards), at-home test kits incorporating capillary blood collection technologies and microbiome testing (2009 onwards), up to the present day where we received Emergency Use Authorization (EUA) approval for self-collected nasopharyngeal swabs for SARS-CoV-2 diagnosis. Matthew Dulik: Prior to March 2020, the Genomic Diagnostic Laboratory at The Children’s Hospital of Philadelphia had made limited use of the alternative specimen matrices. Saliva was accepted in certain scenarios with the most common being sequencing of comparator samples for trio analysis of our clinical exome test. With the impact of the pandemic’s initial wave on hospital operations, we validated the use of saliva specimens for the remainder of our commonly ordered genomic tests to make sure our patients continued to receive necessary testing. We currently receive over 10 times the number of saliva specimens compared to pre-pandemic testing, accounting for about 15% of our total testing. Denise Heaney: As a former laboratory director, I have experience with dried blood spots used for a variety of downstream assays focused on infectious diseases within the pediatric population. Now working in industry, my company and others are interested in finding solutions that address the challenges that exist for access to diagnostic testing, particularly for the underserved populations. As part of a goal of increasing access to reliable HIV testing, we developed the Plasma Separation Card as a stable and easy-to-use sample collection device for HIV plasma viral load for patients with HIV living in remote areas—even areas of extreme heat and humidity (e.g., sub-Saharan Africa). This is not currently available in the United States. James Rudge: In 2009, I invented a technique called volumetric absorptive microsampling (VAMS) for the quantitative collection of microsamples from biological fluids. This led to development of a VAMS product that features an absorptive tip. The device based on VAMS is a next-generation dried matrix sampling technology that enables remote collection of microsamples, which can be posted to a laboratory for extraction and analysis using standard equipment, including liquid handling robots. I currently work with scientists in onboarding the processing of VAMS microsamples into their research workflows. This includes helping to develop and validate robust analytical methods from dried matrices. This allows scientists to transition from a liquid-based matrix workflow, such as urine and plasma, to a workflow where the primary sample matrix is a dried microsample. Jane Dickerson: DBS testing is best known for its worldwide application in newborn screening programs. In the past few decades, we’ve seen adoption of DBS several testing areas beyond newborn screening, including viral screening, epidemiological studies, clinical trials, therapeutic drug monitoring, sports-related doping screening, and direct-to-consumer nutritional screening. In our laboratory, we validated 3 separate assays to measure (a) creatinine, (b) tacrolimus, sirolimus, everolimus, cyclosporine, and (c) HbA1c in Whatman 903 dried blood spots. James Rudge: Due to the volumetric nature of the VAMS technology, most analytes can be accurately measured, but this is based on several assumptions, including: (a) the analyte is stable in its dried form. Thankfully most are, but analyte integrity needs to be tested in the method validation; (b) the analyte is not volatile, since losses can be observed in the drying process; (c) if the matrix is blood, then the hematocrit needs to be considered since this can lead to biases in the results, especially if the analyte of interest is found in the plasma portion only; and (d) the analytical technology is sensitive enough to reliably measure microsamples that are often diluted to allow for enough volume for the instrument. Russell Grant: That is an interesting question. There are 2 fundamental aspects of alternate matrix utility that guide the definition of accuracy. Firstly, almost universally, the agreement between an alternate matrix and venous specimens is a primary indicator of accuracy. In context, the venous results are considered clinical truth and thus split pairwise correlative agreement between venous and alternate matrix types are studied. Secondly, and perhaps most importantly, is the analytical performance of the alternate approach, mostly in terms of imprecision when comparing standard and alternate matrices or sampling technologies. When taken together, pairwise agreement (slope, bias, correlation coefficient, and clinical concordance) and imprecision (%CV) should be informed by quality expectations that ideally meet minimum criterion for total accuracy as defined by the latest IFCC/European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) guidance. While imprecision is relatively easy to estimate, we are usually constrained in terms of accuracy (bias). The mean bias for highly correlated, split-pairwise samples is used to determine the total error of the alternate matrix [total error = bias + (1.65 × imprecision)], and consequently inform clinical use. Matthew Dulik: The primary target of our laboratory’s diagnostic testing is DNA, which is readily available in saliva specimens. We can perform DNA sequence analysis through traditional Sanger/capillary electrophoresis techniques as well as multiple next-generation sequencing methodologies. Copy number variation can also be assessed through chromosomal Single nucleotide polymorphism arrays, targeted array comparative hybridization, multiplex ligation-dependent probe amplification, droplet digital and real-time PCR methods, and next-generation sequencing. Also amendable to DNA extracted from saliva is fragment analysis and repeat primed PCR, where the assay determines the length of DNA repeats for conditions like fragile X syndrome. Matthew Dulik: The primary advantage to remote sample collection is accessibility. For a hospital-based laboratory such as ours, the ability to collect a sample regardless of physical location has allowed us to continue to serve our patients and clinicians with the same high level of service that they have come to expect. This gives clinicians the ability to continue use of the full breadth of the molecular testing modalities contributing to the diagnosis, management, and treatment of patients. For the patients, there are additional advantages. The ability to provide a specimen for diagnostic testing at home, without taking time off from work and/or school and without traveling to a specimen collection site makes undergoing a diagnostic test less of a hardship in an often stressful and anxious time for a patient and their family. Some patients are also better served by providing a specimen at home where the setting is more comfortable and familiar. Since the first month of the pandemic, volumes in our laboratory have increased along with the frequency of telemedicine visits. Current volumes are surpassing our pre-pandemic numbers, suggesting that accessibility to testing has certainly improved. Denise Heaney: One of the primary advantages of remote sample collection is the expanded access to care for individuals who cannot or choose not to access healthcare in traditional clinical settings. With remote sample collection, providers now can expand access to testing to more people who may otherwise not receive any care at all. Care delivery may become more efficient if chronic diseases can be managed remotely. In addition, a clinical implication that could be readily recognized is the ability to understand the true prevalence of certain conditions that we currently struggle to properly screen today in adult populations (e.g., diabetes, infectious diseases, sexually transmitted infections, maternal care, urinary tract infection screening). There are many areas that a remote sample collection could benefit. Jane Dickerson: We were motivated to offer a remote DBS program to our transplant patients to improve continuity of care and patient/family compliance with obtaining blood draws. Families are up against a host of barriers that can prevent timely adherence to their therapeutic drug monitoring, including needing to travel to their medical center, getting to the laboratory early or late for timed trough values, obtaining venous access in small children, and blood volume limits for small children who require many laboratory tests. Being able to collect a sample at home and mail or drop it off is an attractive solution for many of these challenges. The COVID pandemic amplified these challenges, and we responded by quickly deploying our existing program to all eligible patients. We also rolled out a parallel remote collection option for patients seen in our diabetes clinics with HbA1c in DBS. Russell Grant: Accessibility to actionable testing results, particularly in patient management of underserved populations. Access to early, clinically actionable results through screening is a wonderful benefit to societal health, and one that we as a community should consider as our North Star when evaluating and implementing these newer testing modalities. As noted, the quality of results in terms of total error is still not truly disclosed for most alternate matrix (microsampling) approaches. This leads to confusion as to how good or dependable the results are and consequently the clinical should results to patients that not have appropriate medical in terms of has clinical utility James Rudge: The advantage of remote sampling is that patients or research not need to to a for certain such as Prior to the pandemic, a of analytes were at COVID-19 has a of is to monitor using technologies that care providers to make clinical with to or other treatment remote specimen collection are focused on sample integrity and sample through the of Russell Grant: Our experience has us that by is with in terms of the for error in collection and and and The process is often for the to perform the of to a We have many working through these challenges, for use and using analysis to improve the of our most technologies of to be within the laboratory DBS with with a for minimum of a technology as one about a for that is a of As we to target through of all aspects of the process, with for our The limitations can from to the impact of during (e.g., blood and challenges are to the of samples through extraction from DBS or dried matrices. While are not particularly which includes of venous blood with clinical of many of the clinical creatinine, are by the limited volume available and the need to determine the volume being from dried matrix of the of any analyte is to results in the appropriate (e.g., one many clinical have limitations in the ability to more volume from an extracted sample for the of and are highly to the of the laboratory has to develop criteria to the of collection and of a specimen when received in the laboratory prior to testing. Denise Heaney: tests using these alternative specimen matrices must be validated and performance in the use populations. The use of alternative specimen matrices without could in in analytical and that could impact clinical challenges include sample to large where testing is sample and specimen Some of the limitations are the of sample and how it is are as well as providing all that is for blood collection for the integrity of the sample with collection can the sample and for downstream the sample is of the the transport is as that samples are within the and humidity can also be a Jane Dickerson: We have focused on analytes that are currently in blood, since we can similar with analytes in blood in dried blood spots. 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We changed the to make the of that are We also changed how we the kits to appropriate specimen While these have of sample the is not The for sample is when a target is being tested as testing of a with of against Denise Heaney: The most that needs to be is the of who the the laboratory a remote or device or the be and to all downstream assays that include the alternate collection are properly a sample has not been or by the and for a the laboratory this specimen need to perform a to the performance are not by an sample With the COVID-19 pandemic, has become a or one may even a The for healthcare providers for this be expanded beyond expanded beyond Some of the performance for have focused on humidity and to the for are still relatively in the There is an for from patients and healthcare could be that we and this is we may to an out One is who the collection require a to collect the a to transport the and a to delivery of results to patients and their workflow are by separate and often not the of the all of these a and experience for the can be a Russell Grant: The current regulatory landscape is our of alternate specimens into use Firstly, collection of alternate samples with Secondly, of specimens for nutritional also by the or self-collected samples for assays require of to the for the of regulatory self-collected specimens for diagnostic and utility currently we understand that this is together, these should inform the laboratory community of the and of that be including and approval to the Jane Dickerson: Our require medical must be able to to the a and for the to become the and mail it We a of on to are not and venous draws. 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