By mining results of unrelated blood tests, the CIRRUS algorithm can inform doctors and patients earlier than usual of liver disease
For years Dark Daily and its sister publication The Dark Report have predicted that the same type of analytical software used on Wall Street to analyze bundles of debt, such as car loans, mortgages, and installment loans, would eventually find application in healthcare and clinical laboratory medicine. Now, researchers at the University of Southampton in England have developed just such an analytical tool.
The UK researchers call their algorithm CIRRUS, which stands for CIRRhosis Using Standard tests. It can, they say, accurately predict if a patient has cirrhosis of the liver at a much earlier stage than usual and produce information that is clinically actionable, using results from several common, routinely-ordered medical laboratory tests.
The University of Southampton scientists published their findings in BMJ Open.
Currently, the leading edge for this in clinical laboratory medicine is analysis of digital pathology images using image analysis tools and artificial intelligence (AI). However, CIRRUS is an example that analytical software is advancing in its ability to mine data from a number of clinically-unrelated lab tests on a patient and identify a health condition that might otherwise remain unknown.
The UK researchers designed the CIRRUS algorithm using routine clinical laboratory blood tests often requested in general practice to identify individuals at risk of advanced liver disease. These tests include:
“More than 80% of liver cirrhosis deaths are linked to alcohol or obesity and are potentially preventable,” noted Nick Sheron, MD, FRCP, Head of Population Hepatology at University of Southampton, and lead author of the study, in a press release. “However, the process of developing liver cirrhosis is silent and often completely unsuspected by GPs [general practitioners]. In 90% of these patients, the liver blood test that is performed is normal, and so liver disease is often excluded.
“This new CIRRUS algorithm can find a fingerprint for cirrhosis in the common blood tests done routinely by GPs,” he continued. “In most cases the data needed to find these patients already exists and we could give patients the information they need to change their lifestyle. Even at this late stage, if people address the cause by stopping drinking alcohol or reducing their weight, the liver can still recover.”
Mining Clinical Laboratory Blood Test Results
To perform the study, the research team analyzed data on blood test results for nearly 600,000 patients. Unlike most diagnostic liver algorithms, the CIRRUS model was created using a dataset comprised of patients from both primary and secondary care without the main intent of preselecting for liver disease. This renders it better suited for detecting liver disease outside a secondary care hepatology environment.
“Whilst we are all preoccupied with the coronavirus pandemic we must not lose sight of other potentially preventable causes of death and serious illness,” said Michael Moore, BM, BS, MRCP, FRCGP, Professor of Primary Health Care Research and Head of Academic Unit Primary Care and Population Sciences at University of Southampton, in the press release. Professor Moore co-authored the CIRRUS study.
“This test using routine blood test data available, gives us the opportunity to pick up serious liver disease earlier, which might prevent future emergency admission to hospital and serious ill health,” he said.
Cirrhosis (shown above in a trichrome stained micrograph) is a condition in which the liver is scarred and permanently damaged. As the condition progresses, more scar tissue replaces healthy liver tissue. This accumulated scar tissue prevents the liver from doing its primary job of regulating chemical levels in the blood and excreting bile, a substance which helps eliminate toxins from the body and breaks down fats during digestion. As cirrhosis worsens, the liver begins to fail. (Photo copyright: Wikipedia.)
According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), cirrhosis is most common in adults ages 45 to 54 and about 1 in 400 adults in the US live with the disease. However, the actual number may be much higher as many people are not aware they have cirrhosis, because they do not experience symptoms until the liver is badly damaged.
The NIDDK reports complications from cirrhosis include:
Portal Hypertension, a condition where scar tissue partially blocks the normal flow of blood through the liver,
“Liver cirrhosis is a silent killer. The tests used most by GPs are not picking up the right people and too many people are dying preventable deaths. We looked at half a million anonymous records and the data we needed to run CIRRUS was already there in 96% of the people who went on to have a first liver admission,” stated Sheron in the press release. “With just a small change in the way we handle this data it should be possible to intervene in time to prevent many of these unnecessary deaths.”
“Alcohol-related liver diseases are far and away the most significant cause of alcohol-specific deaths, yet currently the vast majority of people find out that their liver is diseased way too late,” said Richard Piper, PhD, Chief Executive of Alcohol Change UK, a British charity and campaign group dedicated to reducing harm caused by alcohol abuse. “What is needed is a reliable means of alerting doctors and their patients to potential liver disease as early as possible. The CIRRUS process shows real promise, and we want to see it further developed, tested and implemented, to help save hundreds of thousands, if not millions, of lives.”
CIRRUS is a true milestone in the development of computer-assisted healthcare diagnostics. It will need more research, but the University of Southampton study shows that analytical software tools can mine clinical laboratory test results that were ordered for unrelated diagnostics and identify existing health conditions that might otherwise remain hidden to the patient’s physicians.
VCU scientists used the technique to measure mutations associated with acute myeloid leukemia, potentially offering an attractive alternative to DNA sequencing
More accurate but less-costly cancer diagnostics are the Holy Grail of cancer research. Now, research scientists at Virginia Commonwealth University (VCU) say they have developed a clinical laboratory diagnostic technique that could be far cheaper and more capable than standard DNA sequencing in diagnosing some diseases. Their method combines digital polymerase chain reaction (dPCR) technology with high-speed atomic force microscopy (HS-AFM) to generate nanoscale-resolution images of DNA.
The technique allows the researchers to measure polymorphisms—variations in gene lengths—that are associated with many cancers and neurological diseases. The VCU scientists say the new technique costs less than $1 to scan each dPCR reaction.
“We chose to focus on FLT3 mutations because they are difficult to [diagnose], and the standard assay is limited in capability,” said physicist Jason Reed, PhD, Assistant Professor in the Virginia Commonwealth University Department of Physics, in a VCU press release.
Reed is an expert in nanotechnology as it relates to biology and medicine. He led a team that included other researchers in VCU’s physics department as well as physicians from VCU Massey Cancer Center and the Department of Internal Medicine at VCU School of Medicine.
“The technology needed to detect DNA sequence rearrangements is expensive and limited in availability, yet medicine increasingly relies on the information it provides to accurately diagnose and treat cancers and many other diseases,” said Jason Reed, PhD (above center, with Andrey Mikheikin, PhD, on left and Sean Koebley, PhD, on right), in a press release from Virginia Commonwealth University (VCU). “We’ve developed a system that combines a routine laboratory process with an inexpensive yet powerful atomic microscope that provides many benefits over standard DNA sequencing for this application, at a fraction of the cost.” (Photo copyright: Virginia Commonwealth University.)
Validating the Clinical Laboratory Test
The physicists worked with two VCU physicians—hematologist/oncologist Amir Toor, MD, and hematopathologist Alden Chesney, MD—to compare the imaging technique to the LeukoStrat CDx FLT3 Mutation Assay, which they described as the “current gold standard test” for diagnosing FLT3 gene mutations.
The researchers said their technique matched the results of the LeukoStrat test in diagnosing the mutations. But unlike that test, the new technique also can measure variant allele frequency (VAL). This “can show whether the mutation is inherited and allows the detection of mutations that could potentially be missed by the current test,” states the VCU press release.
“We plan to continue developing and testing this technology in other diseases involving DNA structural mutations,” Reed said. “We hope it can be a powerful and cost-effective tool for doctors around the world treating cancer and other devastating diseases driven by DNA mutations.”
“In our approach we first used digital PCR, in which a mixed sample is diluted to less than one target molecule per aliquot and the aliquots are amplified to yield homogeneous populations of amplicons,” he said. “Then, we deposited each population onto an atomically-flat partitioned surface.”
The VCU researchers “scanned each partition with high-speed atomic force microscopy, in which an extremely sharp tip is rastered across the surface, returning a 3D map of the surface with nanoscale resolution,” he said. “We wrote code that traced the length of each imaged DNA molecule, and the distribution of lengths was used to determine whether the aliquot was a wild type [unmutated] or variant.”
In Diagnostics World, Reed said the method “doesn’t really have any more complexity than a PCR assay itself. It can easily be done by most lab technicians.”
Earlier Research
A VCU press release from 2017 noted that Reed’s research team had developed technology that uses optical lasers (similar to those in a DVD player) to accelerate the scanning. The researchers previously published a study about the technique in Nature Communications, and a patent is currently pending.
“DNA sequencing is a powerful tool, but it is still quite expensive and has several technological and functional limitations that make it difficult to map large areas of the genome efficiently and accurately,” Reed said in the 2017 VCU press release. “Our approach bridges the gap between DNA sequencing and other physical mapping techniques that lack resolution. It can be used as a stand-alone method or it can complement DNA sequencing by reducing complexity and error when piecing together the small bits of genome analyzed during the sequencing process.”
Using CRISPR technology, the team also developed what they described as a “chemical barcoding solution,” placing markers on DNA molecules to identify genetic mutations.
New DNA Clinical Laboratory Testing?
Cancer diagnostics are constantly evolving and improving. It is not clear how long it will be before VCU’s new technique will reach clinical laboratories that perform DNA testing, if at all. But VCU’s new technique is intriguing, and should it prove viable for clinical diagnostic use it could revolutionize cancer diagnosis. It is a development worth watching.
Results of the UK study confirm for clinical laboratory professionals the importance of fully understanding the design and function of SNP chips they may be using in their labs
Here is another example of a long-established clinical laboratory test that—upon new evidence—turns out to be not as accurate as once thought. According to research conducted at the University of Exeter in Devon, UK, Single-nucleotide polymorphism (SNP) chips (aka, SNP microarrays)—technology commonly used in commercial genetic testing—is inadequate at detecting rare gene variants that can increase breast cancer risk.
A news release announcing the results of the large-scale study states, “A technology that is widely used by commercial genetic testing companies is ‘extremely unreliable’ in detecting very rare variants, meaning results suggesting individuals carry rare disease-causing genetic variants are usually wrong.”
Why is this a significant finding for clinical laboratories? Because medical laboratories performing genetic tests that use SNP chips should be aware that rare genetic variants—which are clinically relevant to a patient’s case—may not be detected and/or reported by the tests they are running.
UK Researchers Find ‘Shockingly High False Positives’
The conclusion reached by the Exeter researchers, the BMJ study states, is that “SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.”
Leigh Jackson, PhD, Lecturer in Genomic Medicine at University of Exeter and co-author of the BMJ study, said in the news release, “The number of false positives on rare genetic variants produced by SNP chips was shockingly high. To be clear: a very rare, disease-causing variant detected using [an] SNP chip is more likely to be wrong than right.”
In the news release, Caroline Wright, PhD (above), Professor in Genomic Medicine at the University of Exeter Medical School and senior author of the BMJ study, said, “SNP chips are fantastic at detecting common genetic variants, yet we have to recognize that tests that perform well in one scenario are not necessarily applicable to others.” She added, “We’ve confirmed that SNP chips are extremely poor at detecting very rare disease-causing genetic variants, often giving false positive results that can have profound clinical impact. These false results had been used to schedule invasive medical procedures that were both unnecessary and unwarranted.” (Photo copyright: University of Exeter.)
Large-Scale Study Taps UK Biobank Data
The Exeter researchers were concerned about cases of unnecessary invasive medical procedures being scheduled by women after learning of rare genetic variations in BRCA1 (breast cancer type 1) and BRCA2 (breast cancer 2) tests.
“The inherent technical limitation of SNP chips for correctly detecting rare genetic variants is further exacerbated when the variants themselves are linked to very rare diseases. As with any diagnostic test, the positive predictive value for low prevalence conditions will necessarily be low in most individuals. For pathogenic BRCA variants in the UK Biobank, the SNP chips had an extremely low positive predictive value (1-17%) when compared with sequencing. Were these results to be fed back to individuals, the clinical implications would be profound. Women with a positive BRCA result face a lifetime of additional screening and potentially prophylactic surgery that is unwarranted in the case of a false positive result,” they wrote.
Using UK Biobank data from 49,908 participants (55% were female), the researchers compared next-generation sequencing (NGS) to SNP chip genotyping. They found that SNP chips—which test genetic variation at hundreds-of-thousands of specific locations across the genome—performed well when compared to NGS for common variants, such as those related to type 2 diabetes and ancestry assessment, the study noted.
“Because SNP chips are such a widely used and high-performing assay for common genetic variants, we were also surprised that the differing performance of SNP chips for detecting rare variants was not well appreciated in the wider research or medical communities. Luckily, we had recently received both SNP chip and genome-wide DNA sequencing data on 50,000 individuals through the UK Biobank—a population cohort of adult volunteers from across the UK. This large dataset allowed us to systematically investigate the performance of SNP chips across millions of genetic variants with a wide range of frequencies, down to those present in fewer than 1 in 50,000 individuals,” wrote Wright and Associate Professor of Bioinformatics and Human Genetics at Exeter, Michael Weedon, PhD, in a BMJ blog post.
The Exeter researchers also analyzed data from a small group of people in the Personal Genome Project who had both SNP genotyping and sequencing information available. They focused their analysis on rare pathogenic variants in BRCA1 and BRCA2 genes.
The researchers found:
The rarer the variant, the less reliable the test result. For example, for “very rare variants” in less than one in 100,000 people, 84% found by SNP chips were false positives.
Low positive predictive values of about 16% for very rare variants in the UK Biobank.
Nearly all (20 of 21) customers of commercial genetic testing had at least one false positive rare disease-causing variant incorrectly genotyped.
SNP chips detect common genetic variants “extremely well.”
Advantages and Capabilities of SNP Chips
Compared to next-gen genetic sequencing, SNP chips are less costly. The chips use “grids of hundreds of thousands of beads that react to specific gene variants by glowing in different colors,” New Scientist explained.
Common variants of BRCA1 and BRCA2 can be found using SNP chips with 99% accuracy, New Scientist reported based on study data.
However, when the task is to find thousands of rare variants in BRCA1 and BRCA2 genes, SNP chips do not fare so well.
“It is just not the right technology for the job when it comes to rare variants. They’re excellent for the common variants that are present in lots of people. But the rarer the variant is, the less likely they are to be able to correctly detect it,” Wright told CNN.
SNP chips can’t detect all variants because they struggle to cluster needed data, the Exeter researchers explained.
“SNP chips perform poorly for genotyping rare genetic variants owing to their reliance on data clustering. Clustering data from multiple individuals with similar genotypes works very well when variants are common,” the researchers wrote. “Clustering becomes more difficult as the number of people with a particular genotype decreases.”
Clinical laboratories Using SNP Chips
The researchers at Exeter unveiled important information that pathologists and medical laboratory professionals will want to understand and monitor. Cancer patients with rare genetic variants may not be diagnosed accurately because SNP chips were not designed to identify specific genetic variants. Those patients may need additional testing to validate diagnoses and prevent harm.
At-home genetic test kits face scrutiny for providing information that may provide consumers with an incomplete picture of their genetic health risks and ancestry
Genetic testing for disease risk and heritage are hugely popular. But though clinical laboratory and pathology professionals understand the difference between a doctor-ordered genetic health risk (GHR) test and a direct-to-consumer (DTC) genetic test, the typical genetic test customer may not. And misunderstanding the results of a DTC at-home genetic test can lead to confusion, loss of privacy, and potential harm, according to Consumer Reports.
To help educate consumers about the “potential pitfalls” of at-home DTC testing kits offered by companies such as Ancestry and 23andMe, Consumer Reports has published an article, titled, “Read This Before You Buy a Genetic Testing Kit.” The article covers “four common claims from the manufacturers of these products, whether they deliver, and what to know about their potential pitfalls.”
Are Genetic Ancestry Tests Accurate?
Ancestry and 23andMe are the DTC genetic test industry leaders, with databases of genetic information about 18 million individuals and 10 million individuals respectively. According to a Consumer Reports survey, as of October 2020 about one in five Americans had taken a DTC genetic test. Reported reasons for doing so included:
66% of respondents wanted to learn more about their ancestry.
20% wanted to locate relatives.
18% wanted to learn more about their health.
11% wanted to learn if they have or are a carrier for any medical conditions.
3% wanted to get a medical test they could not get through their doctor.
Though DTC genetic tests remain popular, Consumer Reports is now warning consumers to view the genealogical or medical insights gleaned through these tests with caution. “If you go in there thinking that this test is going to tell you who you are, you’re going to be wrong,” Wendy Roth, PhD (above), Associate Professor of Sociology at the University of Pennsylvania, told the publication. (Photo copyright: University of Pennsylvania.)
As Consumer Reports notes, doctor-ordered genetic health risk (GHR) testing typically aims to answer a specific question about a patient’s risk for a certain disease. DTC at-home genetic testing, on the other hand, examines a “whole range of variants that have been linked—sometimes quite loosely—to a number of traits, some not related to your health at all.
“Think of it this way: When your doctor orders genetic testing, it’s akin to fishing for a particular fish, in a part of the ocean where it’s known to live,” Consumer Reports noted, “A DTC test is more like throwing a net into the ocean and seeing what comes back.”
In its article, Consumer Reports addressed four common DTC genetic test claims:
The Tests Can Find Far-Flung Relatives: While the tests can unearth people in its database whom you might be related to, 9% of respondents in the Consumer Reports survey discovered unsettling information about a relative.
Testing Can Uncover Where Your Ancestors Are From: Genetic tests may show the percentage of your DNA that comes from Europe or Asia or Africa, but accuracy depends on how many DNA samples a company has from a particular region. As genetic test manufacturers’ reference databases widen, a customer’s genetic ancestry test results can “change over time.” Also, finding a particular variation in genetic code does not definitively place someone in a specific region, or ethnic or racial group.
Genetic Tests Can Reveal Your Risk for Certain Diseases: Testing companies such as 23andMe are authorized by the Food and Drug Administration (FDA) to offer physician-mediated tests, which are analyzed in a federally-certified clinical laboratory. However, test results may provide a false sense of security because DTC tests look for only select variants known to cause disease.
The Tests Can Tell What Diet Is Best for You: Incorporating genetic information into diet advice has the potential to be transformative, but the science is not yet there to offer personalized nutritional advice.
Consumer Reports pointed to a 2020 study published in the MDPI journal Nutrients, titled, “Direct-to-Consumer Nutrigenetics Testing: An Overview,” which evaluated 45 DTC companies offering nutrigenetics testing and found a need for “specific guidelines” and “minimum quality standards” for the services offered. For example, the study authors noted that more than 900 genetic variants contribute to obesity risk. However, weight-loss advice from DTC test companies was based on a “limited set of genetic markers.”
In the Consumer Reports article, Mwenza Blell, PhD, a biosocial medical anthropologist and Rutherford Fellow and NUAcT Fellow at Newcastle University in the United Kingdom, said “genetic ancestry tests are closer to palm reading than science.”
Seattle Cancer Care Alliance and an Associate Professor of Oncology at the University of Washington, fears consumers “miss important limitations on a test’s scope” or “misunderstand critical nuances in the results.”
Cheng says the ability to use flexible or health savings accounts (HSAs) to cover the cost of 23andMe’s GHR assessments, as well as the FDA’s approval of 23andMe’s Personal Genome Service Pharmacogenetic Reports test on medication metabolism, may have added to the confusion.
“This may further mislead people into thinking these tests are clinically sound. Again, they are not,” Cheng wrote.
As an oncologist, Cheng is particularly concerned about consumer GHR testing for heritable cancer risk, which screen for only a handful of genetic variants.
“The results are inadequate for most people at high risk of cancers associated with inherited mutations in BRCA1 or BRCA2 genes, including families whose members have experienced ovarian cancer, male breast cancer, multiple early breast cancers, pancreatic cancer, or prostate cancer,” Cheng wrote. “Put simply, this recreational test has zero value for the majority of people who may need it for true medical purposes.”
DTC genetic health-risk assessments may one day lead to consumers collecting samples at home for tests that aid in the diagnosis of disease. In the meantime, clinical laboratory professionals can play a role in educating the public about the limitations of current DTC genetic test offerings.
Painless technology could one day replace some phlebotomy blood draws as the go-to specimen-collection method for clinical laboratory testing and health monitoring
Clinical laboratories have long sought a non-invasive way to do useful medical laboratory testing without the need for either a venipuncture or a needle stick. Now engineers at the McKelvey School of Engineering at Washington University in St. Louis in Missouri have developed a disposable microneedle patch that one day could be a painless alternative to some blood draws for diagnostics tests and health monitoring.
The technology uses an easy-to-administer low-cost patch that can be applied to the skin like an adhesive bandage. The patch is virtually painless because the microneedles are too small to reach nerve receptors. Another unique aspect to this innovative approach to collecting a specimen for diagnostic testing is that the Washington University in St. Louis (WashU) research team designed the microneedle patch to include plasmonic-fluor. These are ultrabright gold nanolabels that light up target protein biomarkers and can make the biomarkers up to 1,400 times brighter at low concentrations, compared to traditional fluorescent labels.
The patch, states a WashU news release, “… can be applied to the skin, capture a biomarker of interest and, thanks to its unprecedented sensitivity, allow clinicians to detect its presence.”
The technology is low cost, easy for clinicians or patients themselves to use, and could eliminate the need for a trip to patient service center where a phlebotomist would draw blood for clinical laboratory testing, the news release states.
“We have created a platform technology that anyone can use. And they can use it to find their own biomarker of interest,” study leader Srikanth Singamaneni, PhD (above), Lilyan and E. Lisle Hughes Professor in the Department of Mechanical Engineering and Materials Sciences at Washington University in St. Louis, said in the WashU news release. Singamaneni and his colleagues are developing a new specimen collection method that might someday be widely used by clinical laboratories. (Photo copyright: Washington University in St. Louis.)
“We used the microneedle patch in mice for minimally invasive evaluation of the efficiency of a cocaine vaccine, for longitudinal monitoring of the levels of inflammatory biomarkers, and for efficient sampling of the calvarial periosteum [a skull membrane]—a challenging site for biomarker detection—and the quantification of its levels of the matricellular protein periostin, which cannot be accurately inferred from blood or other systemic biofluids,” the researchers wrote. “Microneedle patches for the minimally invasive collection and analysis of biomarkers in interstitial fluid might facilitate point-of-care diagnostics and longitudinal monitoring.”
Mark Prausnitz, PhD, Regents’ Professor, J. Erskine Love Jr. Chair in Chemical and Biomolecular Engineering, and Director of the Center for Drug Design, Development, and Delivery at Georgia Tech, told WIRED, “Blood is a tiny fraction of the fluid in our body. Other fluids should have something useful—it’s just hard to get those fluids.”
“Previously, concentrations of a biomarker had to be on the order of a few micrograms per milliliter of fluid,” said Zheyu (Ryan) Wang, a PhD candidate in Srikanth Singamaneni’s lab at McKelvey School of Engineering and a lead author of the paper, in the WashU news release. By using plasmonic-fluor, researchers were able to detect biomarkers on the order of picograms per milliliter—one millionth of the concentration.
“That’s orders of magnitude more sensitive,” Wang said.
Unlike blood, dermal interstitial fluid often does not contain high enough concentrations of biomarkers to be easily detectable. To overcome this hurdle, the Washington University in St. Louis research team developed a microneedle patch with plasmonic-fluor—ultrabright gold nanolabels (above)—which lit up target protein biomarkers, making them roughly 1,400 times brighter at low concentrations than when using traditional fluorescent labels commonly used in many medical laboratory tests. (Photo copyright: Washington University in St. Louis.)
Can Microneedles Be Used as a Diagnostic Tool?
As reported in WIRED, the polystyrene patch developed by Srikanth Singamaneni’s lab at McKelvey School of Engineering removes interstitial fluid from the skin and turns the needles into “biomarker traps” by coating them with antibodies known to bind to specific proteins, such as Interleukin 6 (IL-6). Once the microneedles are mixed with plasmonic-fluor, the patch will glow if the IL-6 biomarkers are present.
The development of such a highly sensitive biomarker-detection method means skin becomes a potential pathway for using microneedles to diagnose conditions, such as myocardial infarction or to measure COVID-19 antibodies in vaccinated persons.
“Now we can actually use this tool to understand what’s going on with interstitial fluid, and how we’re going to be able to use it to answer healthcare-related or medical problems,” Maral Mousavi, PhD, Assistant Professor of Biomedical Engineering, Viterbi School of Engineering at the University of Southern California, told WIRED. “I think it has the potential to be that kind of a game changer.”
Because the WashU study is a proof-of-concept in mice, it may be many years before this technology finds its way to clinical application. Many skin biomarkers will need to be verified for direct links to disease before microneedle patches will be of practical use to clinicians for diagnostics. However, microneedle patch technology has already proven viable for the collection of blood.
In 2017, Massachusetts-based Seventh Sense Biosystems (7SBio) received 510(k) clearance for a new microneedle blood collection device. Called TAP, the device is placed on the upper arm and blood collection starts with a press of a button. The process takes two to three minutes.
Initially, the FDA clearance permitted only healthcare workers to use the device “to collect capillary blood for hemoglobin A1c (HbA1c) testing, which is routinely used to monitor blood sugar levels in diabetic or pre-diabetic patients,” a Flagship Pioneering news release noted.
Then, in 2019, the FDA extended its authorization “to include blood collection by laypersons. Regulators are also allowing the device to be used ‘at-home’ for wellness testing,” a 7SBio news release stated. This opened the door for a microneedle device to be used for home care blood collection.
“No one likes getting blood drawn, but blood is the single-most important source of medical information in healthcare today, with about 90% of all diagnostic information coming from blood and its components,” Howard Weisman, former CEO of 7SBio and current CEO of PaxMedica, a clinical-stage biopharmaceutical company, said in the Flagship Pioneering news release. “TAP has the potential to transform blood collection from an inconvenient, stressful, and painful experience to one people can do themselves anywhere, making health monitoring much easier for both healthcare professionals and patients.”
As microneedle technology continues to evolve, clinical laboratories should expect patches to be used in a growing number of drug delivery systems and diagnostic tests. But further research will be needed to determine whether interstitial fluid can provide an alternate pathway for diagnosing disease.
The palm-sized device could one day be engineered to track down explosives and gas leaks or could even be used by medical laboratories to detect disease
Here’s a technology breakthrough with many implications for diagnostics and clinical laboratory testing. Researchers at the at the University of Washington (UW) are pushing the envelope on what can be achieved by combining technology with biology. They developed “Smellicopter,” a flying drone that uses a living moth antenna to hunt for odors.
According to their published study, the UW scientists believe an odor-guided drone could “reduce human hazard and drastically improve performance on tasks such as locating disaster survivors, hazardous gas leaks, incipient fires or explosives.”
“Nature really blows our human-made odor sensors out of the water,” lead author Melanie Anderson, a UW doctoral student in mechanical engineering, told UW News. “By using an actual moth antenna with Smellicopter, we’re able to get the best of both worlds: the sensitivity of a biological organism on a robotic platform where we can control its motion.”
The researchers believe their Smellicopter is the first odor-sensing flying biohybrid robot system to incorporate a live moth antenna that capitalizes on the insect’s excellent odor-detecting and odor-locating abilities.
In their paper, titled, “A Bio-Hybrid Odor-Guided Autonomous Palm-Sized Air Vehicle,” published in the IOPscience journal Bioinspiration and Biomimetics, the researchers wrote, “Biohybrid systems integrate living materials with synthetic devices, exploiting their respective advantages to solve challenging engineering problems. … Our robot is the first flying biohybrid system to successfully perform odor localization in a confined space, and it is able to do so while detecting and avoiding obstacles in its flight path. We show that insect antennae respond more quickly than metal oxide gas sensors, enabling odor localization at an improved speed over previous flying robots. By using the insect antennae, we anticipate a feasible path toward improved chemical specificity and sensitivity by leveraging recent advances in gene editing.”
How Does it Work?
In nature, a moth uses its antennae to sense chemicals in its environment and navigate toward sources of food or a potential mate.
“Cells in a moth antenna amplify chemical signals,” said study co-author Thomas Daniel, PhD, UW Professor of Biology, in UW News. “The moths do it really efficiently—one scent molecule can trigger lots of cellular responses, and that’s the trick. This process is super-efficient, specific, and fast.”
To keep the moth antennae “alive,” scientists place Manduca sexta hawk moths (above) in a refrigerator to anesthetize them before removing their antennae. Once separated from the live moth, the antenna stays “biologically and chemically active” for up to four hours. Refrigerating the antennas further extends that time span, researchers explained in the UW News article. (Photo copyright: University of Washington.)
Because the moth antenna is hollow, researchers are able to add wires into the ends of the antenna. By connecting the antenna to an electrical circuit, they can measure the average signal from all of the cells in the antenna. When compared to a metal oxide gas sensor, the antenna-powered sensor responded more quickly to a floral scent. It also took less time to recover between tracking puffs of scent.
Anderson compared the antenna-drone circuitry to a human heart monitor.
“A lot like a heart monitor, which measures the electrical voltage that is produced by the heart when it beats, we measure the electrical signal produced by the antenna when it smells odor,” Anderson told WIRED. “And very similarly, the antenna will produce these spike-shaped pulses in response to patches of odor.”
Making a Drone Hunt Like a Moth
Anderson told WIRED her team programmed the drone to hunt for odors using the same technique moths employ to stay targeted on an odor, called crosswind casting.
“If the wind shifts, or you fly a little bit off-course, then you’ll lose the odor,” Anderson said. “And so, you cast crosswind to try and pick back up that trail. And in that way, the Smellicopter gets closer and closer to the odor source.”
However, the researchers had to figure out how to keep the commercially available $195 Crazyflie drone facing upwind. The fix, co-author and co-advisor Sawyer Fuller, PhD, UW Assistant Professor of Mechanical Engineering told UW News, was to add two plastic fins to create drag and keep the vehicle on course.
“From a robotics perspective, this is genius,” Fuller said. “The classic approach in robotics is to add more sensors, and maybe build a fancy algorithm or use machine learning to estimate wind direction. It turns out, all you need is to add a fin.”
A live moth antenna is attached to wires in an arc sharp on the “Smellicopter” drone (above), developed at the University of Washington in Seattle. The autonomous drone uses the moth antenna to navigate toward smells. By connecting the antenna to a circuit board, the UW researchers were able to study the drone’s response to a puff of floral scent. The Smellicopter tracking skills proved superior to that of a human-made sensor. (Photo copyright: University of Washington.)
Other Applications for Odor Detecting Robots
While any practical clinical application of this breakthrough is years away, the scientific team’s next step is to use gene editing to engineer moths with antennae sensitive to a specific desired chemical, such as those found in explosives.
“I think it is a powerful concept,” roboticist Antonio Loquercio, a PhD candidate in machine learning at the University of Zurich who researches drone navigation, told WIRED. “Nature provides us plenty of examples of living organisms whose life depends on this capacity. This could have as well a strong impact on autonomous machines—not only drones—that could use odors to find, for example, survivors in the aftermath of an earthquake or could identify gas leaks in a man-made environment.”
Could a palm-sized autonomous device one day be used to not only track down explosives and gas leaks but also to detect disease?
As clinical pathologists and medical laboratory scientists know, dogs have demonstrated keen ability to detect disease using their heightened sense of smell.
Therefore, it is not inconceivable that smell-seeking technology might one day be part of clinical laboratory testing for certain diseases.
This latest research is another example of how breakthroughs in unrelated fields of science offer the potential for creation of diagnostic tools that one day may be useful to medical laboratories.
