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.
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.
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.”
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.
Since Alexa is now programed to be compliant with HIPAA privacy rules, it’s likely similar voice assistance technologies will soon become available in US healthcare as well
Shortages of physicians and other types of caregivers—including
histopathologists
and pathology
laboratory workers—in the United Kingdom (UK) has the UK’s National Health Service (NHS) seeking alternate
ways to get patients needed health and medical information. This has prompted a
partnership with Amazon to use the Alexa virtual assistant to
answer patients healthcare inquiries.
Here in the United States, pathologists and clinical
laboratory executives should take the time to understand this development.
The fact that the NHS is willing to use a device like Alexa to help it maintain
access to services expected by patients in the United Kingdom shows how rapidly
the concept of “virtual clinical care” is moving to become mainstream.
If the NHS can make it work in a health system serving 66-million
people, it can be expected that health insurers, hospitals, and physicians in
the United States will follow that example and deploy similar virtual health
services to their patients.
For these reasons, all clinical laboratories and anatomic
pathology groups will want to develop a strategy as to how their
organizations will interact with virtual health services and how their labs
will want to deploy similar virtual patient information services.
Critical Shortages in Healthcare Services
While virtual assistants have
been answering commonly-asked health questions by mining popular responses on
the Internet for some time, this new agreement allows Alexa to provide
government-endorsed medical advice drawn from the NHS website.
By doing this, the NHS hopes to reduce the burden on
healthcare workers by making it easier for UK patients to access health
information and receive answers to commonly-asked health questions directly from
their homes, GeekWire
reported.
“The public needs to be able to get reliable information
about their health easily and in ways they actually use. By working closely
with Amazon and other tech companies, big and small, we can ensure that the
millions of users looking for health information every day can get simple,
validated advice at the touch of a button or voice command,” Matthew Gould, CEO of NHSX, a division of the NHS that focuses
on digital initiatives, told GeekWire.
The
Verge reported that when the British government officially announced
the partnership in a July press
release, the sample questions that Alexa could answer included:
Alexa, how do I treat a migraine?
Alexa, what are the symptoms of the flu?
Alexa, what are the symptoms of chickenpox?
“We want to empower every patient to take better control of
their healthcare and technology like this is a great example of how people can
access reliable, world-leading NHS advice from the comfort of their home,
reducing the pressure on our hardworking GPs (General Practitioners) and
pharmacists,” said Matt
Hancock, Secretary of State for Health and Social Care, in the press release.
MD
Connect notes that the NHS provides healthcare services free of charge to
more than 66-million individuals residing in the UK. With 1.2 million
employees, the NHS is the largest employer in Europe, according to The
Economist. That article also stated that the biggest problem facing the
NHS is a staff shortage, citing research conducted by three independent
organizations:
Their findings indicate “that NHS hospitals, mental-health
providers, and community services have 100,000 vacancies, and that there are
another 110,000 gaps in adult social care. If things stay on their current
trajectory, the think-tanks predict that there will be 250,000 NHS vacancies in
a decade,” The Economist reported.
“This idea is certainly interesting and it has the potential
to help some patients work out what kind of care they need before considering
whether to seek face-to-face medical help, especially for minor ailments that
rarely need a GP appointment, such as coughs and colds that can be safely
treated at home,” Professor
Helen Stokes-Lampard, Chairman at the Royal
College of General Practitioners, and Chair of the Board Of
Directors/Trustees at National
Academy of Social Prescribing, told Sky News.
“However,” she continued, “it is vital that independent
research is done to ensure that the advice given is safe, otherwise it could
prevent people seeking proper medical help and create even more pressure on our
overstretched GP service.”
Amazon has assured consumers that all data obtained by Alexa
through the NHS partnership will be encrypted to ensure privacy and security,
MD Connect notes. Amazon also promised that the personal information will not
be shared or sold to third parties.
Alexa Now HIPAA Compliant in the US
This new agreement with the UK follows the announcement in April
of a new Alexa
Skills Kit that “enables select Covered Entities and their Business
Associates, subject to the US Health
Insurance Portability and Accountability Act of 1996 (HIPAA), to build
Alexa skills that transmit and receive protected
health information (PHI) as part of an invite-only program. Six new Alexa
healthcare skills from industry-leading healthcare providers, payors, pharmacy
benefit managers, and digital health coaching companies are now operating in
our HIPAA-eligible environment.”
Developers of voice assistance technologies can freely use
these Alexa skills, which are “designed to help customers manage a variety of
healthcare needs at home simply using voice—whether it’s booking a medical
appointment, accessing hospital post-discharge instructions, checking on the
status of a prescription delivery, and more,” an Amazon
Developer Alexa blog states.
The blog lists the HIPAA-compliant Alexa skills as:
Express
Scripts: Members can check the status of a home delivery prescription and can
request Alexa notifications when their prescription orders are shipped.
Cigna
Health Today by Cigna (NYSE:CI): Eligible employees with one of Cigna’s
large national accounts can now manage their health improvement goals and
increase opportunities for earning personalized wellness incentives.
Swedish
Health Connect by Providence St.
Joseph Health, a healthcare system with 51 hospitals across seven states
and 829 clinics: Customers can find an urgent care center near them and
schedule a same-day appointment.
Atrium
Health, a healthcare system with more than 40 hospitals and 900 care
locations throughout North and South Carolina and Georgia: Customers in North
and South Carolina can find an urgent care location near them and schedule a
same-day appointment.
Livongo,
a digital health company that creates new and different experiences for people
with chronic conditions: Members can query their last blood sugar reading,
blood sugar measurement trends, and receive insights and Health Nudges that are
personalized to them.
HIPAA Journal notes: “This is not the first time that Alexa skills have been developed, but a stumbling block has been the requirements of HIPAA Privacy Rules, which limit the use of voice technology with protected health information. Now, thanks to HIPAA compliant data transfers, the voice assistant can be used by a select group of healthcare organizations to communicate PHI without violating the HIPAA Privacy Rule.”
Steady increases associated with the costs of medical care
combined with a shortage of healthcare professionals on both continents are
driving trends that motivate government health programs and providers to
experiment with non-traditional ways to interact with patients.
New digital and Artificial
Intelligence (AI) tools like Alexa may continue to emerge as methods for
providing care—including clinical laboratory and pathology advice—to healthcare
consumers.
Based on clinical trials of the medical laboratory test, pregnant women can expect a reduced risk for experiencing complications associated with the dangerous blood disorder
Clinical pathology laboratories and obstetricians in the UK may soon have a new blood test that can help provide earlier diagnoses of pre-eclampsia, a hypertensive disorder of pregnancy that can cause liver and kidney disfunctions and, if untreated, can lead to eclampsia and deadly seizures.
Following a clinical trial conducted by scientists at King’s College London (King’s College), the National Health Service (NHS) in the United
Kingdom (UK) announced it would be making the new test widely available.
The researchers published their findings in The
Lancet medical journal. Their paper explains that the clinical trial
took place in 11 maternity units in the UK from June 2016 through October 2017.
And that 1,023 women were divided into two groups:
576 (56%) were in the “intervention group,”
meaning they had PGF test results made available to their maternity teams;
447 (44%) did not have PGF test results made
available.
The researchers, the Independent
reported, wanted to determine the impact, if any, the new test’s results would
have on diagnoses.
Significantly Reduced Time to Diagnosis
Trial results indicated that measuring the placental growth factor (PGF) in women who are suspected of having pre-eclampsia can increase speed to diagnosis. “PGF testing was shown to reduce the average time to pre-eclampsia diagnosis from 4.1 days to 1.9 days, and serious complications before birth (such as eclampsia, stroke, and maternal death) [dropped] from 5% to 4%,” a King’s College press release stated.
“Complications like stroke, seizures and maternal death fell
by 20% when doctors had access to PGF testing,” the Independent
reported.
The researchers stated in their study, “Our trial has shown
that, in women presenting with suspected pre-eclampsia, PGF measurement,
incorporated into a management algorithm based on national guidelines,
significantly reduces the time taken for treating clinicians to diagnose
pre-eclampsia. This improvement was associated with a significant reduction in
maternal adverse outcomes, with no detected difference in gestational age at
delivery or adverse perinatal outcomes.”
The King’s College press release states, “Pre-eclampsia is
suspected in around 10% of UK pregnancies, affecting approximately 80,000 women
annually. If untreated, it can progress to cause complications in the woman,
including damage to vital organs, fits, and can be fatal for the woman and
baby. Globally, 100 women die as a result of the condition every day.”
The release also noted that “doctors were able to diagnose
pre-eclampsia on average two days sooner. This was associated with significant
improvements in outcomes for women without causing health problems for babies.”
Measuring PGF in Clinical Laboratory Study
PGF is a molecular marker for inflammation associated mostly
with the mother’s placenta.
The King’s College researchers wanted to find out if a quicker diagnosis of
pre-eclampsia was possible. And, if so, could it reduce adverse outcomes in the
mother and baby?
“For the last hundred years, we have diagnosed pre-eclampsia
through measuring blood pressure and checking for protein in a woman’s urine.
These are relatively imprecise and often quite subjective,” said Lucy Chappell, PhD,
NIHR Research Professor in Obstetrics at King’s College, and lead author of the
study, in the news release.
“We knew that monitoring PGF was an accurate way to help
detect the condition, but [we] were unsure whether making this tool available
to clinicians would lead to better care for women. Now we know that it does,” she
concluded.
Pre-eclampsia can lead to stroke, seizures, and even death
of expectant mothers and unborn children. It is usually diagnosed after 20
weeks of gestation through blood pressure tests and urine tests that show
hypertension and elevated protein levels.
“We found that the availability of PGF test results
substantially reduced the time to clinical confirmation of pre-eclampsia. Where
PGF was implemented, we found a lower incidence of maternal adverse outcomes,”
the researchers wrote in their study.
Similar Study in the US
In the UK, pre-eclampsia affects about one in 20 pregnancies
or 80,000 women each year, New
Scientist explained. While in the US, data compiled from the Centers for Disease Control
and Prevention (CDC) indicate that pre-eclampsia affects one in 25
pregnancies or about 154,220 women annually.
Researchers in Ohio also recently reported on a test and a piloted
clinical study for rapid diagnosis of pre-eclampsia.
“This is the first clinical study using the point-of-care,
paper-based Congo Red Dot (CRD) diagnostic test, and the mechanism proved
superior in establishing or ruling out a diagnosis of pre-eclampsia,” Kara Rood, MD, a maternal-fetal
medicine physician at Wexner Medical Center and first author of the study said
in the Wexner press release. “Our findings will have a huge impact on the
health of women and children.”
The researchers published their findings in EClinicalMedicine,
a Lancet Journal.
“Pre-eclampsia is often described as ‘mysterious’ because
it’s difficult to diagnose. Our researchers show that there’s an easy,
non-invasive test that will help diagnose this condition and maintain the
health of pregnant women and their babies,” K. Craig
Kent, MD, OSU Dean of the College of Medicine, said in the press release.
Clinical laboratory tests such as these being developed in
the US and abroad could help pregnant women worldwide experience happy
pregnancies and give birth to healthy babies. Medical laboratory leaders in
this country may want to stay abreast of the development of these simple blood
and urine tests.
This new atlas of leukemia proteomes may prove useful for medical laboratories and pathologists providing diagnostic and prognostic services to physicians treating leukemia patients
Researchers at the University of Texas at San Antonio (UTSA) and the University of Texas MD Anderson Cancer Center created the online atlases—categorized into adult and pediatric datasets—to “provide quantitative, molecular hallmarks of leukemia; a broadly applicable computational approach to quantifying heterogeneity and similarity in molecular data; and a guide to new therapeutic targets for leukemias,” according to the Leukemia Atlases website.
In building the Leukemia Proteome Atlases, the researchers identified and classified protein signatures that are present when patients are diagnosed with AML. Their goal is to improve survival rates and aid scientific research for this deadly disease, as well as develop personalized, effective precision medicine treatments for patients.
To perform the study, the scientists looked at the proteomic screens of 205
biopsies of patients with AML and analyzed the genetic, epigenetic, and
environmental diversity in the cancer cells. Their analysis “revealed 154 functional
patterns based on common molecular pathways, 11 constellations of correlated
functional patterns, and 13 signatures that stratify the outcomes of patients.”
Amina Qutub, PhD, Associate Professor at UTSA and one of the authors of the research, told UTSA Today, “Acute myelogenous leukemia presents as a cancer so heterogeneous that it is often described as not one, but a collection of diseases.”
To better understand the proteomic levels associated with AML, and share their work globally with other scientists, the researchers created the Leukemia Proteome Atlases web portal. The information is displayed in an interactive format and divided into adult and pediatric databases. The atlases provide quantitative, molecular hallmarks of AML and a guide to new therapeutic targets for the disease.
The NCI predicts there will be approximately 21,540 new
cases of AML diagnosed this year. They will account for about 1.2% of all new
cancer cases. The disease will be responsible for approximately 10,920 deaths in
2019, or 1.8% of all cancer deaths. In 2016, there were an estimated 61,048
people living with AML in the US.
“Our ‘hallmark’ predictions are being experimentally tested
through drug screens and can be ‘programmed’
into cells through synthetic manipulation of proteins,” Qutub continued. “A
next step to bring this work to the clinic and impact
patient care is testing whether these signatures lead to the aggressive growth
or resistance to chemotherapy observed in
leukemia patients.
“At the same time, to rapidly accelerate research in
leukemia and advance the hunt for treatments,
we provide the hallmarks in an online compendium [LeukemiaAtlas.org] where fellow
researchers and oncologists worldwide can build from the resource, tools, and
findings.”
By mapping AML patients from the proteins present in their
blood and bone marrow, the researchers hope that healthcare professionals will
be able to better categorize patients into risk groups and improve treatment
outcomes and survival rates for this aggressive form of cancer.
The Leukemia Proteome Atlases are another example of the
trend where researchers work together to compile data from patients and share
that information with other scientists and medical professionals. Hopefully, having
this type of data readily available in a searchable database will enable
researchers—as well as clinical laboratory scientists and pathologists—to gain
a better understanding of AML and benefit cancer patients through improved
diagnosis, treatment, and monitoring.