Newly-defined Cardiovascular-Kidney-Metabolic Syndrome (CKM) means physicians will be in close collaboration with clinical laboratories to make accurate diagnoses
In a presidential advisory, the AHA defines a newly described systemic health disorder called Cardiovascular-Kidney-Metabolic Syndrome (CKM). The syndrome “is a systemic disorder characterized by pathophysiological interactions among metabolic risk factors, CKD (chronic kidney disease), and the cardiovascular system leading to multi-organ failure and a high rate of adverse cardiovascular outcomes.”
A CKM diagnosis, which is meant to identify patients who are at high risk of dying from heart disease, is based on a combination of risk factors, including:
weight problems,
issues with blood pressure, cholesterol, and/or blood sugar,
reduced kidney function.
CKM is a new term and doctors will be ordering medical laboratory tests associated with diagnosing patients with multiple symptoms to see if they match this diagnosis. Thus, clinical laboratory managers and pathologists will want to follow the adoption/implementation of this new recommendation.
“The advisory addresses the connections among these conditions with a particular focus on identifying people at early stages of CKM syndrome,” said Chiadi Ndumele, MD, PhD (above), Associate Professor of Medicine at Johns Hopkins University and one of the authors of the AHA paper, in a news release. “Screening for kidney and metabolic disease will help us start protective therapies earlier to most effectively prevent heart disease and best manage existing heart disease.” Clinical laboratories will play a key role in those screenings and in diagnosis of the new syndrome. (Photo copyright: Johns Hopkins University.)
Stages of CKM Syndrome
In its presidential advisory, the AHA wrote, “Cardiovascular-Kidney-Metabolic (CKM) syndrome is defined as a health disorder attributable to connections among obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD), including heart failure, atrial fibrillation, coronary heart disease, stroke, and peripheral artery disease. CKM syndrome includes those at risk for CVD and those with existing CVD.”
The five stages of CKM syndrome, which the AHA provided to give a framework for patients to work towards regression of the syndrome, are:
Stage 0: No CKM risk factors. Individuals should be screened every three to five years for blood pressure, cholesterol, and blood sugar levels, and for maintaining a healthy body weight.
Stage 1: Excess body fat and/or an unhealthy distribution of body fat, such as abdominal obesity, and/or impaired glucose tolerance or prediabetes. Patients have risk factors such as weight problems or prediabetes and are encouraged to make healthy lifestyle changes and try to lose at least 5% of their body weight.
Stage 2: Metabolic risk factors and kidney disease. Includes people who already have Type 2 diabetes, high blood pressure, high triglyceride levels, and/or kidney disease. Medications that target kidney function, lower blood sugar, and which help with weight loss should be considered at this stage to prevent diseases of the heart and blood vessels or kidney failure.
Stage 3: Early cardiovascular disease without symptoms in people with metabolic risk factors or kidney disease or those at high predicted risk for cardiovascular disease. People show signs of disease in their arteries, or have heart function issues, or may have already had a stroke or heart attack or have kidney or heart failure. Medication may also be needed at this stage.
Stage 4: Symptomatic cardiovascular disease in people with excess body fat, metabolic risk factors or kidney disease. In this stage, people are categorized as with or without having kidney failure. May also have already had a heart attack, stroke or heart failure, or cardiovascular conditions such as peripheral artery disease or atrial fibrillation.
“We now have several therapies that prevent both worsening kidney disease and heart disease,” said Chiadi Ndumele, MD, PhD, Associate Professor of Medicine at Johns Hopkins University and one of the authors of the Circulation paper, in a news release. “The advisory provides guidance for healthcare professionals about how and when to use those therapies, and for the medical community and general public about the best ways to prevent and manage CKM syndrome.”
According to an AHA 2023 Statistical Update, one in three adults in the US have three or more risk factors that contribute to cardiovascular disease, metabolic disorders, or kidney disease. While CKM affects nearly every major organ in the body, it has the biggest impact on the cardiovascular system where it can affect the blood vessels, heart muscle function, the rate of fatty buildup in the arteries, electrical impulses in the heart and more.
“There is a need for fundamental changes in how we educate healthcare professionals and the public, how we organize care and how we reimburse care related to CKM syndrome,” Ndumele noted. “Key partnerships among stakeholders are needed to improve access to therapies, to support new care models, and to make it easier for people from diverse communities and circumstances to live healthier lifestyles and to achieve ideal cardiovascular health.”
New AHA Risk Calculator
In November, the AHA announced PREVENT (Predicting risk of cardiovascular disease EVENTs), a tool that doctors can use to assess a person’s risk for heart attack, stroke, and heart failure. The new risk calculator, which incorporates CKM, allows physicians to evaluate younger people as well, and examine their long-term risks for cardiovascular issues.
Doctors can use PREVENT to assess people ages 30 to 79 and predict risk for heart attack, stroke, or heart failure over 10 to 30 years.
“Longer-term estimates are important because short-term or 10-year risk in most young adults is still going to be low. We wanted to think more broadly and apply a life-course perspective,” Khan said. “Providing information on 30-year risk may reveal earlier opportunities for intervention and prevention efforts in younger people.”
According to CDC data, about 695,000 people died of heart disease in the US in 2021. That equates to one in every five deaths. Clinical pathologists will need to understand the AHA recommendations and how doctors will be ordering clinical laboratory tests to determine if a patient has CKM. Then, labs will play a role in helping doctors monitor patients to optimize health and prevent acute episodes that put patients in the hospital.
OIG warns that without adequate clinical laboratory testing healthcare organizations could see more deaths and increased spending
Clinical laboratory leaders and pathologists know that lab test volume decreased dramatically during the early months of the COVID-19 pandemic. That was primarily because community lockdowns stopped people from seeing their doctors for the standard range of chronic health conditions, many of which require clinical laboratory tests for diagnosis and chronic disease management.
• 24% reduction in Medicare Part B test volumes in March • 53% in April • 30% in May
The decline of Medicare patients visiting clinical laboratories continued through the balance of 2020. During the first 10 months of the pandemic—March through December 2020—Medicare beneficiaries who pursued lab testing decreased by about 9% compared to the same 10-month period in 2019, according to a news release.
This is a strong indicator that the government’s response to the pandemic had a measurable effect on clinical laboratory testing volume among all age groups, especially among the elderly.
“The cumulative decline in lab test volume across all client labs for [March 9 to April 12] was just over 40%. But in that time, some of our lab customers were hit with a decline of maybe 50% to 60% in test volume,” Kyle Fetter (above), COO, XIFIN, told The Dark Report in 2020. Clinical laboratory testing that originates from a routine patient visit to a doctor—such as blood testing—may have been affected the most, Fetter explained. (Photo copyright: XIFIN.)
Clinical Laboratory Tests Key to Well-being of Patients with Chronic Conditions
The OIG study was limited to Medicare beneficiaries and thus did not provide information about testing fall-off among people who have private health insurance. But in “From Mid-March, Labs Saw Big Drop in Revenue,” Dark Daily’s sister publication The Dark Report reported early in 2020 on a 40% decline in test volumes and the pandemic’s varying effects on clinical labs, anatomic pathology (AP) groups, and AP subspecialties.
The OIG’s Report in Brief on its study recognized that medical laboratory testing is critical to helping healthcare providers manage chronic conditions that affect patients’ well-being and increase their healthcare costs.
“Lab tests are important for beneficiaries with chronic medical conditions, which are associated with hospitalizations, billions of dollars in Medicare costs, and deaths,” the OIG said.
“The information may be useful to stakeholders involved in ensuring that beneficiaries avoid the potential bad outcomes that may result from missing or delaying appropriate care,” the report noted.
Overall, 23.7 million Medicare beneficiaries received medical laboratory tests during the first 10 months of the pandemic, down 2.4 million from 26.1 million in 2019, the OIG reported.
Overall Medicare lab test volume and spending also declined during the reported period:
Part B clinical laboratory tests for Medicare beneficiaries decreased 15% from 419.9 million tests in 2019 to 358.4 million tests in the first 10 months of the pandemic.
Medicare spending for these tests decreased 16% from $6.6 billion in 2019 to $5.5 billion during the first 10 months of the pandemic.
“OIG’s audit of Part B clinical laboratory tests, reimbursed under the Clinical Laboratory Fee Schedule (CLFS) is a useful benchmark for how Medicare beneficiaries received fewer lab tests during the pandemic, especially during the early months,” said Robert Michel, Editor-in-Chief of Dark Daily and The Dark Report.
Medical Laboratory Tests That Were Down Most During COVID-19
The following 10 clinical laboratory tests experienced a 10% or more decline in Medicare beneficiaries seeking them during the pandemic period as compared to pre-pandemic, according to the OIG report:
Comprehensive urine culture test fell 16% to three million Medicare patients.
Uric acid level blood down 13% to 1.9 million Medicare beneficiaries.
Evaluation of antimicrobial drug decreased 17% to 1.74 million Medicare patients.
Folic acid level down 12% to 1.73 million Medicare beneficiaries.
Urinalysis manual test plunged 28% to 1.4 million Medicare patients.
Beyond Medicare, Clinical Laboratory Test Volume Dropped 40%
OIG was not the only organization to analyze medical laboratory testing volume during the pandemic’s early phase.
The Dark Report correlated data tracked by XIFIN, a San Diego-based health information technology (HIT) company providing revenue cycle management services to clinical laboratories and pathology groups. XIFIN’s collected data showed a steep drop in routine test volume as COVID-19 testing ramped up.
“Starting in the third week of March, we saw medical laboratories suffer a sharp drop in routine testing. But at about the same time, many labs began to offset those revenue losses with testing for the novel coronavirus,” Kyle Fetter, XIFIN’s then Executive Vice President and General Manager of Diagnostic Services told The Dark Report in 2020. Fetter is now XIFIN’S Chief Operating Officer.
“Over four weeks beginning March 9, we saw a cumulative drop of over 40% in test volume from all of our lab clients,” he added.
According to XIFIN’s data, lab specialty organizations experienced the following drop in routine testing during the period March 9 to April 16, 2020:
58% at clinical laboratories.
61% at hospital outreach laboratories.
52% at molecular and genetic testing laboratories.
44% at anatomic pathology (AP) groups.
70% to 80% at AP dermatology and other AP subspecialties.
Many medical laboratories are still recovering from the COVID-19 pandemic’s effects on testing volume.
Notably, the OIG’s report acknowledges the importance of adequate clinical laboratory testing and declares that—without these essential lab tests to manage some healthcare conditions—the healthcare industry could see increased morbidity, deaths, and Medicare spending.
The focus of the ongoing GenoVA study is to “determine the clinical effectiveness of polygenic risk score testing among patients at high genetic risk for at least one of six diseases measured by time-to-diagnosis of prevalent or incident disease over 24 months,” according to the National Institutes of Health.
The scientists used data obtained from 36,423 patients enrolled in the Mass General Brigham Biobank. The six diseases they researched were:
The polygenic scores were then tested among 227 healthy adult patients to determine their risk for the six diseases. The researchers found that:
11% of the patients had a high-risk score for atrial fibrillation,
7% for coronary artery disease,
8% for diabetes, and
6% for colorectal cancer.
Among the subjects used for the study:
15% of the men in the study had a high-risk score for prostate cancer, and
13% of the women in the study had a high score for breast cancer.
The researchers concluded that the implementation of PRS may help improve disease prevention and management and give doctor’s a way to assess a patient’s risk for these conditions. They published their findings in the journal Nature Medicine, titled, “Development of a Clinical Polygenic Risk Score Assay and Reporting Workflow.”
“We have shown that [medical] laboratory assay development and PRS reporting to patients and physicians are feasible … As the performance of PRS continues to improve—particularly for individuals of underrepresented ancestry groups—the implementation processes we describe can serve as generalizable models for laboratories and health systems looking to realize the potential of PRS for improved patient health,” the researchers wrote.
Using PRS in Clinical Decision Support
Polygenetic risk scores examine multiple genetic markers for risk of certain diseases. A calculation based on hundreds or thousands of these genetic markers could help doctors and patients make personalized treatment decisions, a core tenet of precision medicine.
“As a primary care physician myself, I knew that busy physicians were not going to have time to take an entire course on polygenic risk scores. Instead, we wanted to design a lab report and informational resources that succinctly told the doctor and patient what they need to know to make a decision about using a polygenic risk score result in their healthcare,” epidemiologist Jason Vassy, MD, told The Harvard Gazette. Vassy is Associate Professor, Harvard Medical School at VA Boston Healthcare System and one of the authors of the research.
“This is another great example of precision medicine,” Jason Vassy, MD (above), Adjunct Assistant Professor, General Internal Medicine at Boston University School of Medicine, told WebMD. “There’s always been a tantalizing idea that someone’s genetic makeup might help tailor preventative medicine and treatment.” Personalized clinical laboratory testing is increasingly becoming based on an individual’s genetics. (Photo copyright: Harvard Medical School.)
Increasing Diversity of Patients in Genomic Research
The team did encounter some challenges during their analysis. Because most existing genomic research was performed on persons of European descent, the risk scores are less accurate among non-European populations. The researchers for this study addressed this limitation by applying additional statistical methods to qualify accurate PRS calculations across multiple racial groups.
“Researchers must continue working to increase the diversity of patients participating in genomics research,” said Matthew Lebo, PhD, Chief Laboratory Director, Laboratory Molecular Medicine, at Mass General Brigham and one of the authors of the study. “In the meantime, we were heartened to see that we could generate and implement valid genetic scores for patients of diverse backgrounds,” he told The Harvard Gazette.
The team hopes the scores may be utilized in the future to help doctors and patients make better decisions regarding preventative care and screenings.
“It’s easy to say that everyone needs a colonoscopy at age 45,” Vassy told WebMD. “But what if you’re such a low risk that you could put it off for longer? We may get to the point where we understand risk so much that someone may not need one at all.”
Future of PRS in Clinical Decision Making
The scientists plan to enroll more than 1,000 patients in a new program and track them for two years to assess how medical professionals use PRS in clinical care. It is feasible that patients who are at high risk for certain diseases may opt for more frequent screenings or take preventative medicines to mitigate their risk.
“Getting to that point will take time,” Vassy added. “But I can see this type of information playing a role in shared decision making between doctor and patient in the near future.”
The team also established resources and educational materials to assist both doctors and patients in using the scores.
“It’s still very early days for precision prevention,” Vassy noted, “but we have shown it is feasible to overcome some of the first barriers to bringing polygenic risk scores into the clinic.”
More research and studies are needed to prove the effectiveness of using PRS tests in clinical care and determine its role in customized treatment plans based on personal genetics. Nevertheless, pathologists and medical scientists will want to follow the GenoVA study.
“It is probably most helpful to think of polygenic risk scores as a risk factor for disease, not a diagnostic test or an indication that an individual will certainly develop the disease,” Vassy said. “Most diseases have complex, multifactorial etiologies, and a high polygenic risk score is just one piece of the puzzle.”
Pathologists and clinical laboratory managers may want to stay informed as researchers in the GenoVA study tease new useful diagnostic insights from their ongoing study of the whole human genome. Meanwhile, the GenoVA team is moving forward with the 1,000-patient study with the expectation that this new knowledge may enable earlier and more accurate diagnoses of the health conditions that were the focus of the GenoVA study.
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.
CDC reports more than 93-million US adults are obese, and health issues related to obesity include heart disease, stroke, type 2 diabetes, and cancers
In recent years, the role of the human microbiome in weight loss or weight gain has been studied by different research groups. There is keen interest in this subject because of the high rates of obesity, and diagnostic companies know that development of a clinical laboratory test that could assess how an individual’s microbiome affects his/her weight would be a high-demand test.
This is true of a study published this year in Mayo Clinic Proceedings. Researchers at Mayo Clinic looked at obese patients who were in an active lifestyle intervention program designed to help them lose weight. It was determined that gut microbiota can have a role in both hindering weight loss and supporting weight loss.
Gut Microbiota More Complicated than Previously Thought
The Mayo researchers determined “an increased abundance of Phascolarctobacterium was associated with [successful weight loss]. In contrast, an increased abundance of Dialister and of genes encoding gut microbial carbohydrate-active enzymes was associated with failure to [lose] body weight. A gut microbiota with increased capability for carbohydrate metabolism appears to be associated with decreased weight loss in overweight and obese patients undergoing a lifestyle intervention program.”
How do bacteria impede weight loss? Vandana Nehra, MD, Mayo Clinic Gastroenterologist and co-senior author of the study, explained in a news release.
“Gut bacteria have the capacity to break down complex food particles, which provides us with additional energy. And this is normally is good for us,” she says. “However, for some individuals trying to lose weight, this process may become a hindrance.”
Put another away: people who more effectively metabolized carbohydrates were the ones who struggled to drop the pounds, New Atlas pointed out.
Vandana Nehra, MD (left), and Purna Kashyap, MBBS (right), are Mayo Clinic Gastroenterologists and co-senior authors of the Mayo study. “While we need to replicate these findings in a bigger study, we now have an important direction to pursue in terms of potentially providing more individualized strategies for people who struggle with obesity,” Nehra noted in the news release. Thus, precision medicine therapy for obese individuals could be based on Mayo Clinic’s research. (Photo copyright: Mayo Clinic.)
Mayo Study Provides Clues to Microbiota Potential in Weight Loss
The Mayo researchers wanted to know how gut bacteria behave in people who are trying to lose weight.
They recruited 26 people, ranging in age from 18 to 65, from the Mayo Clinic Obesity Treatment Research Program. Fecal stool samples, for researchers’ analysis, were collected from participants at the start of the three-month study period and at the end. The definition of successful weight loss was at least 5% of body weight.
Researchers found the following, according Live Science:
2 lbs. lost, on average, among all participants;
Nine people were successful, losing an average of 17.4 lbs.;
17 people did not meet the goal, losing on average just 3.3 lbs.; and,
More gut bacterial genes that break down carbohydrates were found in stool samples of the unsuccessful weight loss group, as compared to the successful dieters.
The researchers concluded that “An increased abundance of microbial genes encoding carbohydrate-active enzyme pathways and a decreased abundance of Phascolarctobacterium in the gut microbiota of obese and overweight individuals are associated with failure to lose at least 5% weight following a 3-month comprehensive lifestyle intervention program.”
Purna Kashyap, MBBS, Mayo Clinic Gastroenterologist and co-senior author of the study, told Live Science, “The study suggests there is a need to take the microbiome into account in clinical studies (on weight loss), and it also provides an important direction to pursue in terms of providing individualized care in obesity.” The very basis of precision medicine.
Future Weight-Loss Plans Based on Patient’s Microbiota
The Mayo Clinic researchers acknowledged the small sample size and need for more studies with larger samples over a longer time period. They also noted in their paper that Dialister has been associated with oral infections, such as gingivitis, and its role in energy expenditure and metabolism is unclear.
Still, the study suggests that it may soon be possible to give people individualized weight loss plans based on their gut bacteria. Clinical laboratory professionals and pathologists will want to stay abreast of follow-up studies and replication of findings by other research teams. A future medical laboratory test to analyze patients’ microbiomes could help obese people worldwide as well as lab business volume.
