Recognizing disease through early and accurate detection of genomic and proteomic biomarkers in molecular diagnostic (MDx) assays is a key capability for…
Recognizing disease through early and accurate detection of genomic and proteomic biomarkers in molecular diagnostic (MDx) assays is a key capability for clinical pathologists, public healthcare experts, pharmaceutical developers, and basic researchers. Clinical decision-making, therapeutic outcomes, and personalized medicine approaches are bolstered by advances in MDx technology, including bioengineering innovations and insights on pathogenesis and immune response. In the evolving landscape of MDx technology, diagnosticians must keep abreast of emerging assays and be mindful of pitfalls in individual assays to avoid errors in interpretation.
Infectious disease
Many infectious agents result in overlapping symptoms. For instance, COVID-19, influenza, and respiratory syncytial virus manifest as respiratory symptoms. This complicates MDx for physicians who must narrow down potential causes before ordering tests. Syndromic testing circumvents such complications by testing for a broad array of pathogens associated with sets of clinical symptoms, using multiplexed panels. Syndromic RT-PCR panels are being increasingly integrated into routine clinical care for patient stratification and epidemiology.
Syndromic tests pose unique challenges. They include the selection of specific targets among potentially related pathogens, the integration of new tests into established clinical laboratory practice, and the continuous adaptation of tests to newer waves of circulating pathogens. Another challenge is the design of panels that incorporate highly selective primers and probes for various pathogens, and that generate target-specific signals.
Arvind Kothandaraman PerkinElmer
“Assays are optimized such that multiplexing does not compromise the accurate detection of individual targets,” says Arvind Kothandaraman, managing director of specialty diagnostics, PerkinElmer.
With MDx assays, the sensitivity, specificity, and number of pathogens that can be detected in a single syndromic panel depend on several variables, including extraction buffer systems, primers, enzymes, and expertise in sample preparation. “The extraction system plays a major role,” Kothandaraman stresses. “We are fortunate at PerkinElmer that the high quality of the raw materials used in our chemagen technology increases the sensitivity of the data that we obtain for each pathogen.” Additionally, strict quality control at a system level enhances data reliability.
The convenience of syndromic MDx assays over individual assays is greater than one might initially expect. In addition to lowering reagent costs and utilizing existing laboratory expertise, syndromic MDx assays save time. “If clinical laboratories can identify active infections on day zero, individuals can seek help, isolate, and stop the virus from spreading,” Kothandaraman declares.
Although the cost of next-generation sequencing (NGS) has been decreasing consistently, RT-PCR is still cheaper, Kothandaraman insists. Costs aside, the higher level of expertise in instrumentation and data analysis required for NGS makes RT-PCR the better option for known pathogens. However, for detecting novel pathogens, NGS remains the only option.
“We saw this in action during the pandemic, where a percentage of the samples were screened using NGS to monitor for emerging variants,” Kothandaraman notes. “As costs go down and people gain expertise, NGS will be a game changer for zero-day pathogen detection.”
In addition to the detection of pathogens, infectious disease MDx assays also encompass the assessment of host immune responses against pathogens. Virax Biolabs is developing a test that indicates whether an individual’s T cells will respond to a virus, should they become infected. T cells in the body actively scan cell surfaces for foreign protein fragments and trigger an immune response if they detect ones they’ve encountered earlier.
Tomasz George, PhD Virax Biolabs
“We’ve developed a method to analyze proteins on the outside of the virus for their ability to activate T cells in the body,” says Tomasz George, PhD, chief scientific officer, Virax. “We’ve mapped these proteins to form a peptide mix with which to treat your T cells outside the body to see how you would cope with these viruses if you were to become infected in the future.” The test, slated for release in 2023, detects several T-cell activation markers.
Virax’s first immune test detects SARS-CoV-2, but George is confident that the test can be rapidly adapted for new viruses. Based on a subscription model and an app, the company hopes to stay ahead of emerging viruses in the Northern Hemisphere by adapting the test each year for highly prevalent viruses in the Southern Hemisphere during winter, and vice versa. “Most viruses are more prevalent and riskier in winter than in summer,” George remarks.
A combination of stable and rapidly mutating peptides works best for such immune tests, but most peptides in Virax’s first test detect stable peptides to identify cross-reactive T cells. “Looking at stable regions inherent to a family of viruses, we can see if you’ve developed T cells to, for instance, a common cold in the past that can cross-react with a new variant of the coronavirus,” George asserts.
The primary roadblock in developing such MDx tests is the speed at which they can be adapted. Flexibility in experimental design and availability of reagents determine whether a test can be developed before new viruses spread.
Gerald Hunter, PhD Fortis Life Sciences
Refrigeration of MDx reagents poses obstacles in storage and transport that are being overcome through lyophilization. “Lyophilized reagents are stable until resuspended,” says Gerald Hunter, PhD, field application scientist, Fortis Life Sciences. “Lyophilization increases shelf life at ambient conditions and cost savings as diagnostic manufacturers no longer have to pay for cold chain handling. Lyophilized reagents improve workflow efficiency by having reagents preserved indefinitely after receipt, minimizing the need to thaw a frozen set of reagents prior to use.”
The applicability of Virax’s MDx test is not limited to individuals who must know how they would respond to viruses to make informed decisions on vaccinations, social distancing, personal protective equipment, or travel. The test is also of use to pharmaceutical companies that must select participants with less adaptive immunity to a particular virus, to estimate efficacy of experimental drugs in compromised populations.
“It provides a purer treatment and control group for clinical trials,” George maintains. “We also want to integrate our test within government and healthcare groups worldwide to help identify populations more susceptible to a virus to guide public health policy.”
Cancers
Detection of pancreatic cancer relies largely on clinical suspicions and imaging findings. Accurate diagnostic tests not only enable optimal treatment, but also help avoid overtreatment and unnecessary surgery of noncancerous cysts.
Aatur D. Singhi, MD, PhD Univ. Pittsburgh
“Although pancreatic cancer has the highest mortality rates of all cancers, it’s relatively rare. Therefore, screening or surveillance protocols are not available,” says Aatur D. Singhi, MD, PhD, associate professor of pathology, University of Pittsburgh. “Most investigators focus on identifying high-risk populations who have a family history of pancreatic cancer, a genetic predisposition, or preconditions such as new-onset diabetes or pancreatic cysts.”
PancreaSeq GC, an MDx test developed by researchers at the University of Pittsburgh, outperforms current imaging-based testing guidelines by separating common, benign pancreatic cysts (such as serous cystadenomas), which have zero malignant potential, from intraductal papillary mucinous neoplasm, which is a precursor to pancreatic cancer. In fluid samples aspirated from pancreatic cysts, the NGS-based test detects a panel of genes associated with gastrointestinal malignancies. The NGS approach makes the test nearly 20-fold more sensitive than a test based on Sanger sequencing, at only a 10th of the cost of imaging-based assays.
“The idea is to maximize sensitivity while maintaining high specificity, so that when we make a call of cancer you can be sure there are no false positives,” Singhi explains.
Not all pancreatic cysts become cancerous. Therefore, PancreaSeq GC is designed to detect two types of somatic mutations—alterations that indicate the type of cyst, and those that indicate the presence of early pancreatic cancer in the cyst.
“We need to start generating a lot more data on patients with pancreatic cysts, especially since they are very common,” Singhi points out.
Earlier studies on pancreatic cysts and cancer have been largely retrospective, and so they have been yielding associative and not causative inferences. “Moving forward, we must integrate our understanding and test patients early, up front, and follow them to understand the ramifications of genetic alterations,” Singhi emphasizes. “There’s huge bias in retrospective testing. In our prospective tests, we found alterations associated with pancreatic cysts that we didn’t even know about earlier.”
Incorporating data from the prospective study, PancreaSeq GC was upgraded from a 22-gene to a 74-gene panel that is now available worldwide.
Rare diseases
Patients with rare, untreatable diseases often opt out of MDx tests. Such diseases include frontotemporal dementia (FTD), which causes progressive nerve cell loss in the brain’s frontal and temporal lobes. FTD, which actually refers to a group of disorders, affects behavior and language. It is frequently misdiagnosed for other neuropsychiatric disorders. Nearly 40% FTD patients have a family history of dementia, but only a fraction of these have known mutations in progranulin, tau, and C9ORF72.
Andrea C. Bozoki, MD UNC-Chapel Hill
“When we talk about finding biomarkers, we’re mostly talking about byproducts of those genetic mutations,” says Andrea C. Bozoki, MD, professor of neurology, University of North Carolina, Chapel Hill. She emphasizes the importance of identifying biomarkers that become abnormal so early that fluorodeoxyglucose–positron emission tomography scans are not yet diagnostic.
FTD patients with progranulin mutations show accumulation of TDP43 in the brain. “Other neurodegenerative conditions also cause abnormal deposition of TDP43,” Bozoki observes. “Currently, we have no way of determining it in the brain or in spinal fluid assays. This leaves a gap in our ability to identify patients with FTD.”
Gary Romano, MD, PhD Alector
A therapeutic that targets progranulin is being developed by Alector. The company’s chief medical officer, Gary Romano, MD, PhD, says that “the day may come when this treatment becomes an incentive for patients to have the genetic test.” Alector uses PCR to detect mutations in the granulin gene that encodes progranulin since RT-PCR levels can fluctuate considerably.
Good molecular markers for identifying disease are close to the root of the pathological mechanism. In the absence of such biomarkers, diagnosticians must settle for biomarkers that are steps removed from the target, in the hope that such biomarkers suffice to give a true reflection of disease states.
An economist digging below the surface of an IMF report has found something that should shock the Western bloc out of any false confidence in its unsurpassed global economic clout...
G7 leaders meeting on June 28, 2022, at Schloss Elmau in Krün, Germany. (White House/Adam Schultz)
Last summer, the Group of 7 (G7), a self-anointed forum of nations that view themselves as the most influential economies in the world, gathered at Schloss Elmau, near Garmisch-Partenkirchen, Germany, to hold their annual meeting. Their focus was punishing Russia through additional sanctions, further arming of Ukraine and the containment of China.
At the same time, China hosted, through video conference, a gathering of the BRICS economic forum. Comprised of Brazil, Russia, India, China and South Africa, this collection of nations relegated to the status of so-called developing economies focused on strengthening economic bonds, international economic development and how to address what they collectively deemed the counter-productive policies of the G7.
In early 2020, Russian Deputy Foreign Minister Sergei Ryabkov had predicted that, based upon purchasing power parity, or PPP, calculations projected by the International Monetary Fund, BRICS would overtake the G7 sometime later that year in terms of percentage of the global total.
(A nation’s gross domestic product at purchasing power parity, or PPP, exchange rates is the sum value of all goods and services produced in the country valued at prices prevailing in the United States and is a more accurate reflection of comparative economic strength than simple GDP calculations.)
Then the pandemic hit and the global economic reset that followed made the IMF projections moot. The world became singularly focused on recovering from the pandemic and, later, managing the fallout from the West’s massive sanctioning of Russia following that nation’s invasion of Ukraine in February 2022.
The G7 failed to heed the economic challenge from BRICS, and instead focused on solidifying its defense of the “rules based international order” that had become the mantra of the administration of U.S. President Joe Biden.
Miscalculation
Since the Russian invasion of Ukraine, an ideological divide that has gripped the world, with one side (led by the G7) condemning the invasion and seeking to punish Russia economically, and the other (led by BRICS) taking a more nuanced stance by neither supporting the Russian action nor joining in on the sanctions. This has created a intellectual vacuum when it comes to assessing the true state of play in global economic affairs.
U.S. President Joe Biden in virtual call with G7 leaders and Ukrainian President Volodymyr Zelenskyy, Feb. 24. (White House/Adam Schultz)
It is now widely accepted that the U.S. and its G7 partners miscalculated both the impact sanctions would have on the Russian economy, as well as the blowback that would hit the West.
Angus King, the Independent senator from Maine, recently observed that he remembers
“when this started a year ago, all the talk was the sanctions are going to cripple Russia. They’re going to be just out of business and riots in the street absolutely hasn’t worked …[w]ere they the wrong sanctions? Were they not applied well? Did we underestimate the Russian capacity to circumvent them? Why have the sanctions regime not played a bigger part in this conflict?”
It should be noted that the IMF calculated that the Russian economy, as a result of these sanctions, would contract by at least 8 percent. The real number was 2 percent and the Russian economy — despite sanctions — is expected to grow in 2023 and beyond.
This kind of miscalculation has permeated Western thinking about the global economy and the respective roles played by the G7 and BRICS. In October 2022, the IMF published its annual World Economic Outlook (WEO), with a focus on traditional GDP calculations. Mainstream economic analysts, accordingly, were comforted that — despite the political challenge put forward by BRICS in the summer of 2022 — the IMF was calculating that the G7 still held strong as the leading global economic bloc.
In January 2023 the IMF published an update to the October 2022 WEO, reinforcing the strong position of the G7. According to Pierre-Olivier Gourinchas, the IMF’s chief economist, the “balance of risks to the outlook remains tilted to the downside but is less skewed toward adverse outcomes than in the October WEO.”
This positive hint prevented mainstream Western economic analysts from digging deeper into the data contained in the update. I can personally attest to the reluctance of conservative editors trying to draw current relevance from “old data.”
Fortunately, there are other economic analysts, such as Richard Dias of Acorn Macro Consulting, a self-described “boutique macroeconomic research firm employing a top-down approach to the analysis of the global economy and financial markets.”
Rather than accept the IMF’s rosy outlook as gospel, Dias did what analysts are supposed to do — dig through the data and extract relevant conclusions.
After rooting through the IMF’s World Economic Outlook Data Base, Dias conducted a comparative analysis of the percentage of global GDP adjusted for PPP between the G7 and BRICS, and made a surprising discovery: BRICS had surpassed the G7.
This was not a projection, but rather a statement of accomplished fact:
BRICS was responsible for 31.5 percent of the PPP-adjusted global GDP, while the G7 provided 30.7 percent.
Making matters worse for the G7, the trends projected showed that the gap between the two economic blocs would only widen going forward.
The reasons for this accelerated accumulation of global economic clout on the part of BRICS can be linked to three primary factors:
residual fallout from the Covid-19 pandemic,
blowback from the sanctioning of Russia by the G7 nations in the aftermath of the Russian invasion of Ukraine and a growing resentment among the developing economies of the world to G7 economic policies and
priorities which are perceived as being rooted more in post-colonial arrogance than a genuine desire to assist in helping nations grow their own economic potential.
Growth Disparities
It is true that BRICS and G7 economic clout is heavily influenced by the economies of China and the U.S., respectively. But one cannot discount the relative economic trajectories of the other member states of these economic forums. While the economic outlook for most of the BRICS countries points to strong growth in the coming years, the G7 nations, in a large part because of the self-inflicted wound that is the current sanctioning of Russia, are seeing slow growth or, in the case of the U.K., negative growth, with little prospect of reversing this trend.
Moreover, while G7 membership remains static, BRICS is growing, with Argentina and Iran having submitted applications, and other major regional economic powers, such as Saudi Arabia, Turkey and Egypt, expressing an interest in joining. Making this potential expansion even more explosive is the recent Chinese diplomatic achievement in normalizing relations between Iran and Saudia Arabia.
Diminishing prospects for the continued global domination by the U.S. dollar, combined with the economic potential of the trans-Eurasian economic union being promoted by Russia and China, put the G7 and BRICS on opposing trajectories. BRICS should overtake the G7 in terms of actual GDP, and not just PPP, in the coming years.
But don’t hold your breath waiting for mainstream economic analysts to reach this conclusion. Thankfully, there are outliers such as Richard Dias and Acorn Macro Consulting who seek to find new meaning from old data.
The U.S. Centers for Disease Control and Prevention (CDC) made at least 25 statistical or numerical errors during the COVID-19 pandemic, and the overwhelming majority exaggerated the severity of the pandemic, according to a new study.
Researchers who have been tracking CDC errors compiled 25 instances where the agency offered demonstrably false information. For each instance, they analyzed whether the error exaggerated or downplayed the severity of COVID-19.
Of the 25 instances, 20 exaggerated the severity, the researchers reported in the study, which was published ahead of peer review on March 23.
“The CDC has expressed significant concern about COVID-19 misinformation. In order for the CDC to be a credible source of information, they must improve the accuracy of the data they provide,” the authors wrote.
The CDC did not respond to a request for comment.
Most Errors Involved Children
Most of the errors were about COVID-19’s impact on children.
In mid-2021, for instance, the CDC claimed that 4 percent of the deaths attributed to COVID-19 were kids. The actual percentage was 0.04 percent. The CDC eventually corrected the misinformation, months after being alerted to the issue.
CDC Director Dr. Rochelle Walensky falsely told a White House press briefing in October 2021 that there had been 745 COVID-19 deaths in children, but the actual number, based on CDC death certificate analysis, was 558.
Walensky and other CDC officials also falsely said in 2022 that COVID-19 was a top five cause of death for children, citing a study that gathered CDC data instead of looking at the data directly. The officials have not corrected the false claims.
Other errors include the CDC claiming in 2022 that pediatric COVID-19 hospitalizations were “increasing again” when they’d actually peaked two weeks earlier; CDC officials in 2023 including deaths among infants younger than 6 months old when reporting COVID-19 deaths among children; and Walensky on Feb. 9, 2023, exaggerating the pediatric death toll before Congress.
“These errors suggest the CDC consistently exaggerates the impact of COVID-19 on children,” the authors of the study said.
WINSTON-SALEM, N.C. – March 24, 2023 – Researchers at Wake Forest University School of Medicine have been awarded a five-year, $7.5 million grant from the National Institutes of Health (NIH) Helping End Addiction Long-term (HEAL) initiative.
Credit: Wake Forest University School of Medicine
WINSTON-SALEM, N.C. – March 24, 2023 – Researchers at Wake Forest University School of Medicine have been awarded a five-year, $7.5 million grant from the National Institutes of Health (NIH) Helping End Addiction Long-term (HEAL) initiative.
The NIH HEAL initiative, which launched in 2018, was created to find scientific solutions to stem the national opioid and pain public health crises. The funding is part of the HEAL Data 2 Action (HD2A) program, designed to use real-time data to guide actions and change processes toward reducing overdoses and improving opioid use disorder treatment and pain management.
With the support of the grant, researchers will create a data infrastructure support center to assist HD2A innovation projects at other institutions across the country. These innovation projects are designed to address gaps in four areas—prevention, harm reduction, treatment of opioid use disorder and recovery support.
“Our center’s goal is to remove barriers so that solutions can be more streamlined and rapidly distributed,” said Meredith C.B. Adams, M.D., associate professor of anesthesiology, biomedical informatics, physiology and pharmacology, and public health sciences at Wake Forest University School of Medicine.
By monitoring opioid overdoses in real time, researchers will be able to identify trends and gaps in resources in local communities where services are most needed.
“We will collect and analyze data that will inform prevention and treatment services,” Adams said. “We’re shifting chronic pain and opioid care in communities to quickly offer solutions.”
The center will also develop data related resources, education and training related to substance use, pain management and the reduction of opioid overdoses.
According to the CDC, there was a 29% increase in drug overdose deaths in the U.S. in 2020, and nearly 75% of those deaths involved an opioid.
“Given the scope of the opioid crises, which was only exacerbated by the COVID-19 pandemic, it’s imperative that we improve and create new prevention strategies,” Adams said. “The funding will create the infrastructure for rapid intervention.”
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