genetics – NIH Director's Blog (original) (raw)

AI Model Takes New Approach to Performing Diagnostic Tasks in Multiple Cancer Types

Posted on October 3rd, 2024 by Dr. Monica M. Bertagnolli

Credit: Donny Bliss/NIH, Adobe Stock

In recent years, medical researchers have been looking for ways to use artificial intelligence (AI) technology for diagnosing cancer. So far, most AI models have been developed to perform specific tasks in cancer diagnosis, such as detecting cancer presence or predicting a tumor’s genetic profile in certain cancer types. But what if an AI system could be more flexible, like a large language model such as ChatGPT, performing a variety of diagnostic tasks across multiple cancer types?

As reported in the journal Nature, researchers have developed an AI system that can perform a wide range of cancer evaluation tasks and outperforms current AI methods in tasks like cancer cell detection and tumor origin identification. It was tested on 19 cancer types, leading the researchers to refer to it as “ChatGPT-like” in its flexibility. According to the research team, whose work is supported in part by NIH, this is also the first AI model based on analyzing slide images to not only accurately predict if a cancer is likely to respond to treatment, but also to validate these predictions across multiple patient groups around the world.

Today, when doctors order a biopsy to find out if cancer is present, those samples are sent to a pathologist, who examines the tissues or cells under a microscope to determine if they are cancerous. The team behind this AI model, led by Kun-Hsing Yu, Harvard Medical School, Boston, recognized that pathologists must analyze a wide variety of disease samples. To make accurate diagnoses in different cancer types, they must take many subtle factors into account.

Most earlier attempts to devise an AI model to analyze tissue samples have depended on training computers to recognize one cancer type at a time. In the new work, the researchers developed a more general-purpose pathology AI system that could analyze a broader range of tissues and sample types. To develop their Clinical Histopathology Imaging Evaluation Foundation (CHIEF) model, the researchers used an AI approach known as self-supervised learning. In this method, a computer is given large volumes of data, in this case 15 million pathology images, to allow it to identify intrinsic patterns and structures. This process allows a computer to “learn” from experience to identify informative features in a vast data set.

The tool was then trained further on more than 60,500 whole-slide images in tissues collected from 19 different parts of the body—such as the lungs, breast, prostate, kidney, brain, and bladder—to bolster the model’s ability to capture similarities and differences among cancer types. This training data was in part comprised of data from The Cancer Genome Atlas (TCGA) program and the Genotype-Tissue Expression (GTEx) Project, both NIH-supported resources. The researchers directed the model to consider both the image as a whole and its finer details, enabling it to interpret the image in a broader context than one region. They then put CHIEF to the test, using another 19,491 whole-slide images from 32 independent slide sets collected from 24 hospitals around the world.

They found that CHIEF worked equally well no matter how the samples were collected (biopsy or surgical excision) and in different clinical settings. In addition to detecting cancers and predicting a cancer’s tissue of origin, CHIEF also predicted with 70% accuracy whether a tissue carried one among dozens of genetic mutations that are commonly seen in cancers. CHIEF showed an ability to predict whether a sample contained mutated copies of 18 genes that oncologists use to make treatment decisions. CHIEF could predict better than earlier models how long a patient was likely to survive following a cancer diagnosis and how aggressively a particular cancer would grow.

This is all good news, but there’s much more work ahead before an AI model like this could be used in the clinic. Next steps for the researchers include training the model on images of tissues from rare cancers, as well as from pre-cancerous and non-cancerous conditions. With continued development and validation, the researchers aim to enable the system to identify cancers most likely to benefit from targeted or experimental therapies in hopes of improving outcomes for more people with cancer in diverse clinical settings around the world.

Reference:

Wang X, et al. A pathology foundation model for cancer diagnosis and prognosis prediction. Nature. DOI: 10.1038/s41586-024-07894-z (2024).

NIH Support: National Institute of General Medical Sciences, National Cancer Institute

Posted In: Health, Science, technology

Tags: AI, artificial intelligence, cancer, cancer diagnosis, computer learning, genetic mutations, genetics, imaging, pathology, technology

Study of Protective Gene Variant Provides Insight into Delaying Onset of Alzheimer’s Dementia

Posted on July 18th, 2024 by Dr. Monica M. Bertagnolli

Credit: Donny Bliss/NIH

Alzheimer’s disease is currently the seventh leading cause of death in the U.S. While your likelihood of developing Alzheimer’s-related cognitive impairment increases with age, risk for this disease and age of its onset depend on many factors, including the genes you carry. An intriguing new study suggests that having just one copy of a protective gene variant may be enough to delay cognitive impairment from this devastating disease in individuals who are otherwise genetically predisposed to developing early-onset Alzheimer’s dementia.

The findings, from a study supported in part by NIH and reported in The New England Journal of Medicine, offer important insights into the genetic factors and underlying pathways involved in Alzheimer’s dementia.1 While much more study is needed, the findings have potential implications for treatments that could one day work like this gene variant does to delay or perhaps even prevent Alzheimer’s dementia.

This research comes from an international team including Yakeel Quiroz, Massachusetts General Hospital, Boston; Joseph Arboleda-Velasquez, Mass Eye and Ear, Boston; and Francisco Lopera, University of Antioquia, Colombia. For the last 40 years, Lopera has been studying a Colombian family of about 6,000 blood relatives, 1,200 of whom carry a mutation known as Paisa (or Presenilin-1 E280A) that predisposes them to developing early-onset Alzheimer’s dementia. Those who carry a single copy of this gene variant typically show signs of cognitive decline in their early 40s, progressing to dementia by age 50. They frequently die from dementia-related complications in their 60s.

In 2019, the researchers reported on an extraordinary individual who was an exception to this prognosis.2 Even though she carried the Paisa mutation, she didn’t develop any notable cognitive decline until her late 70s—30 years later than expected. The researchers traced her protection against dementia to two copies of a rare variant of the APOE gene dubbed Christchurch. Further study of her brain after death also found lower levels of inflammation and tau protein, which forms damaging tangles inside neurons in the Alzheimer’s brain.

Christchurch is a rare variant, and it’s far more common for people to carry one copy of the protective variant versus two. Would a single copy of the Christchurch variant offer some protection against Alzheimer’s dementia, too? To find out in the new study, the researchers analyzed data from 27 members of this family carrying a single copy of the Christchurch variant among 1,077 carriers of the Paisa mutation.

The researchers compared Christchurch carriers to those without the protective variant and found the variant did delay the age of onset of Alzheimer’s-related cognitive decline and dementia. The median age at the onset of mild cognitive impairment was 52 in family members with the Christchurch variant, compared to approximately age 47 in a matched group without the variant. Similarly, the median age at the onset of dementia was 54, compared to the median age of 50 in noncarriers.

To learn more, the researchers imaged the brains of two of the individuals who had one copy of Christchurch. The brain scans showed lower levels of tau and more normal metabolic activity in brain areas that are known to play a role in Alzheimer’s. Interestingly, their brains still showed accumulations of amyloid proteins, which form plaques that are another hallmark of Alzheimer’s. The team also analyzed autopsy samples from four deceased individuals with one copy of the Christchurch variant and found that blood vessels in their brains appeared healthier, which may help to explain the protective effects of Christchurch. The findings suggest a significant role for blood vessel health in protecting the brain from cognitive decline, as well as a role for disease of the brain blood vessels in contributing to cognitive decline and dementia.

The researchers note this study is limited to a relatively small number of people with both the Paisa and Christchurch variants in one group of related individuals. Further studies involving larger and more diverse samples are needed to learn more about this protective gene variant and its effects on the brain in the general population. The hope is these findings may one day yield new approaches to delaying the onset of Alzheimer’s or slowing its progression in millions more people around the world at risk of developing this devastating disease.

References:

[1] Quiroz YT, et al. APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease. The New England Journal of Medicine. DOI: 10.1056/NEJMoa2308583 (2024).

[2] Arboleda-Velasquez JF, et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nature Medicine. DOI: 10.1038/s41591-019-0611-3 (2019).

NIH Support: National Institute on Aging, National Institute of Neurological Disorders and Stroke

Posted In: Health, News, Science

Tags: aging, Alzheimer’s disease, brain, cognitive decline, dementia, DNA, gene variants, genetics, neurological disease

Sequencing Technique Detects Earliest Signs of Genetic Mutations Underlying Cancer, Aging, and More

Posted on July 11th, 2024 by Dr. Monica M. Bertagnolli

Every day, billions of cells in your body divide, each producing two daughter cells. It’s an essential process for your tissues and organs to renew themselves and remain healthy. To do it, cells must first duplicate their DNA to ensure that each daughter cell gets an accurate copy. In this process, mistakes are inevitably made. Most DNA errors are accurately fixed and do not lead to mutations. But when small errors akin to single-letter typos aren’t corrected, they can become permanent in a cell and multiplied with each subsequent cell division. Even cells that don’t divide, such as neurons in your brain, acquire damage and mutations in their DNA with age. As a result, your tissues contain collections of cells with distinct mutations that accumulate over time.

While many of these small errors will show no obvious consequences, others can lead to cancer and other health conditions. Now, a new DNA sequencing technique, described in Natureand developed through research supported by NIH, promises to detect early DNA changes before they become permanent mutations in a cell’s genome. The method, called Hairpin Duplex Enhanced Fidelity Sequencing (HiDEF-seq), could advance our understanding of how and why mutations arise, with potentially important implications for our health. For example, the ability to identify signs that precede mutations may help predict a person’s health risks based on genetic predispositions, environmental exposures, or other factors.

The HiDEF-seq technique comes from an international team led by Gilad Evrony at NYU Grossman School of Medicine’s Center for Human Genetics and Genomics in New York City. To understand how the method works, it helps to remember that each DNA molecule stores genetic information in the form of two complementary strands made up of four molecular “letters,” or chemical bases. Those bases are adenine (A), thymine (T), guanine (G), and cytosine (C). The sequence of about three billion As, Ts, Gs, and Cs in human DNA’s two strands generally should match up, such that As pair with Ts and Gs with Cs.

The first step in which DNA mutations arise usually involves a change in only one of the two DNA strands. Those single-strand errors only become permanent mutations in both strands when a cell’s copying machinery fails to detect the mistake before the cell divides again, or when the cell’s DNA repair machinery makes a mistake in the correction process. However, because other methods to sequence DNA can’t accurately detect changes that are in only one of the DNA strands, it hasn’t been possible for researchers to study this process in detail. This is where HiDEF-seq comes in.

The researchers wanted to develop an approach for directly sequencing single DNA molecules to detect these early-stage DNA errors. Detecting changes that are in only one of the two DNA strands requires an extremely high degree of sequencing accuracy, with less than one error per one billion bases, so the team devised a method to read DNA with higher precision than was previously possible. To put HiDEF-seq to the test, they profiled 134 samples from various human tissues, including those from people with syndromes that predisposed them to cancer due to an unusually high number of new mutations.

The research team found they could use HiDEF-seq to identify changes present in only one of the two DNA strands that were the precursors to mutational events. For example, they identified places where a C was mistakenly paired with a T instead of a G. As expected, those early changes in DNA turned up more often in people with syndromes that increase their risk of cancer than in those without. The patterns of those single-strand DNA changes also looked a lot like the patterns of double-strand DNA mutations seen in people with these syndromes, suggesting that the HiDEF-seq method was indeed seeing the precursors to mutations.

The method can also detect a common form of DNA damage called cytosine deamination, in which cytosine is converted to a different base called uracil (U), which is another source of mutations. Experiments in human sperm, which rarely pick up mutations compared to other cell types, showed a pattern of cytosine deamination that closely matched damage caused by heating healthy DNA in the lab. This led the researchers to suggest that the damage to DNA happens similarly in both situations.

The researchers have already begun to produce a catalog of the various single-strand DNA errors they’ve uncovered. They suggest that HiDEF-seq may allow new ways to monitor the everyday effects of environmental exposures or other insults on our DNA and shed light on the balance in cells between DNA damage, repair, and replication. Along the way, this new technique will enable the continued study of DNA damage and the origins of mutations in a way that hasn’t been possible before.

Reference:

Liu MH, et al. Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing. Nature. DOI: 10.1038/s41586-024-07532-8 (2024).

NIH Support: Common Fund, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Cancer Institute

Posted In: Health, News, Science

Tags: aging, cancer, cell division, DNA, DNA damage, DNA sequencing, genetics, genomics, mutations

Molecular Portrait of Key Driver of Pancreatic Cancer Offers Hope for Continued Treatment Advances

Posted on June 27th, 2024 by Dr. Monica M. Bertagnolli

Credit: magicmine/Adobe Stock

Cancer arises when changes in genes that normally control cell division lead to unchecked growth at the expense of healthy tissues. One of the most common genetic alterations across human cancers—occurring in 95% of pancreatic cancers but also many non-small cell lung cancers, colorectal cancers, and others—is in a gene known as KRAS. While promising new treatments targeting KRAS to shrink cancerous tumors have recently gained approval, less than 40% of pancreatic cancers respond to treatment with KRAS inhibitors for reasons that aren’t well understood.

There’s much more to learn about how KRAS spurs cancer growth—and how KRAS-mutant cancers resist treatment with existing KRAS inhibitors. To address this need, researchers behind two studies in Science have established the most comprehensive molecular portrait yet of the workings of KRAS and how its many downstream impacts may influence outcomes for people with pancreatic cancer.1,2 The findings could lead to new treatment approaches, including ways to potentially guide treatment for individuals with pancreatic cancer, the third leading cause of cancer-related death in the U.S.

These studies, supported in part by NIH, come from a team led by Channing Der and Adrienne Cox, together with Jeffrey Klomp, Clint Stalnecker, and Jennifer Klomp, at the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. The researchers were inspired in part by the Food and Drug Administration’s recent approval of treatments that block a mutated version of KRAS that drives many pancreatic cancers. The team was also motivated by the realization that many patients whose cancers initially respond to the new treatments relapse rather quickly as the cancers find ways to reactivate underlying growth pathways.

The researchers wanted to know more about KRAS and its influence on another essential pathway, including a protein called ERK, by defining all the genes that are actively transcribed into proteins in KRAS-mutant cancer cell lines and tumors. Their findings show that changes in KRAS signaling drive cancer growth mainly though the ERK network. In turn, ERK regulates many other genes to determine which ones are switched on or off while also influencing the activity of many other proteins. This shows that the effect of mutant KRAS on the ERK protein alone leads to widespread effects on the activity of thousands of other genes and proteins. The study uncovered underlying mechanisms that affected multiple stages of the cell cycle that leads to cell division.

Kinases, including ERK, alter the activity of other proteins by the addition of a chemical phosphate group. One of the things that makes ERK unique is that it activates a wide range of functionally distinct proteins, both directly and indirectly. To learn more about its influence, the team explored the many proteins ERK chemically modifies in pancreatic cancers that rely on mutant KRAS. Altogether, they found more than 2,100 proteins that were modified by activated ERK, more than half of which had not been associated with this protein before. Because activation of this pathway is so important for the response to KRAS inhibitors, the findings promise to help elucidate the underlying mechanisms involved in treatment responses as well as drug resistance.

Importantly, the researchers found that the molecular signatures they’ve uncovered may predict tumor responses in patients treated with KRAS inhibitors or ERK inhibitors. Based on their findings, they suspect that the reason so many pancreatic cancers don’t respond to KRAS inhibitors may be because the drugs simply don’t block KRAS well enough—and not because the cancers no longer depend on KRAS signals for their growth. The researchers suggest it may be beneficial to monitor these underlying molecular pathways in patients to better understand treatment outcomes and guide treatment decisions.

The team plans to continue exploring the role of these and other important drivers of cancer growth and treatment resistance. Ultimately, their goal is to help advance the development of the next generation of KRAS inhibitors that will work even better for many more people with pancreatic or other KRAS-driven cancers.

References:

[1] Klomp JA, et al. Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers. Science. DOI: 10.1126/science.adk0775 (2024).

[2] Klomp JE, et al. Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer. Science. DOI: 10.1126/science.adk0850 (2024).

NIH Support: National Cancer Institute, National Institute of General Medical Sciences

Machine Learning Study Offers Clues to Why Some People Have Rheumatoid Arthritis Pain Without Inflammation

Posted on May 2nd, 2024 by Dr. Monica M. Bertagnolli

Credit: Yakobchuk Olena/Adobe Stock

About 1.5 million adults in the U.S. are living with rheumatoid arthritis (RA), an autoimmune disease in which the immune system attacks joint tissue, causing inflammation, swelling, and pain. Treatments often do a good job fighting inflammation to slow or even stop joint damage and ease pain. But this doesn’t work for everyone. Many people with RA don’t find pain relief, even with the strongest anti-inflammatory, disease-modifying therapies now available.

Why is that? A new study supported in part by NIH and reported in Science Translational Medicine has an intriguing answer.1 The findings suggest that in some people with RA, the joint lining may direct the growth of pain-sensing neurons to cause pain in the absence of inflammation. This discovery, made possible with the help of machine learning, suggests potential new ways to treat this painful disease.

The findings come from a team led by Fei Wang, Weill Cornell Medicine, New York City, and Dana E. Orange, Rockefeller University, New York City. They were inspired by recent studies showing that RA pain and inflammation don’t always go together. In fact, people with RA who have limited inflammation in some cases report just as much pain as those who have extreme inflammation. As a result, they also tend to get less benefit from anti-inflammatory drugs.

To find out why, the researchers studied the soft tissue, or synovium, lining the spaces of the joints from people with this less common form of RA. They were in search of underlying differences in gene activity to explain the pain without inflammation. They knew it wouldn’t be easy, given the variation in the way people experience and report pain and the limited availability of surgically removed tissue samples. To overcome those roadblocks, they developed a machine learning approach that could pinpoint pain-associated patterns of gene activity in the complex data that would otherwise be too difficult to discern.

Their RNA sequencing analysis turned up 815 genes that were expressed at unusually high levels in the joint tissue of 22 people who had RA pain with low inflammation. They also confirmed this same pattern of gene activity in a second group of patients with early untreated RA and little inflammation.

The researchers went on to find that this pattern was clearest in fibroblast cells (a major cell type of the synovium) which provide the structural framework of the joint space, but become a key driver of inflammation and joint damage in RA. Those fibroblasts also expressed a gene that encodes a protein called netrin-4, which is related to a family of proteins that play a role in the growth of neurons. It led them to wonder whether the joint tissue might be producing substances that could alter pain-sensing nerves to cause pain.

To learn more, they turned to studies in mice. They found that fluid collected from joint fibroblast cell cultures and netrin-4 made mouse neurons sprout new branches carrying pain receptors in the lab. The findings suggested that the RA joint lining was indeed producing substances that could lead to the growth of pain-sensing neurons.

To see if this might play a role in people with RA and little inflammation, they looked closely at the joints. Those images revealed an abundance of blood vessels that could nurture tissue growth. Those vessels were also surrounded by pain-sensing nerve fibers extending toward the joint lining in places where there was an abnormal amount of tissue growth.

The researchers think this process explains why painful, arthritic joints sometimes feel squishy and swollen even when they aren’t inflamed. In future studies, they want to learn more about which sensory neurons are specifically affected, noting that there are about a dozen different types. While much more study is needed, their goal is to find promising new ways to treat RA by targeting this underlying process, giving more people with RA much needed pain relief.

Reference:

[1] Bai Z, et al. Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis. Science Translational Medicine. DOI: 10.1126/scitranslmed.adk3506 (2024).

NIH Support: National Institute of Arthritis and Musculoskeletal and Skin Diseases

Posted In: Health, News, Science

Tags: autoimmune disease, basic research, gene expression, genetics, inflammation, machine learning, neurons, pain, rheumatoid arthritis, treatment

Microbe Normally Found in the Mouth May Drive Progression of Colorectal Cancer

Posted on April 11th, 2024 by Dr. Monica M. Bertagnolli

Study findings suggest a subtype of Fusobacterium nucleatum, a microbe normally found in the mouth, may infect colorectal tumors and drive their growth. Credit: Donny Bliss/NIH, Appledesign/Adobe stock

Colorectal cancer is a leading cause of death from cancer in the United States. We know that risk of colorectal cancer goes up with age, certain coexisting health conditions, family history, smoking, alcohol use, and other factors. Researchers are also trying to learn more about what leads colorectal cancer to grow and spread. Now, findings from a new study supported in part by NIH add to evidence that colorectal tumor growth may be driven by a surprising bad actor: a microbe that’s normally found in the mouth.1

The findings, reported in Nature, suggest that a subtype of the bacterium Fusobacterium nucleatum has distinct genetic properties that may allow it to withstand acidic conditions in the stomach, infect colorectal tumors, and potentially drive their growth, which may lead to poorer patient outcomes. The discoveries suggest that the microbe could eventually be used as a target for detecting and treating colorectal cancer.

The study was conducted by a team led by Susan Bullman and Christopher D. Johnston at the Fred Hutchinson Cancer Center in Seattle. In 2022, the team published findings from a pair of studies implicating Fusobacterium nucleatum in the progression and spread of colorectal cancer.2,3 Their findings weren’t the first to suggest a link between the microbe and colorectal cancer. But their work offered important evidence that the microbe might alter colorectal tumors in ways that made them more likely to grow and spread. They also found that the microbe may affect the way colorectal cancer responds to or resists chemotherapy treatment.

Follow-up studies suggested there might be more to the story, pointing to the possibility that certain strains of the bacterium might differ from others in important ways. The findings suggested that there may be a more specific subtype_,_ not yet defined, that was responsible for driving colorectal cancer growth.

To look deeper into this in the new study, Bullman and Johnston, with first author Martha Zepeda Rivera, analyzed a collection of 55 strains of the microbe taken from human colorectal cancer samples. They also compared these at the genetic level to another 80 strains of the microbe taken from the mouths of people who didn’t have cancer.

Their studies uncovered 483 genetic factors that turned up more often in Fusobacterium nucleatum from colorectal tumors. Those strains mainly belonged to a subspecies called Fusobacterium nucleatum animalis (Fna). More detailed study led to another surprise. The Fna included two genetically distinct groups or “clades” that had never been described, which the researchers called Fna C1 and C2. It turned out that only Fna C2 occurs at high levels in colorectal tumors.

The researchers found that this specific subtype within colorectal tumors carries 195 genetic factors that may allow it to grow more rapidly, withstand the acidic environment in the stomach, and take up residence in the gastrointestinal tract, where it can drive colorectal cancer growth. When the researchers infected a mouse model of colitis, a condition involving inflamed intestines that is a risk factor for colorectal cancer, they found that Fna C2 caused the development of more tumors compared to those infected with Fna C1.

Studies of tumors from 116 patients with colorectal cancer also showed more Fna C2. It was elevated in about 50% of cases. In fact, only this strain turned up more often in cancer compared to healthy tissue nearby. Stool samples of 627 people with colorectal cancer and 619 healthy people also showed more of this specific microbial strain in association with cancer.

This discovery is important because it suggests it’s only the Fna C2 subtype that’s associated with driving colorectal tumor growth, meaning it could help in the development of new methods for colorectal cancer screening and treatment. The researchers suggest it may one day even be possible to develop microbial-based therapies using modified versions of the bacterial strain to deliver treatments straight into tumors.

In addition, while the microbe is normally found in healthy mouths, it’s also enriched in periodontal (gum) disease, dental infections, and oral cancers.4 It will be interesting to learn more in future studies about the connections between various Fusobacterium nucleatum subtypes_,_ oral health, and other health conditions throughout the body, including colorectal cancer.

References:

[1] Zepeda-Rivera M, et al. A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche. Nature. DOI: 10.1038/s41586-024-07182-w (2024).

[2] LaCourse KD, et al. The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota. Cell Rep. DOI: 10.1016/j.celrep.2022.111625 (2022).

[3] Galeano Niño JL, et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature. DOI: 10.1038/s41586-022-05435-0 (2022).

[4] Chen Y, et al. More Than Just a Periodontal Pathogen –the Research Progress on Fusobacterium nucleatum. Front Cell Infect Microbiol. DOI: 10.3389/fcimb.2022.815318 (2022).

NIH Support: National Institute of Dental and Craniofacial Research, National Cancer Institute

Case Study Unlocks Clues to Rare Resilience to Alzheimer’s Disease

Posted on May 30th, 2023 by Lawrence Tabak, D.D.S., Ph.D.

Caption: Newly discovered Reelin-COLBOS gene variation may delay or prevent Alzheimer’s disease. Credit: Donny Bliss, NIH

Biomedical breakthroughs most often involve slow and steady research in studies involving large numbers of people. But sometimes careful study of even just one truly remarkable person can lead the way to fascinating discoveries with far-reaching implications.

An NIH-funded case study published recently in the journal Nature Medicine falls into this far-reaching category [1]. The report highlights the world’s second person known to have an extreme resilience to a rare genetic form of early onset Alzheimer’s disease. These latest findings in a single man follow a 2019 report of a woman with similar resilience to developing symptoms of Alzheimer’s despite having the same strong genetic predisposition for the disease [2].

The new findings raise important new ideas about the series of steps that may lead to Alzheimer’s and its dementia. They’re also pointing the way to key parts of the brain for cognitive resilience—and potentially new treatment targets—that may one day help to delay or even stop progression of Alzheimer’s.

The man in question is a member of a well-studied extended family from the country of Colombia. This group of related individuals, or kindred, is the largest in the world with a genetic variant called the “Paisa” mutation (or Presenilin-1 E280A). This Paisa variant follows an autosomal dominant pattern of inheritance, meaning that those with a single altered copy of the rare variant passed down from one parent usually develop mild cognitive impairment around the age of 44. They typically advance to full-blown dementia around the age of 50 and rarely live past the age of 60. This contrasts with the most common form of Alzheimer’s, which usually begins after age 65.

The new findings come from a team led by Yakeel Quiroz, Massachusetts General Hospital, Boston; Joseph Arboleda-Velasquez, Massachusetts Eye and Ear, Boston; Diego Sepulveda-Falla, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and Francisco Lopera, University of Antioquia, Medellín, Colombia. Lopera first identified this family more than 30 years ago and has been studying them ever since.

In the new case report, the researchers identified a Colombian man who’d been married with two children and retired from his job as a mechanic in his early 60s. Despite carrying the Paisa mutation, his first cognitive assessment at age 67 showed he was cognitively intact, having limited difficulties with verbal learning skills or language. It wasn’t until he turned 70 that he was diagnosed with mild cognitive impairment—more than 20 years later than the expected age for this family—showing some decline in short-term memory and verbal fluency.

At age 73, he enrolled in the Colombia-Boston biomarker research study (COLBOS). This study is a collaborative project between the University of Antioquia and Massachusetts General Hospital involving approximately 6,000 individuals from the Paisa kindred. About 1,500 of those in the study carry the mutation that sets them up for early Alzheimer’s. As a member of the COLBOS study, the man underwent thorough neuroimaging tests to look for amyloid plaques and tau tangles, both of which are hallmarks of Alzheimer’s.

While this man died at age 74 with Alzheimer’s, the big question is: how did he stave off dementia for so long despite his poor genetic odds? The COLBOS study earlier identified a woman with a similar resilience to Alzheimer’s, which they traced to two copies of a rare, protective genetic variant called Christchurch. This variant affects a gene called apolipoprotein E (APOE3), which is well known for its influence on Alzheimer’s risk. However, the man didn’t carry this same protective variant.

The researchers still thought they’d find an answer in his genome and kept looking. While they found several variants of possible interest, they zeroed in on a single gene variant that they’ve named Reelin-COLBOS. What helped them to narrow it down to this variant is the man also had a sister with the Paisa mutation who only progressed to advanced dementia at age 72. It turned out, in addition to the Paisa variant, the siblings also shared an altered copy of the newly discovered Reelin-COLBOS variant.

This Reelin-COLBOS gene is known to encode a protein that controls signals to chemically modify tau proteins, which form tangles that build up over time in the Alzheimer’s brain and have been linked to memory loss. Reelin is also functionally related to APOE, the gene that was altered in the woman with extreme Alzheimer’s protection. Reelin and APOE both interact with common protein receptors in neurons. Together, the findings add to evidence that signaling pathways influencing tau play an important role in Alzheimer’s pathology and protection.

The neuroimaging exams conducted when the man was age 73 have offered further intriguing clues. They showed that his brain had extensive amyloid plaques. He also had tau tangles in some parts of his brain. But one brain region, called the entorhinal cortex, was notable for having a very minimal amount of those hallmark tau tangles.

The entorhinal cortex is a hub for memory, navigation, and the perception of time. Its degeneration also leads to cognitive impairment and dementia. Studies of the newly identified Reelin-COLBOS variant in Alzheimer’s mouse models also help to confirm that the variant offers its protection by diminishing the pathological modifications of tau.

Overall, the findings in this one individual and his sister highlight the Reelin pathway and brain region as promising targets for future study and development of Alzheimer’s treatments. Quiroz and her colleagues report that they are actively exploring treatment approaches inspired by the Christchurch and Reelin-COLBOS discoveries.

Of course, there’s surely more to discover from continued study of these few individuals and others like them. Other as yet undescribed genetic and environmental factors are likely at play. But the current findings certainly offer some encouraging news for those at risk for Alzheimer’s disease—and a reminder of how much can be learned from careful study of remarkable individuals.

References:

[1] Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Lopera F, Marino C, Chandrahas AS, O’Hare M, Reiman EM, Sepulveda-Falla D, Arboleda-Velasquez JF, Quiroz YT, et al. Nat Med. 2023 May;29(5):1243-1252.

[2] Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Arboleda-Velasquez JF, Lopera F, O’Hare M, Delgado-Tirado S, Tariot PN, Johnson KA, Reiman EM, Quiroz YT et al. Nat Med. 2019 Nov;25(11):1680-1683.

Links:

Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)

“NIH Support Spurs Alzheimer’s Research in Colombia,” Global Health Matters, January/February 2014, Fogarty International Center/NIS

“COLBOS Study Reveals Mysteries of Alzheimer’s Disease,” NIH Record, August 19, 2022.

Yakeel Quiroz (Massachusetts General Hospital, Harvard Medical School, Boston)

Joseph Arboleda-Velasquez (Massachusetts Eye and Ear, Harvard Medical School, Boston)

Diego Sepulveda-Falla Lab (University Medical Center Hamburg-Eppendorf, Hamburg, Germany)

Francisco Lopera (University of Antioquia, Medellín, Colombia)

NIH Support: National Institute on Aging; National Eye Institute; National Institute of Neurological Disorders and Stroke; Office of the Director

Posted In: News

Tags: Alzheimer’s disease, APOE3, brain, Christchurch variant, cognitive resilience, Colombia, Colombia-Boston biomarker research study, dementia, genetics, genomics, global health, Paisa mutation, Paisa variant, Presinilin-1, Reelin-COLBOS gene variant, tau, tau protein

All of Us Research Program Participants Fuel Both Scientific and Personal Discovery

Posted on February 7th, 2023 by Josh Denny, M.D., M.S., All of Us Research Program

Credit: All of Us Research Program, NIH

The NIH’s All of Us Research Program is a historic effort to create an unprecedented research resource that will speed biomedical breakthroughs, transform medicine and advance health equity. To create this resource, we are enrolling at least 1 million people who reflect the diversity of the United States.

At the program’s outset, we promised to make research a two-way street by returning health information to our participant partners. We are now delivering on that promise. We are returning personalized health-related DNA reports to participants who choose to receive them.

That includes me. I signed up to receive my “Medicine and Your DNA” and “Hereditary Disease Risk” reports along with nearly 200,000 other participant partners. I recently read my results, and they hit home, revealing an eye-opening connection between my personal and professional lives.

First, the professional. Before coming to All of Us, I was a practicing physician and researcher at Vanderbilt University, Nashville, TN, where I studied how a person’s genes might affect his or her response to medications. One of the drug-gene interactions that I found most interesting is related to clopidogrel, a drug commonly prescribed to keep arteries open after a major cardiovascular event, like a heart attack, stroke, or placement of a stent.

People with certain gene variations are not able to process this medication well, leaving them in a potentially risky situation. The patient and their health care provider may think the condition is being managed. But, since they can’t process the medication, the patient’s symptoms and risks are likely to increase.

The impact on patients has been seen in numerous studies, including one that I published with colleagues last year in the Journal of Stroke and Cerebrovascular Disease [1]. We found that stroke risk is three times higher in patients who were poor responders to clopidogrel and treated with the drug following a “mini-stroke”—also known as a transient ischemic attack. Other studies have shown that major cardiovascular events were 50 percent more common in individuals who were poor responders to clopidogrel [2]. Importantly, there are alternative therapies that work well for people with this genetic variant.

Now, the personal. Reading my health-related results, I learned that I carry some of these very same gene variations. So, if I ever needed a medicine to manage my risk of blood clots, clopidogrel would not likely work well for me.

Instead, should I ever need treatment, my provider and I could bypass this common first-line therapy and choose an alternate medicine. Getting the right treatment on the first try could cut my chances of a heart attack in half. The benefits of this knowledge don’t stop with me. By choosing to share my findings with family members who may have inherited the same genetic variations, they can discuss it with their health care teams.

Other program participants who choose to receive results will experience the same process of learning more about their health. Nearly all will get actionable information about how their body may process certain medications. A small percentage, 2 to 3 percent, may learn they’re at higher risk of developing several severe hereditary health conditions, such as certain preventable heart diseases and cancers. The program will provide a genetic counselor at no cost to all participants to discuss their results.

To enroll participants who reflect the country’s diverse population, All of Us partners with trusted community organizations around the country. Inclusion is vitally important in the field of genomics research, where available data have long originated mostly from people of European ancestry. In contrast, about 50 percent of the _All of Us_’ genomic data come from individuals who self-identify with a racial or ethnic minority group.

More than 3,600 research projects are already underway using data contributed by participants from diverse backgrounds. What’s especially exciting about this “ecosystem” of discovery between participants and researchers is that, by contributing their data, participants are helping researchers decode what our DNA is telling us about health across all types of conditions. In turn, those discoveries will deepen what participants can learn.

Those who have stepped up to join All of Us are the heartbeat of this historic research effort to advance personalized approaches in medicine. Their contributions are already fueling new discoveries in numerous areas of health.

At the same time, making good on our promises to our participant partners ensures that the knowledge gained doesn’t only accumulate in a database but is delivered back to participants to help advance their own health journeys. If you’re interested in joining All of Us, we welcome you to learn more.

References:

[1] CYP2C19 loss-of-function is associated with increased risk of ischemic stroke after transient ischemic attack in intracranial atherosclerotic disease. Patel PD, Vimalathas P, Niu X, Shannon CN, Denny JC, Peterson JF, Chitale RV, Fusco MR. J Stroke Cerebrovasc Dis. 2021 Feb;30(2):105464.

[2] Predicting clopidogrel response using DNA samples linked to an electronic health record. Delaney JT, Ramirez AH, Bowton E, Pulley JM, Basford MA, Schildcrout JS, Shi Y, Zink R, Oetjens M, Xu H, Cleator JH, Jahangir E, Ritchie MD, Masys DR, Roden DM, Crawford DC, Denny JC. Clin Pharmacol Ther. 2012 Feb;91(2):257-263.

Links:

Join All of Us (All of Us/NIH)

NIH’s All of Us Research Program returns genetic health-related results to participants, NIH News Release, December 13, 2022.

NIH’s All of Us Research Program Releases First Genomic Dataset of Nearly 100,000 Whole Genome Sequences, NIH News Release, March 17, 2022.

Funding and Program Partners (All of Us)

Medicine and Your DNA (All of Us)

Clopidogrel Response (National Library of Medicine/NIH)

Hereditary Disease Risk (All of Us)

Preparing for DNA Results: What Is a Genetic Counselor? (All of Us)

Research Projects Directory (All of Us)

Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes, Centers, and Offices to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 24th in the series of NIH guest posts that will run until a new permanent NIH director is in place.

Posted In: Generic

Tags: All of Us, All of Us Research Program, clopidogrel, genetic counseling, genetics, genomics, health equity, heart disease, Hereditary Disease Risk, Medicine and Your DNA, personalized medicine, pharmacogenomics, precision medicine, stroke, transient ischemic attack

NCI Support for Basic Science Paves Way for Kidney Cancer Drug Belzutifan

Posted on January 25th, 2022 by Norman "Ned" Sharpless, M.D., National Cancer Institute

There’s exciting news for people with von Hippel-Lindau (VHL) disease, a rare genetic disorder that can lead to cancerous and non-cancerous tumors in multiple organs, including the brain, spinal cord, kidney, and pancreas. In August 2021, the U.S. Food and Drug Administration (FDA) approved belzutifan (Welireg), a new drug that has been shown in a clinical trial led by National Cancer Institute (NCI) researchers to shrink some tumors associated with VHL disease [1], which is caused by inherited mutations in the VHL tumor suppressor gene.

As exciting as this news is, relatively few people have this rare disease. The greater public health implication of this advancement is for people with sporadic, or non-inherited, clear cell kidney cancer, which is by far the most common subtype of kidney cancer, with more than 70,000 cases and about 14,000 deaths per year. Most cases of sporadic clear cell kidney cancer are caused by spontaneous mutations in the VHL gene.

This advancement is also a great story of how decades of support for basic science through NCI’s scientists in the NIH Intramural Research Program and its grantees through extramural research funding has led to direct patient benefit. And it’s a reminder that we never know where basic science discoveries might lead.

Belzutifan works by disrupting the process by which the loss of VHL in a tumor turns on a series of molecular processes. These processes involve the hypoxia-inducible factor (HIF) transcription factor and one of its subunits, HIF-2α, that lead to tumor formation.

The unraveling of the complex relationship among VHL, the HIF pathway, and cancer progression began in 1984, when Bert Zbar, Laboratory of Immunobiology, NCI-Frederick; and Marston Linehan, NCI’s Urologic Oncology Branch, set out to find the gene responsible for clear cell kidney cancer. At the time, there were no effective treatments for advanced kidney cancer, and 80 percent of patients died within two years.

Zbar and Linehan started by studying patients with sporadic clear cell kidney cancer, but then turned their focus to investigations of people affected with VHL disease, which predisposes a person to developing clear cell kidney cancer. By studying the patients and the genetic patterns of tumors collected from these patients, the researchers hypothesized that they could find genes responsible for kidney cancer.

Linehan established a clinical program at NIH to study and manage VHL patients, which facilitated the genetic studies. It took nearly a decade, but, in 1993, Linehan, Zbar, and Michael Lerman, NCI-Frederick, identified the VHL gene, which is mutated in people with VHL disease. They soon discovered that tumors from patients with sporadic clear cell kidney cancer also have mutations in this gene.

Subsequently, with NCI support, William G. Kaelin Jr., Dana-Farber Cancer Institute, Boston, discovered that VHL is a tumor suppressor gene that, when inactivated, leads to the accumulation of HIF.

Another NCI grantee, Gregg L. Semenza, Johns Hopkins School of Medicine, Baltimore, identified HIF as a transcription factor. And Peter Ratcliffe, University of Oxford, United Kingdom, discovered that HIF plays a role in blood vessel development and tumor growth.

Kaelin and Ratcliffe simultaneously showed that the VHL protein tags a subunit of HIF for destruction when oxygen levels are high. These results collectively answered a very old question in cell biology: How do cells sense the intracellular level of oxygen?

Subsequent studies by Kaelin, with NCI’s Richard Klausner and Linehan, revealed the critical role of HIF in promoting the growth of clear cell kidney cancer. This work ultimately focused on one member of the HIF family, the HIF-2α subunit, as the key mediator of clear cell kidney cancer growth.

The fundamental work of Kaelin, Semenza, and Ratcliffe earned them the 2019 Nobel Prize in Physiology or Medicine. It also paved the way for drug discovery efforts that target numerous points in the pathway leading to clear cell kidney cancer, including directly targeting the transcriptional activity of HIF-2α with belzutifan.

Clinical trials of belzutifan, including several supported by NCI, demonstrated potent anti-cancer activity in VHL-associated kidney cancer, as well as other VHL-associated tumors, leading to the aforementioned recent FDA approval. This is an important development for patients with VHL disease, providing a first-in-class therapy that is effective and well-tolerated.

We believe this is only the beginning for belzutifan’s use in patients with cancer. A number of trials are now studying the effectiveness of belzutifan for sporadic clear cell kidney cancer. A phase 3 trial is ongoing, for example, to look at the effectiveness of belzutifan in treating people with advanced kidney cancer. And promising results from a phase 2 study show that belzutifan, in combination with cabozantinib, a widely used agent to treat kidney cancer, shrinks tumors in patients previously treated for metastatic clear cell kidney cancer [2].

This is a great scientific story. It shows how studies of familial cancer and basic cell biology lead to effective new therapies that can directly benefit patients. I’m proud that NCI’s support for basic science, both intramurally and extramurally, is making possible many of the discoveries leading to more effective treatments for people with cancer.

References:

[1] Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R; MK-6482-004 Investigators. N Engl J Med. 2021 Nov 25;385(22):2036-2046.

[2] Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). Choueiri TK et al. J Clin Oncol. 2021 Feb 20;39(6_suppl): 272-272.

Links:
Von Hippel-Lindau Disease (Genetic and Rare Diseases Information Center/National Center for Advancing Translational Sciences/NIH)

The Long Road to Understanding Kidney Cancer (Intramural Research Program/NIH)

[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s institutes and centers to contribute occasional guest posts to the blog as a way to highlight some of the cool science that they support and conduct. This is the first in the series of NIH institute and center guest posts that will run until a new permanent NIH director is in place.]

Posted In: Generic

Tags: 2019 Nobel Prize in Physiology or Medicine, basic research, belzutifan, cancer, cancer drugs, cell biology, clear cell kidney cancer, clinical trials, FDA, genetics, HIF, kidney cancer, NCI, NCI-MATCH trial, oncology, rare disease, tumor suppressor gene, VHL, von Hippel-Lindau disease, Welireg

A Race-Free Approach to Diagnosing Chronic Kidney Disease

Posted on October 21st, 2021 by Dr. Francis Collins

Credit: True Touch Lifestyle; crystal light/Shutterstock

Race has a long and tortured history in America. Though great strides have been made through the work of leaders like Dr. Martin Luther King, Jr. to build an equal and just society for all, we still have more work to do, as race continues to factor into American life where it shouldn’t. A medical case in point is a common diagnostic tool for chronic kidney disease (CKD), a condition that affects one in seven American adults and causes a gradual weakening of the kidneys that, for some, will lead to renal failure.

The diagnostic tool is a medical algorithm called estimated glomerular filtration rate (eGFR). It involves getting a blood test that measures how well the kidneys filter out a common waste product from the blood and adding in other personal factors to score how well a person’s kidneys are working. Among those factors is whether a person is Black. However, race is a complicated construct that incorporates components that go well beyond biological and genetic factors to social and cultural issues. The concern is that by lumping together Black people, the algorithm lacks diagnostic precision for individuals and could contribute to racial disparities in healthcare delivery—or even runs the risk of reifying race in a way that suggests more biological significance than it deserves.

That’s why I was pleased recently to see the results of two NIH-supported studies published in The New England Journal of Medicine that suggest a way to take race out of the kidney disease equation [1, 2]. The approach involves a new equation that swaps out one blood test for another and doesn’t ask about race.

For a variety of reasons, including socioeconomic issues and access to healthcare, CKD disproportionately affects the Black community. In fact, Blacks with the condition are also almost four times more likely than whites to develop kidney failure. That’s why Blacks with CKD must visit their doctors regularly to monitor their kidney function, and often that visit involves eGFR.

The blood test used in eGFR measures creatinine, a waste product produced from muscle. For about the past 20 years, a few points have been automatically added to the score of African Americans, based on data showing that adults who identify as Black, on average, have a higher baseline level of circulating creatinine. But adjusting the score upward toward normal function runs the risk of making the kidneys seem a bit healthier than they really are and delaying life-preserving dialysis or getting on a transplant list.

A team led by Chi-yuan Hsu, University of California, San Francisco, took a closer look at the current eGFR calculations. The researchers used long-term data from the Chronic Renal Insufficiency Cohort (CRIC) Study, an NIH-supported prospective, observational study of nearly 4,000 racially and ethnically diverse patients with CKD in the U.S. The study design specified that about 40 percent of its participants should identify as Black.

To look for race-free ways to measure kidney function, the researchers randomly selected more than 1,400 of the study’s participants to undergo a procedure that allows kidney function to be measured directly instead of being estimated based on blood tests. The goal was to develop an accurate approach to estimating GFR, the rate of fluid flow through the kidneys, from blood test results that didn’t rely on race.

Their studies showed that simply omitting race from the equation would underestimate GFR in Black study participants. The best solution, they found, was to calculate eGFR based on cystatin C, a small protein that the kidneys filter from the blood, in place of the standard creatinine. Estimation of GFR using cystatin C generated similarly accurate results but without the need to factor in race.

The second NIH-supported study led by Lesley Inker, Tufts Medical Center, Boston, MA, came to similar conclusions. They set out to develop new equations without race using data from several prior studies. They then compared the accuracy of their new eGFR equations to measured GFR in a validation set of 12 other studies, including about 4,000 participants.

Their findings show that currently used equations that include race, sex, and age overestimated measured GFR in Black Americans. However, taking race out of the equation without other adjustments underestimated measured GFR in Black people. Equations including both creatinine and cystatin C, but omitting race, were more accurate. The new equations also led to smaller estimated differences between Black and non-Black study participants.

The hope is that these findings will build momentum toward widespread adoption of cystatin C for estimating GFR. Already, a national task force has recommended immediate implementation of a new diagnostic equation that eliminates race and called for national efforts to increase the routine and timely measurement of cystatin C [3]. This will require a sea change in the standard measurements of blood chemistries in clinical and hospital labs—where creatinine is routinely measured, but cystatin C is not. As these findings are implemented into routine clinical care, let’s hope they’ll reduce health disparities by leading to more accurate and timely diagnosis, supporting the goals of precision health and encouraging treatment of CKD for all people, regardless of their race.

References:

[1] Race, genetic ancestry, and estimating kidney function in CKD. Hsu CY, Yang W, Parikh RV, Anderson AH, Chen TK, Cohen DL, He J, Mohanty MJ, Lash JP, Mills KT, Muiru AN, Parsa A, Saunders MR, Shafi T, Townsend RR, Waikar SS, Wang J, Wolf M, Tan TC, Feldman HI, Go AS; CRIC Study Investigators. N Engl J Med. 2021 Sep 23.

[2] New creatinine- and cystatin C-based equations to estimate GFR without race. Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, Crews DC, Doria A, Estrella MM, Froissart M, Grams ME, Greene T, Grubb A, Gudnason V, Gutiérrez OM, Kalil R, Karger AB, Mauer M, Navis G, Nelson RG, Poggio ED, Rodby R, Rossing P, Rule AD, Selvin E, Seegmiller JC, Shlipak MG, Torres VE, Yang W, Ballew SH,Couture SJ, Powe NR, Levey AS; Chronic Kidney Disease Epidemiology Collaboration. N Engl J Med. 2021 Sep 23.

[3] A unifying approach for GFR estimation: recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. Delgado C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, Miller WG, Moxey-Mims MM, Roberts GV, St Peter WL, Warfield C, Powe NR. Am J Kidney Dis. 2021 Sep 22:S0272-6386(21)00828-3.

Links:

Chronic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Explaining Your Kidney Test Results: A Tool for Clinical Use (NIDDK)

Chronic Renal Insufficiency Cohort Study

Chi-yuan Hsu (University of California, San Francisco)

Lesley Inker (Tufts Medical Center, Boston)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases

Posted In: News

Tags: African American health, African Americans, blacks, chronic kidney disease, Chronic Renal Insufficiency Cohort Study, CKD, creatinine, CRIC Study, cystatin C, diagnostics, eGFR, estimated glomerular filtration rate, genetics, GFR, glomerular filtration rate, health disparities, kidney dialysis, kidney disease, kidney failure, kidney transplantation, kidneys, muscle, precision health, precision medicine, race, renal failure

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