The research, led by Helena D. Hopson and Ellen M. Leffler of the University of Utah School of Medicine together with Sandrine E. Nsango of the Centre Pasteur du Cameroun and colleagues, focused on a question that has long been underexplored: what happens to the parasite’s genotype in asymptomatic infections? Most previous work on parasite adaptation to sickle haemoglobin examined children who were visibly sick with malaria. But in regions of intense transmission, a large share of infections produce no fever or other symptoms at all, and these silent infections are a major reservoir that keeps transmission going. Understanding whether the parasite’s sickle-associated alleles persist in these quiet infections offers a window into how the host-parasite relationship is actually playing out on the ground.

To answer it, the team conducted a cross-sectional survey of 2,246 healthy schoolchildren in the Mfou region of Cameroon, an area of about 3,300 square kilometres near the capital Yaoundé where malaria transmission is high. Samples were collected across three high-transmission seasons, spanning October to December 2022, April to May 2023, and November to December 2023, from eleven villages with individual sample sizes ranging from 6 to 638 children. The researchers genotyped each child for the human HbS variant and, using multiplexed amplicon deep sequencing, characterised the parasite genotypes in the blood samples, including the parasite loci known as Pfsa1 and Pfsa3, which carry alleles previously associated with sickle haemoglobin in studies of symptomatic disease.

The first key result was, in a sense, a negative finding. Children with the heterozygous sickle cell trait, genotype HbAS, and children with two normal haemoglobin copies, genotype HbAA, showed similar rates of asymptomatic infection. Out of the schoolchildren surveyed, 1,701 carried asymptomatic Plasmodium falciparum infections that could be genotyped. This means that sickle cell trait does not appear to prevent infection altogether in this setting; carriers are being infected at rates comparable to their non-carrier peers. The protection that HbS confers is therefore not a simple wall against the parasite, at least not against the parasite populations circulating in Mfou.

However, the composition of those infections differed dramatically by host genotype. The HbS genotype was strongly associated with parasites carrying the sickle-associated alleles, designated Pfsa-positive, at both the Pfsa1 and Pfsa3 loci. In other words, among children carrying one sickle haemoglobin copy, the parasites they harboured were significantly enriched for these specific variants, indicating a selective advantage for the Pfsa-positive alleles specifically within HbAS hosts. The association held up across villages and seasons, and additional analyses showed that HbS carriers had lower complexity of infection, meaning fewer distinct parasite genotypes per person, and lower parasitaemia, meaning fewer parasites in the bloodstream, compared with HbAA children.

These parasite alleles were first identified in a 2022 Nature study by Gavin Band and colleagues, who showed that the protective effect of sickle haemoglobin against symptomatic malaria depends on the parasite’s own genotype. Parasites carrying Pfsa-positive alleles appear to partially overcome HbS-mediated protection, which is why they are overrepresented among infections that make HbAS carriers sick. The new Cameroon study extends that logic backwards in the disease course: even before any symptoms appear, the host’s haemoglobin genotype is already shaping which parasite genotypes can establish and persist. The selective pressure exerted by sickle cell trait is visible in the silent reservoir of infection, not just in the clinic.

The authors interpret these findings through the framework of resistance and tolerance, two distinct biological strategies for dealing with infection. Resistance mechanisms reduce the number of parasites in the host, while tolerance mechanisms limit the damage caused by a given parasite burden without reducing the burden itself. Previous work has suggested that sickle haemoglobin acts through both routes: laboratory studies going back to 1978 showed impaired parasite growth in sickle trait red blood cells, driven in part by oxygen-dependent growth inhibition, while a 2011 Cell paper by Ferreira and colleagues argued that sickle haemoglobin confers tolerance to infection. The new data suggest that HbS protects against Pfsa-negative parasites before symptoms appear, consistent with a resistance effect, while the enrichment of Pfsa-positive parasites in asymptomatic carriers hints that these variants may contribute to the lower rates of symptomatic disease observed in HbAS individuals, a pattern more consistent with tolerance.

There is also a striking population-genetic detail in the study. The Pfsa1 and Pfsa3 loci showed strong inter-chromosomal linkage disequilibrium, meaning the sickle-associated alleles at the two loci tend to be inherited together on different chromosomes far more often than chance would predict. This non-random association suggests that the combination of Pfsa-positive alleles at both loci functions as a coordinated adaptation, and that recombination has not yet broken it apart in the Cameroonian parasite population. Such structure in a recombining parasite genome is a signature of recent or ongoing selection, consistent with the idea that P. falciparum is actively evolving in response to the sickle cell variant in human populations.

The broader implication is that the classic red-queen narrative of malaria and sickle cell is more accurately described as a genuine two-sided co-evolution. The sickle cell mutation arose in African populations and was driven to high frequency by the enormous mortality toll of falciparum malaria; recent work suggests rainforest hunter-gatherers acquired the mutation as recently as the Late Pleistocene. But the parasite, with its enormous population sizes and rapid generation times, has not stood still. Alleles that partially mitigate sickle-mediated protection have arisen and spread, and the new study demonstrates that this adaptation is detectable in the everyday, symptomless infections that sustain transmission between seasonal peaks. Host genotype and parasite genotype are locked in a reciprocal dance, and neither side’s moves can be understood in isolation.

For public health, the findings carry practical weight. Asymptomatic infections are increasingly recognised as the silent engine of malaria transmission, persisting through dry seasons and fuelling resurgent outbreaks even where control measures reduce clinical disease. If the parasite genotypes that dominate these reservoirs differ systematically by host haemoglobin status, then surveillance and intervention strategies may need to account for host genetics when interpreting parasite population structure. The study’s data, including human and parasite amplicon sequence reads deposited in the NCBI Sequence Read Archive under BioProject PRJNA1503656, and its analysis code released on GitHub, provide a resource for such efforts. What emerges is a refined view of a celebrated evolutionary story: sickle haemoglobin does protect against malaria, but the protection is a shifting, genotype-specific equilibrium, negotiated afresh by every parasite lineage that encounters a carrier’s red blood cells.

Subject of Research: How sickle cell haemoglobin genotype shapes Plasmodium falciparum parasite genotypes in asymptomatic malaria infections

Article Title: Sickle cell haemoglobin status shapes malaria parasite genotype in asymptomatic infections

Article References: Hopson, H. D., Herbert-Mainero, A., Bouopda-Tuedom, A. G., Nanssong-Vomo, C. T., Tumamo Fotso, B., Kiam, B. C., Ibrahima, I., Onguene, C., Abate, L., Omelianczyk, R. I., Evans, H. D., Horton, L. E., Band, G., Lamb, T. J., Ayong, L. S., Nsango, S. E., & Leffler, E. M. (2026). Sickle cell haemoglobin status shapes malaria parasite genotype in asymptomatic infections. Nature Microbiology. https://doi.org/10.1038/s41564-026-02502-4

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02502-4

Keywords: sickle cell trait, HbS, malaria, Plasmodium falciparum, asymptomatic infection, Pfsa alleles, host-parasite coevolution, genetic association study, Cameroon, disease tolerance, parasite genotype, Nature Microbiology

The research, led by Yasmina Drissi-El Boukili and Anna Rosanas-Urgell together with colleagues at the Clinical Research Unit of Nanoro and the Institute of Tropical Medicine in Antwerp, examined people naturally infected with Plasmodium falciparum, the deadliest of the malaria parasites that infect humans. The team focused on mutations in the beta-globin gene, HBB, which encodes one of the protein chains of hemoglobin, the oxygen-carrying molecule inside red blood cells. Two variant hemoglobins in particular drew their attention: hemoglobin S and hemoglobin C, both of which are common in West Africa precisely because they confer survival advantages against falciparum malaria.

People who carry one normal copy of the gene and one variant copy produce red blood cells containing a mixture of hemoglobins, a condition known as the HbAS trait for hemoglobin S or HbAC for hemoglobin C. These heterozygous states are famously protective: carriers are far less likely to develop the life-threatening complications of malaria, which is why natural selection has maintained these variants at high frequency in malaria-endemic regions. What has remained far less clear is whether these altered red blood cells affect another dimension of the parasite’s life cycle, namely its ability to commit to producing the sexual stages that make transmission possible.

That commitment process, called sexual conversion, is the opening move of gametocytogenesis. Most parasites circulating in a patient’s blood are asexual forms that multiply relentlessly inside red blood cells, consuming hemoglobin and driving the fevers and anemia of clinical malaria. But a small fraction of parasites instead differentiates into gametocytes, the sexual forms that lie dormant in the bloodstream until a mosquito takes a blood meal and ingests them. Inside the mosquito, these gametocytes transform again into gametes, fertilize, and give rise to the sporozoites that the insect will inject into its next human victim. Without sexual conversion, the entire transmission chain would collapse, which makes the factors that regulate this switch a matter of intense interest for anyone hoping to block the spread of malaria.

Measuring sexual conversion in natural infections, however, has long been technically difficult. To overcome this obstacle, the researchers developed a new ex vivo assay, which they called the evSCA, designed to quantify how frequently parasites drawn directly from infected patients commit to the sexual pathway. Using blood samples collected in Nanoro, a malaria-endemic district in central Burkina Faso, they compared sexual conversion rates among infected individuals grouped by their HBB genotype: those with the standard HbAA hemoglobin, those with the sickle-cell trait HbAS, and those with the HbAC variant.

The results were striking. Sexual conversion rates were significantly higher in infected individuals carrying HbAS or HbAC than in those with wild-type HbAA red blood cells. In other words, the very red blood cells that shield their owners from severe disease appeared to be nudging the parasites inside them toward the sexual pathway at a greater rate. Because gametocytes are the only forms the mosquito can pick up, elevated sexual conversion could in principle raise the number of transmissible parasites in the carrier’s blood, with consequences for how malaria spreads through communities where these hemoglobin variants are common.

To test whether this association reflected a direct effect of the red blood cell environment rather than some other difference between patients, the team turned to a controlled in vitro system. They cultured parasites in red blood cells of different hemoglobin compositions and measured sexual conversion using a reporter parasite line, NF54-gexp02-Tom, in which the expression of a fluorescent marker is tied to the activation of ap2-g, the master regulator gene that triggers sexual commitment. This reporter line allowed the researchers to count precisely how many parasites flipped the genetic switch under each culture condition. Consistent with the ex vivo findings from patient samples, parasites grown in HbAS red blood cells showed higher sexual conversion rates than parasites grown in HbAA cells, supporting the idea that the altered intracellular environment of variant-hemoglobin red blood cells actively promotes the sexual switch.

The researchers also considered an alternative explanation rooted in immunity rather than in the red blood cell itself. Antibodies directed against infected red blood cells can shape which parasite stages survive and flourish in a given host, so differences in antibody responses between HBB genotypes might conceivably account for the observed pattern. To investigate this, the team used flow cytometry to quantify immunoglobulin G and immunoglobulin M responses against antigens on the surface of red blood cells infected with trophozoites, the actively feeding asexual stage, and with stage I gametocytes, the earliest sexual stage. When they compared plasma from individuals with different HBB genotypes, they found no significant differences in these antibody responses, arguing against humoral immunity as the driver of the elevated sexual conversion and leaving the red blood cell environment itself as the more likely culprit.

The precise molecular mechanism by which variant hemoglobins encourage sexual commitment remains to be worked out, but the finding adds a fascinating new layer to the long evolutionary story of hemoglobin variants and malaria. Hemoglobin S and hemoglobin C are classic examples of a genetic trade-off: they cost carriers some fitness burden, including, in the case of hemoglobin S, the risk of sickle-cell disease when inherited from both parents, in exchange for protection against a killer disease. The new data suggest the ledger may be even more complicated than previously thought. If carriers of these variants, while suffering less severe illness, also harbor parasites that are more prone to becoming transmissible gametocytes, then human genetics could be quietly shaping the transmission landscape of malaria in endemic regions, influencing how intensively the parasite circulates even as it causes less disease in protected individuals.

From a public health perspective, the study opens several avenues worth pursuing. Understanding how the red blood cell environment modulates ap2-g activation could reveal new targets for transmission-blocking interventions, an area of growing importance as malaria control programs aim not merely to treat sick patients but to interrupt the parasite’s passage from human to mosquito to human. The ex vivo assay developed by the team also provides a practical tool for measuring sexual conversion directly in natural infections, something that has been difficult to achieve and that could now be applied to larger and more diverse populations. As researchers dig deeper into how host genetics sculpt the parasite’s life cycle decisions, the humble red blood cell is emerging not just as the parasite’s home and food source, but as an active participant in determining whether an infection remains a private battle between host and pathogen or becomes the next link in a chain of transmission.

Subject of Research: Effect of HBB hemoglobin variants on Plasmodium falciparum sexual conversion in naturally infected malaria patients

Article Title: Elevated Plasmodium falciparum sexual conversion in HbAC and HbAS red blood cells in naturally infected malaria patients

Article References: Elevated Plasmodium falciparum sexual conversion in HbAC and HbAS red blood cells in naturally infected malaria patients. (n.d.). https://doi.org/10.1371/journal.ppat.1014542

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014542

Keywords: malaria, Plasmodium falciparum, gametocytes, sexual conversion, hemoglobin S, hemoglobin C, HBB gene, red blood cells, Burkina Faso, transmission, ap2-g, ex vivo assay

The research, published in Nature Microbiology by a team led by scientists at the University of Utah Health, the University of Douala, and the Centre Pasteur du Cameroun, combined large-scale genetic analysis of human blood samples with equally detailed sequencing of the malaria parasites infecting them. Working in Mfou, a malaria-endemic community in Cameroon, the researchers analyzed genetic material from more than 2,000 people, capturing both symptomatic infections and the far more numerous asymptomatic ones. What emerged was a picture of host-pathogen interaction far more intricate than the conventional narrative of a human mutation simply blocking parasite growth inside red blood cells.

The central discovery is striking: people who carry the sickle cell variant are almost exclusively infected by a genetically distinct variety of malaria parasites. In other words, the parasite population infecting a person is not random with respect to their hemoglobin genotype. Parasites with one genetic signature dominate infections in carriers of the sickle cell trait, while parasites with a different genetic makeup are more commonly found in people without the variant. This pattern held not only in the rare cases where carriers fall ill, but also — and crucially — in the vast pool of asymptomatic infections that make up most malaria transmission in endemic settings.

Asymptomatic infections are the quiet majority of the malaria burden. In the Mfou study population, roughly three-quarters of apparently healthy participants carried malaria parasites in their blood without showing any symptoms. These silent reservoirs are less visible to clinics and surveillance systems than the fevers and hospitalizations of clinical malaria, but they sustain transmission and represent the environment in which the parasite and its human host negotiate their long evolutionary standoff. By extending their analysis to this hidden majority, the researchers uncovered a relationship that earlier work focused on symptomatic disease could not fully reveal.

Perhaps the most consequential finding concerns infection rates versus disease rates. People carrying the sickle cell variant become infected with malaria parasites at roughly the same overall frequency as people without the variant — they simply tend to harbor a different genetic variety of the parasite. Yet carriers are about ten times less likely to develop harmful, symptomatic disease. This observation upends a tempting earlier hypothesis. When the distinct parasite strain was first identified in symptomatic carriers of the sickle cell trait, scientists speculated that it might be a kind of superbug, unusually adept at breaking through the carriers’ defenses and causing illness. The new data suggest nearly the opposite: the biological properties of this parasite variety may themselves contribute to the carriers’ protection, rather than undermining it.

That reframing matters because it changes where researchers should look for answers. The classical explanation for sickle cell trait protection centers on the human host: the altered hemoglobin environment inside red blood cells is thought to stress the parasite, shorten the lifespan of infected cells, and impair the parasite’s ability to replicate and to cause the sequestration in small blood vessels that underlies severe disease. The new findings do not overturn that biology, but they add a second dimension. If the parasites capable of establishing infection in sickle cell trait carriers are systematically different from those infecting other people, then part of the protective effect may lie in the parasite’s own characteristics — how virulent it is, how efficiently it multiplies, or how readily it triggers the inflammatory cascades that produce symptoms.

Sandrine Nsango, associate professor of molecular biology at the University of Douala, researcher at the Centre Pasteur du Cameroun, and one of the senior authors of the study, framed the result as evidence of a two-way evolutionary conversation. The sickle cell mutation, she noted, is one of the clearest examples of how an infectious disease can shape human evolution, but the findings suggest that humans also shape the evolution of the parasite in return. The parasite lineages that can survive in the red blood cells of trait carriers are, in effect, a selected subset of the parasite population — filtered by generations of host genetics. Understanding that filtering process, she argued, may help scientists anticipate how malaria parasites adapt in the future and design more effective strategies for malaria control.

Ellen Leffler, assistant professor of human genetics at University of Utah Health and the study’s other senior author, described the discovery as something that had been hiding in plain sight. Researchers have studied the association between sickle cell trait and malaria protection for more than half a century, but the parasite’s side of the story required tools that only became practical recently: high-throughput DNA sequencing capable of characterizing whole parasite populations directly from human blood samples. As Leffler put it, people have been examining this association for a long time, but you have to be able to ask the parasite for it to tell you this. The new sequencing approach effectively did exactly that, revealing that the genotype of the infecting parasite is a variable that previous study designs largely ignored.

The implications extend beyond evolutionary theory into practical medicine and public health. If specific parasite genotypes are associated with asymptomatic carriage in sickle cell trait carriers, then parasite genetics could become a tool for tracking transmission, identifying which parasite lineages circulate in a community, and monitoring how the parasite population shifts under the pressure of interventions such as bed nets, drugs, and vaccines. Leffler emphasized that the work opens a new dimension for understanding what determines the outcome of an infection, and expressed hope that it will lead to a deeper biological understanding of the parasite and of this co-evolutionary system — one she described as quite unique in humans — and ideally to practical new strategies for tracking or treating infections.

The study also serves as a reminder of how much remains unknown about one of biology’s most famous examples of natural selection. The sickle cell allele’s protective effect was first proposed in the 1950s and has since become a textbook staple, yet the full mechanism has never been a single tidy story. Red blood cell physiology, immune responses, and parasite biology all appear to contribute, and disentangling them requires studying real populations in endemic regions, where people are repeatedly exposed to genetically diverse parasites over a lifetime. The Mfou cohort, sequenced at the level of both human and parasite genomes, offers exactly that kind of window. The work was supported by the Fondation Pierre Fabre under the IMPAS project and by the American Heart Association, and the authors report no competing interests. As malaria control efforts worldwide confront drug resistance and shifting parasite populations, the message of this study is clear: to understand why some people are protected, scientists must listen not only to the human genome but to the parasite’s as well.

Subject of Research: How sickle cell haemoglobin status shapes the genotypes of malaria parasites in asymptomatic human infections

Article Title: Distinct malaria parasites “hidden in plain sight” may contribute to human disease protection

Article References: Distinct malaria parasites “hidden in plain sight” may contribute to human disease protection. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: malaria, sickle cell trait, Plasmodium, hemoglobin, genomics, asymptomatic infection, coevolution, Cameroon, parasite genetics, Nature Microbiology, human evolution, disease protection

Sickle cell disease is caused by mutations in the hemoglobin gene and comes in several distinct genotypes. The most common and often most severe form is hemoglobin SS, but patients may also carry hemoglobin SC disease or one of two sickle beta-thalassemia variants, Sβ+ and Sβ0, each with different clinical trajectories and treatment needs. Complicating matters further, many people carry only the sickle cell trait, a benign carrier state that must be reliably distinguished from actual disease in any epidemiological analysis. Hospital databases, which increasingly fuel retrospective research on these rare conditions, typically identify patients through ICD-10 diagnostic codes, but those codes frequently record only that a patient has sickle cell disease, not which subtype, and sometimes they flag patients who do not have the disease at all.

To address this, Loris Azoyan of Sorbonne Université, INSERM and the Assistance Publique – Hôpitaux de Paris, along with Olivier Steichen and colleagues across five French expert centers, developed an algorithm built from regular expressions: pattern-matching rules that scan unstructured clinical text for the specific phrases clinicians use when documenting a patient’s hemoglobin genotype. The approach deliberately avoided heavyweight machine learning. Instead, it relied on the fact that French clinical reports, from consultation notes to laboratory results, tend to mention sickle cell genotypes in formulaic ways, using standard genetic shorthand that can be captured with carefully crafted textual patterns. The researchers made the regular expressions, the R analysis script containing the classification algorithm, and fictional illustrative patient texts openly available in an Open Science Framework repository, so that other teams can adapt the method to their own data warehouses.

The scale of the evaluation was considerable. The team included every adult patient with at least one ICD-10 code for sickle cell disease who had consulted or been hospitalized at least once between August 1, 2017 and January 29, 2025 at the five participating expert centers of the Greater Paris University Hospitals. In total, 10,868 patients met the entry criteria, and their records contained 561,924 clinical documents issued between 2013 and 2025. The algorithm processed all of those reports in five minutes, a throughput that would be unthinkable with manual chart review and that demonstrates why text-mining tools are becoming essential for research on conditions whose clinical details live in narrative documents rather than structured fields.

The results painted a nuanced picture of the cohort. For 1,259 patients, no sickle-related term could be found anywhere in their clinical reports, immediately raising questions about why their coded diagnoses existed in the first place. Among the remaining 9,609 patients, 1,802, or 18.8 percent, had only non-specific sickle mentions that did not permit any classification. Another 1,502 patients, 15.6 percent, were classified as having sickle cell trait rather than disease. The algorithm assigned 6,234 patients, or 64.9 percent, to a definite sickle cell disease subtype: 4,443 of them, or 71.3 percent, had hemoglobin SS disease; 1,431, or 23.0 percent, had SC disease; 263, or 4.2 percent, had the Sβ+ form; and 97, or 1.6 percent, carried the more severe Sβ0 genotype. Just 71 patients, 0.7 percent, remained unresolved even after the full analysis.

To determine whether the algorithm’s assignments could be trusted, the researchers conducted a manual review of a stratified random sample of 1,510 patients, using that expert adjudication as the reference standard against which the automated classification was measured. The algorithm achieved an overall positive predictive value of 94.0 percent, with a 95 percent confidence interval of 92.6 to 95.4, and subtype-level performance ranged from 91.4 percent to a perfect 100 percent. In practical terms, when the algorithm says a patient has hemoglobin SC disease or Sβ0 thalassemia, that statement is very likely to be confirmed by a human expert reading the same records. For retrospective cohort studies, where the alternative is either laborious manual review or crude diagnostic codes, that level of precision represents a meaningful advance.

Perhaps the most consequential finding of the study concerns the ICD-10 codes that medico-administrative research typically relies on. The team evaluated several commonly used selection strategies based on those codes, varying how many codes were required to confirm a patient’s status and how unclassified patients were treated. The positive predictive value of code-only strategies ranged from as low as 58.1 percent to 88.3 percent depending on those assumptions. In other words, depending on the strategy chosen, a substantial fraction of patients identified through coding alone may not actually have sickle cell disease, or may carry only the trait. The authors warn that this creates a real risk of misclassification when researchers rely solely on administrative coding, a concern that echoes previous validation work on hospital discharge diagnoses in France and on sickle cell case definitions in the United States.

The implications reach beyond sickle cell disease itself. As hospital data warehouses and national health databases become standard infrastructure for epidemiology, the gap between what is coded and what is clinically true has become a central methodological challenge. Previous efforts have used natural language processing to extract information from clinical text for populating registries, identifying patients with specific conditions, and detecting complications such as contrast-associated kidney injury. The Paris team’s contribution is to demonstrate that even a deliberately simple, transparent set of pattern-matching rules, rather than a complex deep-learning model, can achieve high accuracy for a genetically defined condition, provided clinicians document the relevant details consistently. The authors emphasize, however, that their performance figures may reflect the specific subtype demographics, the expertise of the five expert centers, and local documentation practices, so other institutions should expect to validate and adapt the approach on their own data.

The study also touches on the emerging role of generative artificial intelligence in medical informatics research, though in an unusual way. The authors disclose that they used OpenAI’s ChatGPT solely to generate fictional illustrative clinical texts demonstrating the algorithm’s functionality, allowing them to publish realistic French-language medical report examples without exposing any real patient data. No generative AI tool was used for the analysis itself, the design of the algorithm, or the writing of the manuscript, and the authors take full responsibility for the generated content. The underlying clinical reports and patient-level data, meanwhile, cannot be shared publicly because of their sensitive nature and French data protection regulations, with access restricted under the governance of the AP-HP Clinical Data Warehouse, whose scientific and ethics committee approved the retrospective study under the French MR-004 reference methodology for reusing healthcare data in research.

For clinicians and researchers, the message is twofold. First, high-quality clinical documentation matters: the algorithm’s success depended entirely on clinicians writing genotype information into reports, and the authors highlight the importance of such documentation for retrospective research. Second, any study that builds a sickle cell cohort purely from ICD-10 codes should treat its findings with caution, because a meaningful proportion of code-positive patients may be misclassified. By pairing an open, reusable text-classification algorithm with a rigorous manual validation and an honest assessment of coding accuracy, the Paris team has provided both a practical tool and a methodological warning, ones that could shape how sickle cell disease research is conducted across France and beyond as hospitals continue to digitize their clinical narratives.

Subject of Research: Validation of a regular-expression algorithm for classifying sickle cell disease subtypes from unstructured clinical reports and assessing ICD-10 coding accuracy

Article Title: Classifying Sickle Cell Disease Subtypes from Clinical Reports: Algorithm Validation and ICD-10 Accuracy Assessment in Five French Hospitals

Article References: Azoyan, L., Leblanc, J., Santin, A., Chantalat-Auger, C., Le Jeune, S., Affo, L., Arlet, J.-B., Bartolucci, P., & Steichen, O. (2026). Classifying Sickle Cell Disease Subtypes from Clinical Reports: Algorithm Validation and ICD-10 Accuracy Assessment in Five French Hospitals. Journal of Medical Systems, 50(1), Article 134. https://doi.org/10.1007/s10916-026-02461-7

Image Credits: AI Generated

DOI: 10.1007/s10916-026-02461-7

Keywords: sickle cell disease, sickle cell trait, natural language processing, electronic health records, ICD-10, clinical text mining, hemoglobin SS, hemoglobin SC, regular expressions, rare disease research, hospital databases, diagnostic coding accuracy