A foundation model for generalizable disease detection from retinal images

Medical artificial intelligence (AI) offers great potential for recognizing signs of health conditions in retinal images and expediting the diagnosis of eye diseases and systemic disorders 1. However, the development of AI models requires substantial annotation and models are usually task-specific with limited generalizability to different clinical applications 2. Here, we present RETFound, a foundation model for retinal images that learns generalizable representations from unlabelled retinal images and provides a basis for label-efficient model adaptation in several applications. Specifically, RETFound is trained on 1.6 million unlabelled retinal images by means of self-supervised learning and then adapted to disease detection tasks with explicit labels. We show that adapted RETFound consistently outperforms several comparison models in the diagnosis and prognosis of sight-threatening eye diseases, as well as incident prediction of complex systemic disorders such as heart failure and myocardial infarction with fewer labelled data. RETFound provides a generalizable solution to improve model performance and alleviate the annotation workload of experts to enable broad clinical AI applications from retinal imaging.</p

A foundation model for generalizable disease detection from retinal images

Medical artificial intelligence (AI) offers great potential for recognizing signs of health conditions in retinal images and expediting the diagnosis of eye diseases and systemic disorders1. However, the development of AI models requires substantial annotation and models are usually task-specific with limited generalizability to different clinical applications2. Here, we present RETFound, a foundation model for retinal images that learns generalizable representations from unlabelled retinal images and provides a basis for label-efficient model adaptation in several applications. Specifically, RETFound is trained on 1.6 million unlabelled retinal images by means of self-supervised learning and then adapted to disease detection tasks with explicit labels. We show that adapted RETFound consistently outperforms several comparison models in the diagnosis and prognosis of sight-threatening eye diseases, as well as incident prediction of complex systemic disorders such as heart failure and myocardial infarction with fewer labelled data. RETFound provides a generalizable solution to improve model performance and alleviate the annotation workload of experts to enable broad clinical AI applications from retinal imaging

Establishing a scalable platform for characterizing the effects of perturbing expression of schizophrenia associated genes

Large scale genomic and transcriptomic analyses are illuminating the complex genetic nature of psychiatric disorders such as schizophrenia. Newly identified associations between genetic variations and disease risk must be functionally validated, in order to understand the underlying cellular and molecular mechanism contributing to disease. A scalable, robust platform for modeling the effects that such myriad perturbations might have on neural systems is necessary. Here, we combine human induced pluripotent stem cells, cerebral organoid differentiations, and a catalytically inactivated endonuclease dCas9 fused to the KRAB transcriptional repressor. We further demonstrate the feasibility of, and important considerations associated with, developing such a platform, by applying it to study the effects of perturbing FURIN, a gene with an expression quantitative trait locus significantly associated with schizophrenia. Our data demonstrate the utility and scalability of this system for manipulating disease-associated gene expression in order to query cellular phenotypic effect

From “Directed Differentiation” to “Neuronal Induction”: Modeling Neuropsychiatric Disease

Aberrant behavior and function of neurons are believed to be the primary causes of most neurological diseases and psychiatric disorders. Human postmortem samples have limited availability and, while they provide clues to the state of the brain after a prolonged illness, they offer limited insight into the factors contributing to disease onset. Conversely, animal models cannot recapitulate the polygenic origins of neuropsychiatric disease. Novel methods, such as somatic cell reprogramming, deliver nearly limitless numbers of pathogenic human neurons for the study of the mechanism of neuropsychiatric disease initiation and progression. First, this article reviews the advent of human induced pluripotent stem cell (hiPSC) technology and introduces two major methods, “directed differentiation” and “neuronal induction,” by which it is now possible to generate neurons for modeling neuropsychiatric disease. Second, it discusses the recent applications, and the limitations, of these technologies to in vitro studies of psychiatric disorders

Algae-produced Pfs25 elicits antibodies that inhibit malaria transmission.

Subunit vaccines are significantly more expensive to produce than traditional vaccines because they are based primarily on recombinant proteins that must be purified from the expression system. Despite the increased cost, subunit vaccines are being developed because they are safe, effective, and can elicit antibodies that confer protection against diseases that are not currently vaccine-preventable. Algae are an attractive platform for producing subunit vaccines because they are relatively inexpensive to grow, genetically tractable, easily scaled to large volumes, have a short generation time, and are devoid of inflammatory, viral, or prion contaminants often present in other systems. We tested whether algal chloroplasts can produce malaria transmission blocking vaccine candidates, Plasmodium falciparum surface protein 25 (Pfs25) and 28 (Pfs28). Antibodies that recognize Pfs25 and Pfs28 disrupt the sexual development of parasites within the mosquito midgut, thus preventing transmission of malaria from one human host to the next. These proteins have been difficult to produce in traditional recombinant systems because they contain tandem repeats of structurally complex epidermal growth factor-like domains, which cannot be produced in bacterial systems, and because they are not glycosylated, so they must be modified for production in eukaryotic systems. Production in algal chloroplasts avoids these issues because chloroplasts can fold complex eukaryotic proteins and do not glycosylate proteins. Here we demonstrate that algae are the first recombinant system to successfully produce an unmodified and aglycosylated version of Pfs25 or Pfs28. These antigens are structurally similar to the native proteins and antibodies raised to these recombinant proteins recognize Pfs25 and Pfs28 from P. falciparum. Furthermore, antibodies to algae-produced Pfs25 bind the surface of in-vitro cultured P. falciparum sexual stage parasites and exhibit transmission blocking activity. Thus, algae are promising organisms for producing cysteine-disulfide-containing malaria transmission blocking vaccine candidate proteins

Immunoblot of reduced and non-reduced algae-produced Pfs25 and Pfs28 with monoclonal transmission blocking antibodies.

<p>Reduced and non-reduced a-Pfs25 and a-Pfs28 were resolved by SDS-PAGE, transferred to nitrocellulose, and detected with (A) anti-Pfs25 4B7 mAb and (B) anti-Pfs28-2D8 mAbs, respectively.</p

Immunoblot and Coomassie-blue stain of algae-produced Pfs25 and Pfs28 analyzed by SDS and Native-PAGE.

<p>Five micrograms of reduced and non-reduced affinity purified (A) a-Pfs25 and (B) a-Pfs28 were resolved by SDS-PAGE, transferred to nitrocellulose, and detected with anti-FLAG mAbs. (C) Five micrograms of reduced a-Pfs25, a-Pfs28, and BSA were resolved by SDS-PAGE and stained with Coomassie-blue. (D) Five micrograms of non-reduced a-Pfs25, a-Pfs28, and BSA were resolved by Native-PAGE and stained with Coomassie-blue. (R – reduced, N – non-reduced).</p

Analysis of antibodies from mice immunized with algae-produced Pfs25 or Pfs28.

<p>(A) ELISA titers of mouse anti-sera elicited by algae-produced Pfs25 and Pfs28. Mice were immunized with affinity purified a-Pfs25 or a-Pfs28 using complete Freund's adjuvant followed by boosters with incomplete Fruend's adjuvant by intraperitoneal injection. Pooled sera was serially diluted and tested in triplicate against the corresponding algae-produced Pfs antigen; error bars are one standard deviation. Prebleed sera were tested as a negative control; error bars are four standard deviations. (B–D) Western blot analysis of <i>P. falciparum</i> mixed sexual stage lysates with anti-Pfs25-4B7 mAbs, a-Pfs 25 antisera, or a-Pfs28 antisera. Reduced and non-reduced sexual stage lysates were resolved by SDS-PAGE and transferred to nitrocellulose. Blots were probed with (B) anti-Pfs25-4B7 mAbs, (C) antibodies raised to a- Pfs25, and (D) antibodies raised to a-Pfs28. (R – reduced, N – non-reduced).</p