Reviews & Analysis

Using a systems-level, multi-omics approach, we reveal several genes associated with arachnoid cysts and identify four phenotypic subtypes of arachnoid cysts, the severity of which correlates with the presence of protein-damaging de novo variants. All candidate genes are expressed in the developing brain and encode molecules implicated in chromatin modification or transcriptional regulation.

Using observational data from over 200,000 participants with up to 32 years of follow-up, we compared the strengths of eight healthy dietary patterns for general health. We found that diets that lowered hyperinsulinemia, chronic inflammation and diabetes risk may offer the greatest protection against chronic diseases.

We developed a compact database, called a ‘Rareservoir’, that contains the rare variant genotypes and phenotypes of 34,523 patients with a rare disease and 43,016 unaffected relatives. We inferred 260 genetic associations with rare disease classes, of which 19 were previously unidentified, and validated etiological roles for ERG, PMEPA1 and GPR156.

To meet a current unmet medical need, we generated 15 genetically engineered mouse models that accurately reflect the key pathogenetic aspects of human multiple myeloma. By coupling mechanistic investigations and pre-clinical immunotherapy testing, these pre-clinical platforms provide knowledge that will aid the optimization of future immunotherapy clinical trial design.

We describe a 53-year-old man with HIV-1 who received allogeneic CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) in 2013 to treat acute myeloid leukemia. Four years after analytic treatment interruption (ATI), the absence of viral rebound and the lack of immunological correlates of HIV-1 antigen persistence provide convincing evidence for HIV-1 cure.

The largest whole-exome sequencing study of individuals with premature ovarian insufficiency (POI) so far identifies 20 new disease-associated genes, yields an overall genetic contribution to POI of 23.5%, and provides detailed characterization of the genetic landscape of this disorder.

Smoldering multiple myeloma is an asymptomatic precursor condition to multiple myeloma, a cancer in the bone marrow. We conducted a population-based screening study — in which 51% of the population over 40 years of age in Iceland participated — and found that the prevalence of smoldering multiple myeloma was 0.5% in the study population.

Tumor mutation burden is an imperfect predictor of response to immunotherapies. Mutations in regions of the genome unlikely to undergo loss during tumor evolution constitute a persistent tumor mutation burden that may drive sustained immunological tumor control in the context of cancer immunotherapy.

We demonstrate the power of a data-informed medicines-based approach in discovering the indirect effect of the COVID-19 pandemic on cardiovascular events using 1.32 billion records of dispensed medications in England, Scotland and Wales. We estimate that interruption of preventive care could result in more than 13,000 extra cardiovascular events.

By performing a large-scale biobank-based genome-wide association study, we identified a strong link between the underlying risk of cardiometabolic disease and patterns of lifelong medication use in hyperlipidemia, hypertension and type 2 diabetes. We discover hundreds of genetic predictors of medication use behavior and show medication-use-enhanced applications for polygenic prediction in cardiometabolic diseases.

The cause of pregnancy loss or perinatal death often remains unexplained, even following a standard autopsy. Comprehensive genomic investigation of pregnancy loss or perinatal death identifies a cause in over 50% of cases, particularly where congenital abnormalities are present. Causes of stillbirths without congenital abnormalities remain difficult to identify.

Clinical trials in neurological diseases often involve subjective, qualitative endpoints, such ‘by eye’ observations of movement. We developed an artificial intelligence–based method to analyze natural daily behavior data from people with Duchenne muscular dystrophy, using machine-learning algorithms to accurately predict their personal disease trajectories better than conventional clinical assessments.

The large, ongoing CIRCULATE-Japan trial is investigating the role of circulating tumor DNA (ctDNA)-based molecular residual disease testing in patients with resectable colorectal cancer after radical surgery. An interim analysis of GALAXY, a prospective, observational arm of CIRCULATE-Japan, establishes ctDNA as a prognostic and predictive biomarker.

A machine learning algorithm identifies four reproducible clinical subphenotypes of long COVID from the electronic health records of patients with post-acute sequelae of SARS-CoV-2 infection within 30–180 days of infection; these patterns have implications for the treatment and management of long COVID.

Vigorous intermittent lifestyle physical activity (VILPA) refers to brief bouts of strenuous movement performed as part of daily living, such as walking uphill or running for a bus. We find that as little as 3–4 minutes of VILPA per day is associated with substantially reduced mortality risk compared to no VILPA.

Subgroup analysis of the EMPEROR-Preserved clinical trial of the glucose-lowering drug empagliflozin in chronic heart failure with left ventricular ejection fraction (LVEF) >40% found improved clinical outcomes in the cohort of patients with LVEF ≥50%. This is, to our knowledge, the first time a drug therapy has been unequivocally demonstrated to benefit this patient population.

Inhaled particulates from environmental pollutants accumulate in macrophages in lung-associated lymph nodes over years, compromising immune surveillance via direct effects on immune cell function and lymphoid architecture. These findings reveal the importance of improved air quality to preserve immune health against current and emerging pathogens.

To enable large-scale screening for left ventricular dysfunction — a serious and under-detected cardiac disease — we applied artificial intelligence to electrocardiograms recorded by patients using their own Apple watches in a prospective, digital, remote study. We found that patients engaged with the system and that the watch electrocardiograms effectively screened for the disease.

Impaired glucose tolerance (IGT) is a common condition that affects glucose control after sugar consumption. Isolated IGT is undetected by screening and diagnostic strategies, leaving affected individuals at high risk of developing diabetes. Here, a machine-learning framework identifies a three-protein signature for detecting isolated IGT from a single blood sample.

Evidence — provided by a combination of amyloid-β and tau PET examinations — of advanced Alzheimer’s disease pathological changes in the brain in cognitively unimpaired individuals is strongly associated with short-term (3–5 years) cognitive decline. Thus, amyloid-β and tau PET have high clinical relevance.