Optimal-Transport Analysis of Single-Cell Gene Expression Identifies Developmental Trajectories in Reprogramming.

Understanding the molecular programs that guide differentiation during development is a major challenge. Here, we introduce Waddington-OT, an approach for studying developmental time courses to infer ancestor-descendant fates and model the regulatory programs that underlie them. We apply the method to reconstruct the landscape of reprogramming from 315,000 single-cell RNA sequencing (scRNA-seq) profiles, collected at half-day intervals across 18 days. The results reveal a wider range of developmental programs than previously characterized. Cells gradually adopt either a terminal stromal state or a mesenchymal-to-epithelial transition state. The latter gives rise to populations related to pluripotent, extra-embryonic, and neural cells, with each harboring multiple finer subpopulations. The analysis predicts transcription factors and paracrine signals that affect fates and experiments validate that the TF Obox6 and the cytokine GDF9 enhance reprogramming efficiency. Our approach sheds light on the process and outcome of reprogramming and provides a framework applicable to diverse temporal processes in biology.

Cell Reprogramming: The Many Roads to Success.

Cellular reprogramming experiments from somatic cell types have demonstrated the plasticity of terminally differentiated cell states. Recent efforts in understanding the mechanisms of cellular reprogramming have begun to elucidate the differentiation trajectories along the reprogramming processes. In this review, we focus mainly on direct reprogramming strategies by transcription factors and highlight the variables that contribute to cell fate conversion outcomes. We review key studies that shed light on the cellular and molecular mechanisms by investigating differentiation trajectories and alternative cell states as well as transcription factor regulatory activities during cell fate reprogramming. Finally, we highlight a few concepts that we believe require attention, particularly when measuring the success of cell reprogramming experiments.

Species-Independent Attraction to Biofilms through Electrical Signaling.

Bacteria residing within biofilm communities can coordinate their behavior through cell-to-cell signaling. However, it remains unclear if these signals can also influence the behavior of distant cells that are not part of the community. Using a microfluidic approach, we find that potassium ion channel-mediated electrical signaling generated by a Bacillus subtilis biofilm can attract distant cells. Integration of experiments and mathematical modeling indicates that extracellular potassium emitted from the biofilm alters the membrane potential of distant cells, thereby directing their motility. This electrically mediated attraction appears to be a generic mechanism that enables cross-species interactions, as Pseudomonas aeruginosa cells also become attracted to the electrical signal released by the B. subtilis biofilm. Cells within a biofilm community can thus not only coordinate their own behavior but also influence the behavior of diverse bacteria at a distance through long-range electrical signaling. PAPERCLIP.

A new model of human lymphopoiesis across development and aging.

Over the past decade our research has implemented a multimodal approach to human lymphopoiesis, combining clonal-scale mapping of lymphoid developmental architecture with the monitoring of dynamic changes in the pattern of lymphocyte generation across ontogeny. We propose that lymphopoiesis stems from founder populations of CD127/interleukin (IL)7R- or CD127/IL7R+ early lymphoid progenitors (ELPs) polarized respectively toward the T-natural killer (NK)/innate lymphoid cell (ILC) or B lineages, arising from newly characterized CD117lo multi-lymphoid progenitors (MLPs). Recent data on the lifelong lymphocyte dynamics of healthy donors suggest that, after birth, lymphopoiesis may become increasingly oriented toward the production of B lymphocytes. Stemming from this, we posit that there are three major developmental transitions, the first occurring during the neonatal period, the next at puberty, and the last during aging.

Nutritional control of developmental processes.

Nutritional and metabolic cues are integral to animal development. Organisms use them both as sustenance and environmental indicators, fueling, informing and influencing developmental decisions. Classical examples, such as the Warburg effect, clearly illustrate how genetic programs control metabolic changes. However, the way that nutrition and metabolism can also modulate or drive genetic programs to instruct developmental trajectories is much more elusive, owing to several difficulties including uncoupling permissive and instructive functions. Here, we discuss recent advancements in the field that highlight the developmental role of nutritional and metabolic cues across multiple levels of organismal complexity.

Self-esteem trajectories over three decades predict opposition to social equality in midlife.

Although life trajectories are frequently theorized to explain people's attitudes toward different social groups, few studies have been able to directly assess their importance with suitable data. Addressing this gap and focusing on the development of general and domain-specific self-esteem, we report results from a population-based sample of Norwegians (N = 2,215) followed over 28 years and five time points from adolescence to midlife. Growth curve models demonstrated that irrespective of self-esteem domain, low levels of self-esteem in adolescence as well as a depressed self-esteem development over the next three decades were related to more overall opposition to social equality as well as more opposition to gender equality and immigration in midlife. The results held when controlling for participants' baseline political orientations and other key covariates in adolescence. Our findings indicate that low self-esteem and a lack of positive self-esteem development can be detrimental to harmonious intergroup relations in ever-diversifying societies. We discuss how future psychological interventions aimed at enhancing self-esteem may promote support for a more inclusive society.

Combinatorial transcription factor activities on open chromatin induce embryonic heterogeneity in vertebrates.

During vertebrate gastrulation, mesoderm is induced in pluripotent cells, concomitant with dorsal-ventral patterning and establishing of the dorsal axis. We applied single-cell chromatin accessibility and transcriptome analyses to explore the emergence of cellular heterogeneity during gastrulation in Xenopus tropicalis. Transcriptionally inactive lineage-restricted genes exhibit relatively open chromatin in animal caps, whereas chromatin accessibility in dorsal marginal zone cells more closely reflects transcriptional activity. We characterized single-cell trajectories and identified head and trunk organizer cell clusters in early gastrulae. By integrating chromatin accessibility and transcriptome data, we inferred the activity of transcription factors in single-cell clusters and tested the activity of organizer-expressed transcription factors in animal caps, alone or in combination. The expression profile induced by a combination of Foxb1 and Eomes most closely resembles that observed in the head organizer. Genes induced by Eomes, Otx2, or the Irx3-Otx2 combination are enriched for maternally regulated H3K4me3 modifications, whereas Lhx8-induced genes are marked more frequently by zygotically controlled H3K4me3. Taken together, our results show that transcription factors cooperate in a combinatorial fashion in generally open chromatin to orchestrate zygotic gene expression.

Clonal Hematopoiesis and Its Impact on Human Health.

Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal expansion. This process occurs in several tissues but has been best studied in blood. Clonal hematopoiesis is associated with an increased risk of blood cancers, such as acute myeloid leukemia, which result if additional cooperating mutations occur. Surprisingly, it is also associated with an increased risk of nonmalignant diseases, such as atherosclerotic cardiovascular disease. This may be due to enhanced inflammation in mutated innate immune cells, which could be targeted clinically with anti-inflammatory drugs. Recent studies have uncovered other factors that predict poor outcomes in patients with clonal hematopoiesis, such as size of the mutant clone, mutated driver genes, and epigenetic aging. Though clonality is inevitable and largely a function of time, recent work has shown that inherited genetic variation can also influence this process. Clonal hematopoiesis provides a paradigm for understanding how age-related changes in tissue stem cell composition and function influence human health.

The impact of anorexia nervosa and BMI polygenic risk on childhood growth: A 20-year longitudinal population-based study.

Growth deviating from the norm during childhood has been associated with anorexia nervosa (AN) and obesity later in life. In this study, we examined whether polygenic scores (PGSs) for AN and BMI are associated with growth trajectories spanning the first two decades of life. AN PGSs and BMI PGSs were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 8,654). Using generalized (mixed) linear models, we associated PGSs with trajectories of weight, height, body mass index (BMI), fat mass index (FMI), lean mass index (LMI), and bone mineral density (BMD). Female participants with AN PGSs one standard deviation (SD) higher had, on average, 0.004% slower growth in BMI between the ages 6.5 and 24 years and a 0.4% slower gain in BMD between the ages 10 and 24 years. Higher BMI PGSs were associated with faster growth for BMI, FMI, LMI, BMD, and weight trajectories in both sexes throughout childhood. Female participants with both a high AN PGS and a low BMI PGS showed slower growth compared to those with both a low AN PGS and a low BMI PGS. We conclude that AN PGSs and BMI PGSs have detectable sex-specific effects on growth trajectories. Female participants with a high AN PGS and low BMI PGS likely constitute a high-risk group for AN, as their growth was slower compared to their peers with high PGSs on both traits. Further research is needed to better understand how the AN PGS and the BMI PGS co-influence growth during childhood and whether a high BMI PGS can mitigate the effects of a high AN PGS.

Long-term neuropsychological trajectories in children with epilepsy: does surgery halt decline?

Neuropsychological impairments are common in children with drug-resistant epilepsy. It has been proposed that epilepsy surgery might alleviate these impairments by providing seizure freedom; however, findings from prior studies have been inconsistent. We mapped long-term neuropsychological trajectories in children before and after undergoing epilepsy surgery, to measure the impact of disease course and surgery on functioning. We performed a retrospective cohort study of 882 children who had undergone epilepsy surgery at Great Ormond Street Hospital (1990-2018). We extracted patient information and neuropsychological functioning [obtained from IQ tests (domains: full-scale IQ, verbal IQ, performance IQ, working memory and processing speed) and tests of academic attainment (reading, spelling and numeracy)] and investigated changes in functioning using regression analyses. We identified 500 children (248 females) who had undergone epilepsy surgery [median age at surgery = 11.9 years, interquartile range = (7.8, 15.0)] and neuropsychological assessment. These children showed declines in all domains of neuropsychological functioning in the time leading up to surgery (all P-values ≤0.001; e.g. ßFSIQ = -1.9, SEFSIQ = 0.3, PFSIQ < 0.001). Children lost on average one to four points per year, depending on the domain considered; 27%-43% declined by ≥10 points from their first to their last preoperative assessment. At the time of presurgical evaluation, most children (46%-60%) scored one or more standard deviations below the mean (<85) on the different neuropsychological domains; 37% of these met the threshold for intellectual disability (full-scale IQ < 70). On a group level, there was no change in performance from pre- to postoperative assessment on any of the domains (all P-values ≥0.128). However, children who became seizure free through surgery showed higher postoperative neuropsychological performance (e.g. rrb-FSIQ = 0.37, P < 0.001). These children continued to demonstrate improvements in neuropsychological functioning over the course of their long-term follow-up (e.g. ßFSIQ = 0.9, SEFSIQ = 0.3, PFSIQ = 0.004). Children who had discontinued antiseizure medication treatment at 1-year follow-up showed an 8- to 13-point advantage in postoperative working memory, processing speed and numeracy, and greater improvements in verbal IQ, working memory, reading and spelling (all P-values ≤0.034) over the postoperative period compared with children who were seizure free and still receiving antiseizure medication. In conclusion, by providing seizure freedom and the opportunity for antiseizure medication cessation, epilepsy surgery might not only halt but reverse the downward trajectory that children with drug-resistant epilepsy display in neuropsychological functioning. To halt this decline as soon as possible or, potentially, to prevent it from occurring in the first place, children with focal epilepsy should be considered for epilepsy surgery as early as possible after diagnosis.

Multivariate and regional age-related change in basal ganglia iron in neonates.

In the perinatal period, reward and cognitive systems begin trajectories, influencing later psychiatric risk. The basal ganglia is important for reward and cognitive processing but early development has not been fully characterized. To assess age-related development, we used a measure of basal ganglia physiology, specifically brain tissue iron, obtained from nT2* signal in resting-state functional magnetic resonance imaging (rsfMRI), associated with dopaminergic processing. We used data from the Developing Human Connectome Project (n = 464) to assess how moving from the prenatal to the postnatal environment affects rsfMRI nT2*, modeling gestational and postnatal age separately for basal ganglia subregions in linear models. We did not find associations with tissue iron and gestational age [range: 24.29-42.29] but found positive associations with postnatal age [range:0-17.14] in the pallidum and putamen, but not the caudate. We tested if there was an interaction between preterm birth and postnatal age, finding early preterm infants (GA < 35 wk) had higher iron levels and changed less over time. To assess multivariate change, we used support vector regression to predict age from voxel-wise-nT2* maps. We could predict postnatal but not gestational age when maps were residualized for the other age term. This provides evidence subregions differentially change with postnatal experience and preterm birth may disrupt trajectories.

Resilience and Disaster: Flexible Adaptation in the Face of Uncertain Threat.

Disasters cause sweeping damage, hardship, and loss of life. In this article, we first consider the dominant psychological approach to disasters and its narrow focus on psychopathology (e.g., posttraumatic stress disorder). We then review research on a broader approach that has identified heterogeneous, highly replicable trajectories of outcome, the most common being stable mental health or resilience. We review trajectory research for different types of disasters, including the COVID-19 pandemic. Next, we consider correlates of the resilience trajectory and note their paradoxically limited ability to predict future resilient outcomes. Research using machine learning algorithms improved prediction but has not yet illuminated the mechanism behind resilient adaptation. To that end, we propose a more direct psychological explanation for resilience based on research on the motivational and mechanistic components of regulatory flexibility. Finally, we consider how future research might leverage new computational approaches to better capture regulatory flexibility in real time.

Climate Endgame: Exploring catastrophic climate change scenarios.

Prudent risk management requires consideration of bad-to-worst-case scenarios. Yet, for climate change, such potential futures are poorly understood. Could anthropogenic climate change result in worldwide societal collapse or even eventual human extinction? At present, this is a dangerously underexplored topic. Yet there are ample reasons to suspect that climate change could result in a global catastrophe. Analyzing the mechanisms for these extreme consequences could help galvanize action, improve resilience, and inform policy, including emergency responses. We outline current knowledge about the likelihood of extreme climate change, discuss why understanding bad-to-worst cases is vital, articulate reasons for concern about catastrophic outcomes, define key terms, and put forward a research agenda. The proposed agenda covers four main questions: 1) What is the potential for climate change to drive mass extinction events? 2) What are the mechanisms that could result in human mass mortality and morbidity? 3) What are human societies' vulnerabilities to climate-triggered risk cascades, such as from conflict, political instability, and systemic financial risk? 4) How can these multiple strands of evidence-together with other global dangers-be usefully synthesized into an "integrated catastrophe assessment"? It is time for the scientific community to grapple with the challenge of better understanding catastrophic climate change.

Long-term trajectories of sleep duration are associated with incident diabetes in middle-to-older-aged Black and White Americans.

AIMS/HYPOTHESIS: Both short and long sleep durations have been linked to higher diabetes risk. However, sleep duration may vary over time, and there has been limited research focusing on individual sleep trajectories and diabetes risk. There are substantial racial disparities in both sleep health and diabetes risk in the USA. Thus, it is important to understand the role of suboptimal sleep patterns in diabetes risk in different racial groups. METHODS: We assessed long-term trajectories of sleep duration and incident diabetes in 22,285 Black adults (mean age ± SD, 51.1 ± 8.2 years; 64.8% women) and 13,737 White adults (mean age ± SD, 54.4 ± 9.0 years; 63.8% women) enrolled in the Southern Community Cohort Study. Nine sleep trajectories were derived based on self-reported sleep duration at baseline and after a mean of 5 years of follow-up: normal-normal (reference), short-normal, normal-short, short-short, long-normal, normal-long, long-long, long-short and short-long. Diabetes was reported using a validated questionnaire. Multivariable-adjusted logistic regression was used to determine relationships between sleep trajectories and incident diabetes. RESULTS: When compared with the normal-normal trajectory, suboptimal sleep trajectories were associated with higher likelihoods of developing diabetes (OR; 95% CI: short-normal 1.19; 1.09, 1.31; normal-short 1.14; 1.02, 1.27; short-short 1.17; 1.07, 1.28; long-normal 1.13; 0.98, 1.30; normal-long 1.16; 1.00, 1.34; long-long 1.23; 1.02, 1.48; long-short 1.45; 1.19, 1.77; short-long 1.51; 1.28, 1.77). Stratified analyses by race and socioeconomic status (i.e. education and household income) showed that most suboptimal sleep trajectories were consistently associated with incident diabetes in all sociodemographic subgroups. We also noted potential interaction with race and education for several sleep trajectories (i.e. short-long and normal-short with race; long-long and short-short with education). CONCLUSIONS/INTERPRETATION: Adults with suboptimal sleep duration trajectories are more likely to develop incident diabetes. Future research is needed to study how sociodemographic factors modulate this relationship.

Trajectories of BMI before and after diagnosis of type 2 diabetes in a real-world population.

AIMS/HYPOTHESIS: Few studies have examined the clinical characteristics associated with changes in weight before and after diagnosis of type 2 diabetes. Using a large real-world cohort, we derived trajectories of BMI before and after diabetes diagnosis, and examined the clinical characteristics associated with these trajectories, including assessing the impact of pre-diagnosis weight change on post-diagnosis weight change. METHODS: We performed an observational cohort study using electronic medical records from individuals in the Scottish Care Information Diabetes Collaboration database. Two trajectories were calculated, based on observed BMI measurements between 3 years and 6 months before diagnosis and between 1 and 5 years after diagnosis. In the post-diagnosis trajectory, each BMI measurement was time-dependently adjusted for the effects of diabetes medications and HbA1c change. RESULTS: A total of 2736 individuals were included in the study. There was a pattern of pre-diagnosis weight gain, with 1944 individuals (71%) gaining weight overall, and 875 (32%) gaining more than 0.5 kg/m2 per year. This was followed by a pattern of weight loss after diagnosis, with 1722 individuals (63%) losing weight. Younger age and greater social deprivation were associated with increased weight gain before diagnosis. Pre-diagnosis weight change was unrelated to post-diagnosis weight change, but post-diagnosis weight loss was associated with older age, female sex, higher BMI, higher HbA1c and weight gain during the peri-diagnosis period. When considering the peri-diagnostic period (defined as from 6 months before to 12 months after diagnosis), we identified 986 (36%) individuals who had a high HbA1c at diagnosis but who lost weight rapidly and were most aggressively treated at 1 year; this subgroup had the best glycaemic control at 5 years. CONCLUSIONS/INTERPRETATION: Average weight increases before diagnosis and decreases after diagnosis; however, there were significant differences across the population in terms of weight changes. Younger individuals gained weight pre-diagnosis, but, in older individuals, type 2 diabetes is less associated with weight gain, consistent with other drivers for diabetes aetiology in older adults. We have identified a substantial group of individuals who have a rapid deterioration in glycaemic control, together with weight loss, around the time of diagnosis, and who subsequently stabilise, suggesting that a high HbA1c at diagnosis is not inevitably associated with a poor outcome and may be driven by reversible glucose toxicity.

Universal principles of lineage architecture and stem cell identity in renewing tissues.

Adult tissues in multicellular organisms typically contain a variety of stem, progenitor and differentiated cell types arranged in a lineage hierarchy that regulates healthy tissue turnover. Lineage hierarchies in disparate tissues often exhibit common features, yet the general principles regulating their architecture are not known. Here, we provide a formal framework for understanding the relationship between cell molecular 'states' and cell 'types', based on the topology of admissible cell state trajectories. We show that a self-renewing cell type - if defined as suggested by this framework - must reside at the top of any homeostatic renewing lineage hierarchy, and only there. This architecture arises as a natural consequence of homeostasis, and indeed is the only possible way that lineage architectures can be constructed to support homeostasis in renewing tissues. Furthermore, under suitable feedback regulation, for example from the stem cell niche, we show that the property of 'stemness' is entirely determined by the cell environment, in accordance with the notion that stem cell identities are contextual and not determined by hard-wired, cell-intrinsic characteristics. This article has an associated 'The people behind the papers' interview.

Predictive Models for Health Deterioration: Understanding Disease Pathways for Personalized Medicine.

Artificial intelligence (AI) and machine learning (ML) methods are currently widely employed in medicine and healthcare. A PubMed search returns more than 100,000 articles on these topics published between 2018 and 2022 alone. Notwithstanding several recent reviews in various subfields of AI and ML in medicine, we have yet to see a comprehensive review around the methods' use in longitudinal analysis and prediction of an individual patient's health status within a personalized disease pathway. This review seeks to fill that gap. After an overview of the AI and ML methods employed in this field and of specific medical applications of models of this type, the review discusses the strengths and limitations of current studies and looks ahead to future strands of research in this field. We aim to enable interested readers to gain a detailed impression of the research currently available and accordingly plan future work around predictive models for deterioration in health status.

Long-term quantitative hepatitis B surface antigen (HBsAg) trajectories in persons with and without HBsAg loss on tenofovir-containing antiretroviral therapy.

OBJECTIVES: Improving the understanding of the patterns of quantitative hepatitis B surface antigen (qHBsAg) trajectories associated with HBsAg loss is important in light of novel anti-hepatitis B virus agents being developed. We evaluated long-term qHBsAg trajectories in persons with HIV and HBV during tenofovir-containing antiretroviral therapy in the Swiss HIV Cohort Study. METHODS: We included 29 participants with and 29 without HBsAg loss, defined as qHBsAg <0.05 IU/mL. We assessed qHBsAg decline during therapy in both groups and used agglomerative hierarchical clustering to identify different qHBsAg trajectory profiles in persons with HBsAg loss. RESULTS: The median follow-up time was 11.9 years (IQR 8.4-14.1), and the median time to HBsAg loss was 48 months (IQR 12-96). Among participants with HBsAg loss, 79% had a qHBsAg decline ≥1 log10 IU/mL 2 years after starting tenofovir. The trajectories in qHBsAg levels during tenofovir therapy were heterogeneous, characterized by five distinct profiles. Among participants without HBsAg loss, only 7% had a qHBsAg decline ≥1 log10 IU/ml after 2 years. CONCLUSIONS: Most persons with HIV who experienced HBsAg loss had an early decline in qHBsAg levels, with diverse trajectories during long-term tenofovir therapy. In persons without HBsAg loss, qHBsAg levels remained remarkably stable over time.

Anti-Spike IgG antibodies as correlates of protection against SARS-CoV-2 infection in the pre-Omicron and Omicron era.

Anti-Spike IgG antibodies against SARS-CoV-2, which are elicited by vaccination and infection, are correlates of protection against infection with pre-Omicron variants. Whether this association can be generalized to infections with Omicron variants is unclear. We conducted a retrospective cohort study with 8457 blood donors in Tyrol, Austria, analyzing 15,340 anti-Spike IgG antibody measurements from March 2021 to December 2022 assessed by Abbott SARS-CoV-2 IgG II chemiluminescent microparticle immunoassay. Using a Bayesian joint model, we estimated antibody trajectories and adjusted hazard ratios for incident SARS-CoV-2 infection ascertained by self-report or seroconversion of anti-Nucleocapsid antibodies. At the time of their earliest available anti-Spike IgG antibody measurement (median November 23, 2021), participants had a median age of 46.0 years (IQR 32.8-55.2), with 45.3% being female, 41.3% having a prior SARS-CoV-2 infection, and 75.5% having received at least one dose of a COVID-19 vaccine. Among 6159 participants with endpoint data, 3700 incident SARS-CoV-2 infections with predominantly Omicron sublineages were recorded over a median of 8.8 months (IQR 5.7-12.4). The age- and sex-adjusted hazard ratio for SARS-CoV-2 associated with having twice the anti-Spike IgG antibody titer was 0.875 (95% credible interval 0.868-0.881) overall, 0.842 (0.827-0.856) during 2021, and 0.884 (0.877-0.891) during 2022 (all p < 0.001). The associations were similar in females and males (Pinteraction = 0.673) and across age (Pinteraction = 0.590). Higher anti-Spike IgG antibody titers were associated with reduced risk of incident SARS-CoV-2 infection across the entire observation period. While the magnitude of association was slightly weakened in the Omicron era, anti-Spike IgG antibody continues to be a suitable correlate of protection against newer SARS-CoV-2 variants.

Childhood infections, asthma and allergy trajectories, and chronic rhinosinusitis in middle age: A prospective cohort study across six decades.

INTRODUCTION: Evidence on the early life risk factors of adult CRS, and the history of asthma and allergies across the life course, is limited. AIM: To investigate relationships between respiratory infective/allergic conditions in childhood, and asthma and allergies across the life course and CRS in middle age. METHODS: Data were from the population-based Tasmanian Longitudinal Health Study (TAHS) cohort, first studied in 1968 when aged 6-7 years (n = 8583) and serially followed into middle age (n = 3609). Using a well-accepted epidemiological definition, participants were assigned a CRS-severity subtype at age 53: no sinusitis/CRS (reference); past doctor diagnosis only; current symptoms without doctor diagnosis; and doctor-diagnosed CRS with current symptoms. Relationships with infective/allergic respiratory illnesses at age 7, and previously published asthma-allergy trajectories from 7 to 53 years, were examined using multinominal regression. RESULTS: In middle age, 5.8% reported current CRS symptoms with 2.5% doctor-diagnosed. Childhood conditions associated with symptomatic doctor-diagnosed CRS included frequent head colds (multinomial odds ratio [mOR] = 2.04 (95% confidence interval [95% CI]: 1.24, 3.37)), frequent tonsillitis (mOR = 1.61 [95% CI: 1.00, 2.59]) and current childhood asthma (mOR = 2.23 [95% CI: 1.25, 3.98]). Life course trajectories that featured late-onset or persistent asthma and allergies were associated with all CRS subtypes in middle age; early-onset persistent asthma and allergies (mOR = 6.74, 95% CI: 2.76, 16.4); late-onset asthma allergies (mOR = 15.9, 95% CI: 8.06, 31.4), and late-onset hayfever (mOR = 3.02, 95% CI: 1.51, 6.06) were associated with symptomatic doctor-diagnosed CRS. CONCLUSION: Current asthma, frequent head colds and tonsillitis at age 7 could signal a susceptible child who is at higher risk for CRS in mid-adult life and who might benefit from closer monitoring and/or proactive management. Concurrent asthma and allergies were strongly associated and are potential treatable traits of adult CRS.