Case-control Analysis Research Articles

An AluYa5 Insertion in the 3′UTR of COL4A1 and Cerebral Small Vessel Disease

Cerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes. To identify novel genes and mechanisms associated with familial CSVD. This 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset <age 55 years and ≥1 first-degree relative with CSVD) were referred to the French cerebrovascular referral center between 2013 and 2023. The large-scale gnomAD structural variant database and 467 healthy individuals of French ancestry were used as a control group. A pathogenic AluYa5 insertion was identified within the COL4A1 3'UTR in the 2 large families with CSVD. Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), Western blot, and long-read RNA sequencing were used to investigate outcomes associated with the insertion using patient fibroblasts. Clinical and magnetic resonance imaging features of probands with variants and available relatives were assessed. Among 246 probands (141 females [57.3%]; median [IQR] age at referral, 56 [49-64] years), 7 patients of French ancestry carried the insertion. This insertion was absent in 467 healthy French individuals in a control group (odds ratio, ∞; 95% CI, 2.78 to ∞; P = 5 × 10-4) and 10 847 individuals from the gnomAD structural variant database (odds ratio, ∞; 95% CI, 64.77 to ∞; P = 2.42 × 10-12). In these 7 patients' families, 19 family members with CSVD carried the insertion. RT-qPCR and Western blot showed an upregulation of COL4A1 mRNA (10.6-fold increase; 95% CI, 1.4-fold to 17.1-fold increase) and protein levels (2.8-fold increase; 95% CI, 2.1-fold to 3.5-fold increase) in patient vs control group fibroblasts. Long-read RNA sequencing data showed that the insertion was associated with perturbation in the use of canonical COL4A1 polyadenylation signals (approximately 87% of isoforms transcribed from the wild type allele vs 5% of isoforms transcribed from the allele with the insertion used the 2 distal canonical polyadenylation signals). The main clinical feature of individuals with CSVD was the recurrence of pontine ischemic lesions starting at an early age (17 of 19 patients [89.5%]). This study found a novel mechanism associated with COL4A1 upregulation and a highly penetrant adult-onset CSVD. These findings suggest that quantitative alterations of the cerebrovascular matrisome are associated with CSVD pathogenesis, with diagnostic and therapeutic implications.

Incidence and Risk Factors Epilepsy in Patients with Dementia: A Population-Based Study Using Regional Healthcare Databases in Umbria.

Dementia is prevalent among the elderly, also representing a risk for seizures/epilepsy. Estimations of epilepsy risk in dementia patients are not widely available. Our research aims to ascertain the incidence of epilepsy and its associated risk factors in subjects with dementia in the Umbria region, based on data from healthcare databases. In this retrospective study based on the healthcare administrative database of Umbria, we identified all patients diagnosed with dementia from 2013 to 2017, based on ICD-9-CM codes. For epilepsy ascertainment, we used a validated algorithm that required an EEG and the prescription of one or more anti-seizure medications post-dementia diagnosis. A case-control analysis was conducted, matching five non-dementia subjects by gender and age to each dementia patient. Cox proportional hazards models were then utilized in the analysis. We identified 7,314 dementia cases, also including 35,280 age- and sex-matched control subjects. Out of patients with dementia, 148 individuals (2.02%) were diagnosed with epilepsy. We observed a progressive increase in the cumulative incidence of seizures over time, registering 1.45% in the first year following the diagnosis, and rising to 1.96% after three years. Analysis using Cox regression revealed a significant association between the development of epilepsy and dementia (HR = 4.58, 95% CI = 3.67-5.72). Additional risk factors were male gender (HR = 1.35, 95% CI = 1.07-1.69) and a younger age at dementia onset (HR = 1.03, 95% CI=1.02-1.04). Dementia increases epilepsy risk, especially with early onset and male gender. Clinicians should have a low threshold to suspect seizures in dementia cases.

RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses

Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

A comparison of strategies for identifying patients at risk for carbapenem-resistant or extended β-lactam-resistant Pseudomonas aeruginosa.

To assess risk factors for carbapenem-resistant Pseudomonas aeruginosa (CR) and extended-β-lactam-resistant P. aeruginosa (EBR) infection/colonization, and to develop and compare tools for predicting isolation of CR and EBR from clinical cultures. This retrospective study analysed hospitalized patients with positive P. aeruginosa cultures between 2015 and 2021. Two case-control analyses were performed to identify risk factors and develop scoring tools for distinguishing patients with CR versus carbapenem-susceptible (CS) P. aeruginosa and EBR versus CS P. aeruginosa. The performance of institutionally derived scores, externally derived scores and the presence/absence of key risk factors to predict CR and EBR were then compared. A total of 2379 patients were included. Of these, 8.3% had a positive culture for CR, 5.0% for EBR and 86.7% for CS P. aeruginosa. There was substantial overlap in risk factors for CR and EBR. Institutional risk scores demonstrated modestly higher area under the ROC curve values than external scores for predicting CR (0.67 versus 0.58) and EBR (0.76 versus 0.70). Assessing the presence/absence of ≥1 of the two strongest predictors (prior carbapenem use or CR isolation within 90 days) was slightly inferior to scoring tools for predicting CR, and comparable for predicting EBR. Clinicians concerned about CR in P. aeruginosa should consider the likelihood of EBR when making treatment decisions. A simple approach of assessing recent history of CR isolation or carbapenem usage performed similarly to more complex scoring tools and offers a more pragmatic way of identifying patients who require coverage for resistant P. aeruginosa.

Metabolic Profile and Long-Term Risk of Depression, Anxiety, and Stress-Related Disorders

Biomarkers of lipid, apolipoprotein, and carbohydrate metabolism have been previously suggested to be associated with the risk for depression, anxiety, and stress-related disorders, but results are inconsistent. To examine whether the biomarkers of carbohydrate, lipid, and apolipoprotein metabolism are associated with the risk of depression, anxiety, and stress-related disorders. This population-based cohort study with longitudinal data collection assessed 211 200 participants from the Apolipoprotein-Related Mortality Risk (AMORIS) cohort who underwent occupational health screening between January 1, 1985, and December 31, 1996, mainly in the Stockholm region in Sweden. Statistical analysis was performed during 2022 to 2023. Lipid, apolipoprotein, and carbohydrate biomarkers measured in blood. The associations between biomarker levels and the risk of developing depression, anxiety, and stress-related disorders through the end of 2020 were examined using Cox proportional hazards regression models. In addition, nested case-control analyses were conducted within the cohort, including all incident cases of depression, anxiety, and stress-related disorders, and up to 10 control individuals per case who were individually matched to the case by year of birth, sex, and year of enrollment to the AMORIS cohort, using incidence density sampling. Population trajectories were used to illustrate the temporal trends in biomarker levels for cases and controls. A total of 211 200 individuals (mean [SD] age at first biomarker measurement, 42.1 [12.6] years; 122 535 [58.0%] male; 188 895 [89.4%] born in Sweden) participated in the study. During a mean (SD) follow-up of 21.0 (6.7) years, a total of 16 256 individuals were diagnosed with depression, anxiety, or stress-related disorders. High levels of glucose (hazard ratio [HR], 1.30; 95% CI, 1.20-1.41) and triglycerides (HR, 1.15; 95% CI, 1.10-1.20) were associated with an increased subsequent risk of all tested psychiatric disorders, whereas high levels of high-density lipoprotein (HR, 0.88; 95% CI, 0.80-0.97) were associated with a reduced risk. These results were similar for male and female participants as well as for all tested disorders. The nested case-control analyses demonstrated that patients with depression, anxiety, or stress-related disorders had higher levels of glucose, triglycerides, and total cholesterol during the 20 years preceding diagnosis, as well as higher levels of apolipoprotein A-I and apolipoprotein B during the 10 years preceding diagnosis, compared with control participants. In this cohort study of more than 200 000 participants, high levels of glucose and triglycerides and low levels of high-density lipoprotein were associated with future risk of depression, anxiety, and stress-related disorders. These findings may support closer follow-up of individuals with metabolic dysregulations for the prevention and diagnosis of psychiatric disorders.

451 Identification of candidate sudden arrhythmic death -causing variants in a spontaneous animal model

OBJECTIVES/GOALS: 1. Identify candidate AN-SAD-causing variants. 2. Estimate the variant effect size of and genotypic relative risk for arrhythmias and AN-SAD. METHODS/STUDY POPULATION: We performed whole genome sequencing (WGS) on 59 Thoroughbred AN-SAD cases and 58 controls. WGS was mapped and variants identified using a modified version of the Genome Analysis Toolkit best practices. Variants will be selected based on case-control analysis using SnpSift and presence in candidate genes. The top 400 candidate AN-SAD-causing variants will be selected based on being common in cases and rare or absent in controls, and uncommon (allele frequency less than 10%) in a catalog of genetic variation for the horse. The 400 variants will be genotyped in our cohort of 1,200 racehorses to determine variant effect size and genotypic relative risk. RESULTS/ANTICIPATED RESULTS: 17,182,003 variants were identified. 230 variants had significantly different allele frequencies (AF) between cases and controls (SnpSift). 723 high and 4,824 moderate impact variants were identified in 1,072 candidate genes. 3,681 variants were present at an AF 10% in the equine variant catalog. Variant effect prediction is ongoing to select the final 400 variants. Cardiac phenotyping (cardiac auscultation and ECG before, during, and after exercise) was performed on 790 racehorses and we will have 1,200 racehorses with cardiac phenotypes and/or AN-SAD. We will genotype the top 400 candidate AN-SAD-causing variants in these 1,200 horses to identify variants of large effect size. DISCUSSION/SIGNIFICANCE: Identification of candidate AN-SAD variants in a spontaneous animal model can facilitate interpretation of candidate variants in humans and horses. This project will provide further support for the racehorse AN-SAD model and will support future work exploring the genetic and environmental risk factors contributing to AN-SAD in this animal model.

Comparison of Differences in Cohort (Forward) and Case Control (Backward) Methodologic Approaches for Validation of the Hypotension Prediction Index.

The Hypotension Prediction Index (the index) software is a machine learning algorithm that detects physiologic changes that may lead to hypotension. The original validation used a case control (backward) analysis that has been suggested to be biased. This study therefore conducted a cohort (forward) analysis and compared this to the original validation technique. A retrospective analysis of data from previously reported studies was conducted. All data were analyzed identically with two different methodologies, and receiver operating characteristic curves were constructed. Both backward and forward analyses were performed to examine differences in area under the receiver operating characteristic curves for the Hypotension Prediction Index and other hemodynamic variables to predict a mean arterial pressure (MAP) less than 65 mmHg for at least 1 min 5, 10, and 15 min in advance. The analysis included 2,022 patients, yielding 4,152,124 measurements taken at 20-s intervals. The area under the curve for the index predicting hypotension analyzed by backward and forward methodologies respectively was 0.957 (95% CI, 0.947 to 0.964) versus 0.923 (95% CI, 0.912 to 0.933) 5 min in advance, 0.933 (95% CI, 0.924 to 0.942) versus 0.923 (95% CI, 0.911 to 0.933) 10 min in advance, and 0.929 (95% CI, 0.918 to 0.938) versus 0.926 (95% CI, 0.914 to 0.937) 15 min in advance. No variable other than MAP had an area under the curve greater than 0.7. The areas under the curve using forward analysis for MAP predicting hypotension 5, 10, and 15 min in advance were 0.932 (95% CI, 0.920 to 0.940), 0.929 (95% CI, 0.918 to 0.938), and 0.932 (95% CI, 0.921 to 0.940), respectively. The R2 for the variation in the index due to MAP was 0.77. Using an updated methodology, the study found that the utility of the Hypotension Prediction Index to predict future hypotensive events is high, with an area under the receiver operating characteristics curve similar to that of the original validation method.

Risk Factors for Incident Polycystic Ovary Syndrome Diagnosis.

Objective: While highly prevalent, risk factors for incident polycystic ovary syndrome (PCOS) are poorly delineated. Using a population-based cohort, we sought to identify predictors of incident PCOS diagnosis. Materials and Methods: A matched case-control analysis was completed utilizing patients enrolled in Kaiser Permanente Washington from 2006 to 2019. Inclusion criteria included female sex, age 16-40 years, and ≥3 years of prior enrollment with ≥1 health care encounter. PCOS cases were identified using International Classification of Diseases codes. For each incident case (n = 2,491), 5 patients without PCOS (n = 12,455) were matched based on birth year and enrollment status. Potential risk factors preceding diagnosis included family history of PCOS, premature menarche, parity, race, weight gain, obesity, valproate use, metabolic syndrome, epilepsy, prediabetes, and types 1 and 2 diabetes. Potential risk factors for incident PCOS diagnosis were assessed with univariate and multivariable conditional logistic regressions. Results: Mean age of PCOS cases was 26.9 years (SD 6.8). PCOS cases, compared with non-PCOS, were more frequently nulliparous (70.9% versus 62.4%) and in the 3 years prior to index date were more likely to have obesity (53.8% versus 20.7%), metabolic syndrome (14.5% versus 4.3%), prediabetes (7.4% versus 1.6%), and type 2 diabetes (4.1% versus 1.7%) (p < 0.001 for all comparisons). In multivariable models, factors associated with higher risk for incident PCOS included the following: obesity (compared with nonobese) Class I-II (body-mass index [BMI], 30-40 kg/m2; odds ratio [OR], 3.8; 95% confidence interval [CI], 3.4-4.2), Class III (BMI > 40 kg/m2; OR, 7.5, 95% CI, 6.5-8.7), weight gain (compared with weight loss or maintenance) of 1-10% (OR, 1.7, 95% CI, 1.3-2.1), 10-20% (OR, 1.9; 95% CI, 1.5-2.4), and >20% (OR, 2.6; 95% CI, 1.9-3.6), prediabetes (OR, 2.7; 95% CI, 2.1-3.4), and metabolic syndrome (OR, 1.8: 95% CI, 1.5-2.1). Conclusion: Excess weight gain, obesity, and metabolic dysfunction may play a key role in the ensuing phenotypic expression of PCOS. Treatment and prevention strategies targeted at preventing weight gain in early reproductive years may help reduce the risk of this syndrome.

Comparing Three-Dimensional Digitally Enabled Intraoperative OCT With Conventional Microscope-Integrated OCT in Vitreoretinal Surgery: A Post Hoc Analysis of the DISCOVER Study.

This study compared the surgeon experience between conventional microscope-integrated intraoperative optical coherence tomography (iOCT) and digitally enabled microscope-integrated iOCT in vitreoretinal surgery. This is a post hoc case-control analysis of the DISCOVER study. Conventional microscope-integrated iOCT (Rescan 700, Zeiss) was compared with digitally enabled iOCT (Artevo 800, Zeiss). Compared variables included surgical field-based visualization (ie, ocular heads-up display in the conventional group; three-dimensional screen-based visualization in the digital iOCT group) and non-surgical field-based visualization (ie, review on the external two-dimensional monitor). A total of 200 patients were included. Surgical field-based visualization of iOCT was significantly higher in the digitally enabled group (P < 0.0001). Required endoillumination level was significantly lower in the digital iOCT group (P < 0.0001). Surgeons reported "significant" back discomfort and headache more frequently when using conventional iOCT (P = 0.003 and P = 0.001, respectively). Digitally enabled iOCT resulted in greater surgical visualization efficiency, appeared to require a lower illumination level, and may provide advantages for ergonomic-related discomfort. [Ophthalmic Surg Lasers Imaging Retina 2024;55:270-277.].

Exploring autism spectrum disorder (ASD) and attention deficit disorder (ADD/ADHD) in children exposed to polybrominated biphenyl.

Although the causes of attention-deficit/hyperactivity disorder (ADHD) and autism have not been identified, exposure to endocrine-disrupting chemicals, such as polybrominated biphenyl (PBB), during fetal development and early life has been suspected to impact neurological development. This study aims to investigate the association between prenatal and early life exposure to PBB and the development of ADHD and autism later in life. Data from the Michigan PBB Registry, a cohort of Michigan residents who had been exposed to PBB in a mass contamination event in 1973, was leveraged for this nested case-control analysis among two distinct samples: (1) Those who self-reported ADHD or autism diagnosis, and (2) mothers who reported their child's ADHD or autism diagnosis. PBB exposure was measured in participants of the PBB Registry, and the mother's PBB level was used in mother-reported analyses. Cases were matched with controls by sex and year of birth. Conditional logistic regression models were used to estimate the association between PBB level and case status. PBB levels were higher among those who were exposed in early life compared with those exposed in utero (geometric mean: 0.300 ng/ml vs. 0.016 ng/ml). Among women in this cohort, a higher than expected proportion of self-reported ADHD diagnosis (11.11%), compared with population estimates. PBB was not associated with ADHD or autism in either self-reported or mother-reported analyses. This study adds to the sparse literature about prenatal and early life exposure to PBB-153 and ADHD and autism. Future studies should examine potential effect modification by sex.

Association between irritable bowel syndrome and Parkinson’s disease by Cohort study and Mendelian randomization analysis

This study aimed to investigate the association between irritable bowel syndrome (IBS) and Parkinson’s disease (PD) utilizing prospective cohort study and Mendelian randomization. The dataset contained a substantial cohort of 426,911 participants from the UK Biobank, discussing the association between IBS and PD with Cox proportional hazards models and case-control analysis while adjusting for covariates such as age, gender, ethnicity and education level. In univariate Cox regression model, the risk of PD was reduced in IBS patients (HR: 0.774, 95%CI: 0.625–0.956, P = 0.017), but the statistical significance diminished in the three models after adjusting for other variables. In a few subgroup analyses, IBS patients are less likely to develop into PD, and patients diagnosed with IBS after 2000 also had a lower risk (HR: 0.633, 95%CI: 0.403–0.994, P = 0.047) of subsequently developing PD. In addition, we matched five healthy control participants based on gender and age at the end of the study for each IBS patient diagnosed during the follow-up period, and logistic regression results (OR:1.239, 95%CI: 0.896–1.680, P = 0.181) showed that IBS was not associated with the risk of PD. Mendelian randomization did not find significant evidence of the causal relationship between IBS and Parkinson’s disease (OR: 0.801, 95%CI: 0.570–1.278, P = 0.204). Overall, we suggest that IBS status is not associated with the risk of developing PD, and that these findings provide valuable insights into the clinical management and resource allocation of patients with IBS.

Impact of nursing home admission on in-hospital mortality and morbidity and length of stay: A case-control analysis

MethodsWe examined a quality measurement database containing de-identified cases from across Switzerland. All patients with a complete dataset treated between 2015 and 2021 were included. A case-control matching method (same age, comorbidity, sex, diagnosis, admission type, and insurance coverage) was used to evaluate the impact of pre-admission residence. The outcomes measured included complications during hospitalization, in-hospital mortality, and length of stay. Statistical significance was set at a p-value of <0.001 due to our large size of analyzed cases. ResultsWe noted a higher prevalence of comorbidities and higher ASA scores among the 2130 (1.9 %) patients admitted from long-term care facilities (LTCFs). Complication rates in the LTCF group were higher than those in the home group (15 % vs. 6.9 %, p = <0.001). Pneumonia was the most frequent complication in both groups. The in-hospital mortality rate was also significantly higher in the LTCF group than the home group (5.8 % vs. 1.1 %, p = <0.001). However, matched-pair analysis showed no significant difference in complication rates and overall mortality between the two groups. Patients admitted from LTCFs even had a shorter hospital stay (7.5 ± 8.7 days vs. 8.9 ± 7.9 days, p = <0.004). ConclusionsDespite higher complication and mortality rates among LTCF patients, the matched-pair analysis showed no significant differences in these rates between the two groups. However, patients from LTCFs were discharged earlier, indicating the effectiveness of Switzerland's care system for older adults living in nursing homes.

Low-Carbohydrate Diet Score and Risk of Hepatocellular Carcinoma: Findings from a Prospective Cohort Study.

In a large cohort study of more than 63,000 Chinese Singaporeans, we found that a diet with lower carbohydrate and higher animal fat and protein was associated with increased risk of HCC, suggesting that dietary modification could be an effective strategy in primary prevention to reduce the HCC burden.

How to support general practitioners to better detect sarcopenia among older adults: a nested case-control analysis.

This study explores correlations of sarcopenia and its proxies, such as history of falls, asthenia, and ambulation issues, with frailty levels among older adults in primary care. In a cohort of 546,590 patients aged 60years or older, "definite" sarcopenia cases were operationally defined through the use of non-specific diagnostic codes coupled with inspection of free-texts. Proxies of sarcopenia, such as falls history, asthenia, and ambulation issues were considered as well. Frailty was calculated using an Index intended to primary care. Overall, 171 definite sarcopenia cases were found, rising to 51,520 cases when including proxies (9.4% prevalence). There was a significant association between severe frailty and increased odds of sarcopenia, consistently observed across different eventdefinitions. Sarcopenia was strongly associated with severe frailty in primary care. The history of falls, asthenia, and ambulation issues were reliable proxies to raise the suspect of sarcopenia. Improved strategies for sarcopenia detection, focusing on specific indicators within severely frail individuals, are warranted.

Abstract 6119: Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium

Abstract Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks target treatments. It has been reported that African-American women have a higher incidence of TNBC and are diagnosed at an earlier age than women of European ancestry. This disparity may be attributed to both genetic and non-genetic risk factors that are associated with the African ancestry. In this study, we investigated whether genotype-derived African ancestry might be related to an elevated risk of TNBC, with adjustments for several known genetic and non-genetic risk factors. Included in the study are self-reported Black breast cancer patients diagnosed with TNBC (n =2,292) or estrogen receptor (ER)-positive cancer (n =7,863) and 9,324 controls included in the African-ancestry Breast Cancer Genetics (AABCG) Consortium. We estimated the global ancestry by Admixture and the local ancestry by FLARE, using reference of the European- and African-ancestry samples from the 1000 Genome Project. Odds ratios (OR) and 95% confidence interval (CI) per ten percent increase of the global African ancestry proportion were estimated using logistic regressions comparing TNBC with controls (case-control analyses) or with ER-positive cases (case-case analyses), adjusted for age. Similar analyses were conducted for the local African ancestry proportion at each of the 12 genomic regions that were identified in AABCG in relation to TNBC risk. Results for each participating study were meta-analyzed using fixed or random effect models. We further adjusted for non-genetic risk factors including body mass index (BMI), number of live births, breastfeeding, and menopausal status. A polygenic risk score (PRS) was constructed using 13 independent risk variants at the 12 TNBC risk loci. The PRS was additionally adjusted to investigate whether these risk variants mediated the association of African ancestry with TNBC risk. No significant association was observed between TNBC risk and global African ancestry proportion (OR: 1.03, 95% CI: 0.98-1.08) in case-control comparisons. Compared with ER-positive cases, however, TNBC cases had a higher global African ancestry, resulted in an OR of 1.09 (95% CI: 1.04, 1.13, P =5.35×10-5). A similar association was observed with additional adjustment for non-genetic risk factors, with an OR of 1.08 (95% CI: 1.03, 1.12, P =0.003). Similar patterns were also found for local ancestry proportion at six of the 12 TNBC risk loci (P &amp;lt;0.05). Further adjustment for the PRS attenuated the association between global ancestry and a TNBC diagnosis in case-case comparisons (OR: 1.05, 95% CI: 1.01, 1.10, P =0.013). Our study suggests that women with a higher African ancestry are more likely to be diagnosed with a TNBC than ER-positive breast cancer and genetic factors identified to date partially explain this association. Citation Format: Guochong Jia, Lili Liu, Julie R. Palmer, Christopher A. Haiman, Wei Zheng. Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6119.

Abstract 1060: Circulating early myeloid derived suppressor cells as biomarkers for early detection of lung cancer

Abstract Background. Lung cancer (LC) patients, despite innovative cancer treatments such as target and immune-therapies, still have the poorest five-year survival rate. In this context the possibility of an early detection can anticipate therapeutic intervention, avoiding aggressive therapies thus prolonging disease-free and overall survival. Therefore, the identification of new circulating early biomarkers still represents a relevant clinical need. Methods. Lung cancer (LC) patients (n=63) and heavy smokers (HS) cancer free-subjects (n=52) were evaluated for the enrichment of specific subtypes of myeloid cells. Circulating early myeloid derived suppressor cells (eMDSCs) and low-density neutrophils (LDNs) were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). Early MDSCs were defined as CD11b+CD33+CD15-CD14- cells among Lineage negative (Lin-) HLA-DR- PBMCs, whereas LDNs were defined as CD66b+CD15+ cells within the gate of CD11b+ PBMCs. Mature and immature subtypes were discriminated according to the expression of CD10. Results. Performing a sex- and smoking -matched case-control analysis in 39 LC and 39 HS subjects we were able to compare the capacity of specific myeloid population to discriminate lung cancer patients from heavy smokers. The analysis showed significantly higher values of eMDSC (OR=1.12; 95% Confidence Interval (CI) 1.03-1.21), total LDN (CD66b+CD15+; OR=1.23; 95%CI 1.04-1.45) and of mature CD10+ LDN (OR=1.30; 95%CI 1.05-1.61). Moreover, within the overall cohort of 63 LC patients, we analyzed the distributions of the different myeloid populations according to stage (I-II vs III-IV). In this comparison, total LDN (CD66b+CD15+; Kruskal-Wallis (KW) Test p-value=0.014), and mature CD10+ LDN (KW test p-value=0.006) showed significant different distributions according to tumor stage, observing higher values in patients with advanced stage. On the contrary, no difference among stages was observed for the eMDSC population. Conclusions. These findings point to eMDSCs as an early marker for lung cancer detection whereas LDN could be as well associated with disease progression. Citation Format: Orazio Fortunato, Barbara Bassani, Mara Lecchi, Paolo Verderio, Ugo Pastorino, Gabriella Sozzi, Mario Paolo Colombo, Sabina Sangaletti. Circulating early myeloid derived suppressor cells as biomarkers for early detection of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1060.

Health selection into migration from Poland to the Netherlands: a matched case–control analysis

ABSTRACT This study sheds light on health selection into migration from Poland to the Netherlands. Scholars have highlighted health as an important resource to overcome barriers to migration, and suggested that health selection into migration may particularly be expected under specific conditions, e.g. when geographical distances between origin and destination countries are large and when immigration policies in the destination country are restrictive. I assessed whether health selection into migration was also present in a within–European Union migration flow to which such conditions do not apply. I analyzed data from four surveys of Polish migrants in the Netherlands (n = 1,210) and European Social Survey data on Polish natives who stayed in Poland (n = 1,843). I performed conditional logistic regression analyses for matched case–control groups to model health selection into migration. Better health status was associated with a greater propensity to migrate from Poland to the Netherlands. Additional research is needed to determine whether the lower expected returns on migration for people in suboptimal health make them less inclined to migrate than their healthier counterparts, also in the absence of restrictive immigration policies and excessive geographical distances between origin and destination countries.

Longitudinal Change in Serum Neurofilament Light Chain in Type 2 Diabetes and Early Diabetic Polyneuropathy: ADDITION-Denmark.

To investigate the longitudinal development of neurofilament light chain (NfL) levels in type 2 diabetes with and without diabetic polyneuropathy (+/-DPN) and to explore the predictive potential of NfL as a biomarker for DPN. We performed retrospective longitudinal case-control analysis of data from 178 participants of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care-Denmark (ADDITION-Denmark) cohort of people with screen-detected type 2 diabetes. Biobank samples acquired at the ADDITION-Denmark 5- and 10-year follow-ups were analyzed for serum NfL (s-NfL) using single-molecule array, and the results were compared with established reference material to obtain NfL z-scores. DPN was diagnosed according to Toronto criteria for confirmed DPN at the 10-year follow-up. s-NfL increased over time in +DPN (N = 39) and -DPN participants (N = 139) at levels above normal age-induced s-NfL increase. Longitudinal s-NfL change was greater in +DPN than in -DPN participants (17.4% [95% CI 4.3; 32.2] or 0.31 SD [95% CI 0.03; 0.60] higher s-NfL or NfL z-score increase in +DPN compared with -DPN). s-NfL at the 5-year follow-up was positively associated with nerve conduction studies at the 10-year follow-up (P = 0.02 to <0.001), but not with DPN risk. Areas under the curve (AUCs) for s-NfL were not inferior to AUCs for the Michigan Neuropathy Screening Instrument questionnaire score or vibration detection thresholds. Higher yearly s-NfL increase was associated with higher DPN risk (odds ratio 1.36 [95% CI 1.08; 1.71] per 1 ng/L/year). Our findings suggest that preceding s-NfL trajectories differ slightly between those with and without DPN and imply a possible biomarker value of s-NfL trajectories in DPN.

Early Intravenous Magnesium Sulfate and Its Impact on Cerebral Vasospasm as well as Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: A Retrospective Matched Case-Control Analysis

Magnesium sulfate (MgSO4) is a potential neuroprotective agent for patients with aneurysmal subarachnoid hemorrhage (SAH). We analyzed the effect of early application of intraoperative intravenous MgSO4 and compared cerebral vasospasm (CV), delayed cerebral ischemia (DCI), and neurological outcome in 2 patient cohorts. A retrospective matched-pair analysis from patients at a single center in Germany was performed without (group A) and with (group B) MgSO4 application <24 hours after diagnosis. Pairs were matched according to the known risk factors for DCI and CV (age, Fisher grade, smoking, severity of SAH). Incidence of CV and DCI and neurological outcome using the modified Rankin Scale score 3 and 12 months after SAH were recorded. The inclusion criteria were met by 196 patients. After risk stratification, 48 patients were included in the final analysis (age 54.2 ± 8.1 years; 30 women and 18 men) and were assigned to group A (n= 24) or group B (n= 24). CV occurred less frequently in group B (33%) than in group A (46%). Likewise, DCI was present in 13% in group B compared with 42% in group A. After 12 months, 22 patients in group B had a favorable functional outcome (modified Rankin Scale score 0-3) compared with 15 patients in group A. In this study, the incidence of CV and DCI was lower in patients receiving intravenous MgSO4 within 24 hours after aneurysmal SAH onset. Favorable functional outcome was more likely in the MgSO4 group after 12 months of follow-up.

TBX5 genetic variants and SCD-CAD susceptibility: insights from Chinese Han cohorts.

The prevention and prediction of sudden cardiac death (SCD) present persistent challenges, prompting exploration into common genetic variations for potential insights. T-box 5 (TBX5), a critical cardiac transcription factor, plays a pivotal role in cardiovascular development and function. This study systematically examined variants within the 500-bp region downstream of the TBX5 gene, focusing on their potential impact on susceptibility to SCD associated with coronary artery disease (SCD-CAD) in four different Chinese Han populations. In a comprehensive case-control analysis, we explored the association between rs11278315 and SCD-CAD susceptibility using a cohort of 553 controls and 201 SCD-CAD cases. Dual luciferase reporter assays and genotype-phenotype correlation studies using human cardiac tissue samples as well as integrated in silicon analysis were applied to explore the underlining mechanism. Binary logistic regression results underscored a significantly reduced risk of SCD-CAD in individuals harboring the deletion allele (odds ratio = 0.70, 95% CI [0.55-0.88], p = 0.0019). Consistent with the lower transcriptional activity of the deletion allele observed in dual luciferase reporter assays, genotype-phenotype correlation studies on human cardiac tissue samples affirmed lower expression levels associated with the deletion allele at both mRNA and protein levels. Furthermore, our investigation revealed intriguing insights into the role of rs11278315 in TBX5 alternative splicing, which may contribute to alterations in its ultimate functional effects, as suggested by sQTL analysis. Gene ontology analysis and functional annotation further underscored the potential involvement of TBX5 in alternative splicing and cardiac-related transcriptional regulation. In summary, our current dataset points to a plausible correlation between rs11278315 and susceptibility to SCD-CAD, emphasizing the potential of rs11278315 as a genetic risk marker for aiding in molecular diagnosis and risk stratification of SCD-CAD.