Estimates Of Disease Incidence Research Articles

Longitudinal history of mammographic breast density and breast cancer risk by familial risk, menopausal status, and initial mammographic density level in a high risk cohort: a nested case–control study

BackgroundElevated mammographic density is associated with increased breast cancer risk. However, the contribution of longitudinal changes in mammographic density to breast cancer risk beyond initial mammographic density levels, considering familial breast cancer risk and menopausal status, remains uncertain but holds important clinical implications.MethodsIn a nested case–control study within the Sister Study (323 cases, 899 controls; 12,095 mammograms), a cohort enriched for family history of breast cancer, we examined case–control status in relation to the largest annual change in percent density and dense area using mammograms available spanning 5.4 years, on average, using multivariable logistic regression and to the rate of mammographic density change using linear mixed-effects models. We considered effect modification by: mammographic density level of the earlier mammogram, the extent of family history, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation (BOADICEA) risk strata, and menopausal status.ResultsCases (diagnosed < 60 years) had greater initial percent density and dense area levels and a slower rate of decline in dense area than controls. Women with stable mammographic density (≤ 10% annual change) had an increased breast cancer risk as compared with women whose largest mammographic density change was > 10% annual decline (e.g., Odds Ratio (OR) 2.34, 95% Confidence Interval (CI) 1.63–3.37 for dense area). Increasing vs. decreasing dense area was also associated with elevated risk, especially in women with the highest dense area levels at the earlier mammogram (OR: 2.56, 95%CI 1.50–4.36). Although generally similar across menopausal and familial risk categories, the associations of MD change with risk appeared stronger in pre-menopausal and lower-risk women.ConclusionsWomen who maintain higher levels of mammographic density (i.e. do not decrease over time) or have increasing mammographic density over time have a higher risk of subsequent breast cancer than women with high mammographic density that decreases over time. These findings suggest potential for incorporating mammographic density trajectories in clinical risk assessment, and the importance of additional breast cancer monitoring in women not experiencing declines in mammographic density over time.

Estimating the rates of dementia using administrative data linked to cohort studies.

Current estimates of dementia and Alzheimer's disease incidence and prevalence are required to understand the health needs of the elderly. We used two Australia cohort studies, administrative datasets, and data linkage techniques to estimate dementia rates in Australia. The study used Australian Longitudinal Study on Women's Health and the Health in Men Cohort Study. Records of dementia were obtained from linked sources and incidence and prevalence estimates were produced. Capture-recapture methods were used to estimate numbers of dementia cases not identified through data linkage. There were 3399 (28.5%) men with dementia identified from any source and 3767 (34.8%) women. Rates of dementia incidence and prevalence were similar between sexes but were raised in men once estimates of unidentified cases were included. Cohort studies and linked administrative data can be used together to produce current estimates of dementia prevalence and incidence comparable to other population estimates.

First Report of Chili Anthracnose Caused by Colletotrichum sojae in South Korea.

Chili (Capsicum annuum L.) is an economically important crop worldwide, valued for its culinary uses. In South Korea, anthracnose caused by Colletotrichum spp. including C. truncatum, C. gloeosporioides, C. coccodes, C. acutatum, and C. scovillei incurs on substantial economic loss (Kim et al. 2008; Oo and Oh 2020). In August 2022, somewhat different types of symptoms that was not typical on chilli fruits were observed in a field in Yereonggwang (GPS: 35.2579° N, 126.4742° E), South Korea. The disease symptoms appeared as sunken, necrotic lesions with dense black spore masses forming in concentric rings. The estimated disease incidence the 0.2 ha field showing up to 1% of fruits affected. To isolate the pathogen, six symptomatic chilli fruits were collected. Small pieces (5 mm²) were cut from the margins of the lesions, surface-sterilized in 70% ethanol for 30 sec, followed by 1% sodium hypochlorite for 1 minute, and then rinsed three times in sterile distilled water. The tissue pieces were placed on potato dextrose agar (PDA) plates and incubated at 25°C in the dark. After 3 to 5 days, emerging fungal colonies were sub-cultured to obtain pure isolates. A total of five isolates were obtained and initially identified as Colletotrichum spp. based on morphological characteristics. Seven-day old colonies were initially white, turning light orange with age on PDA. Setae (observed on lesion) were dark brown, verruculose and septate. Conidia were cylindrical, hyaline, and measured 14.8 to 19.9 × 4.2 to 6.5 µm (mean 16.7 × 5.6 μm, n = 70) in size; appressoria were brown to dark brown and irregularly shaped. These morphological characteristics of the isolates agree with those reported for the morphology of C. sojae by Damm et al. (2019). To confirm the identity of the isolates, DNA was extracted and specific gene regions were amplified and sequenced using the following primer sets: ITS (ITS1 and ITS4), GAPDH (GDF1 and GDR1), ACT (ACT-512F and ACT-783R), TUB (T1 and Bt2b), HIS3 (CYLH3F and CYLH3R), and CHS-1 (CHS-79F and CHS-345R). The resulting sequences were deposited in the NCBI GenBank with accession numbers (LC830742 to LC830766). Maximum likelihood phylogenetic analysis using combine sequences of ITS, GAPDH, ACT, TUB, HIS3 and CHS-1 in MEGA X confirmed the isolates as C. sojae, marking the first report of this pathogen on chilli in South Korea, previously known to infect soybean. Pathogenicity tests were conducted on wound and nonwounded healthy and mature-green chili fruits (cv. Bicksita) to confirm the pathogenicity of the isolated C. sojae. The fruits were surface-sterilized using 70% ethanol and then rinsed with sterile distilled water. The fruits were wounded using a sterile needle to facilitate infection. A conidial suspension (1x106 conidia/mL) was prepared from 7-day-old PDA cultures. Each fruit was inoculated by placing a 10 µL drop of the conidial suspension onto the wounded and nonwounded sites (4 to 5) of the wound and unwound fruits, respectively. Control fruits were inoculated with sterile water. A total of 40 fruits per treatment were used and the experiment repeated twice. The fruits were placed in plastic box lined with moist paper towels to maintain high humidity and incubated at 25°C. Anthracnose symptoms developed on the inoculated fruits within 7 days, while control and unwounded fruits remained symptom-free. Colletotrichum sojae was successfully reisolated from the symptomatic fruits, fulfilling Koch's postulates and confirming its role as the causal agent of the disease. Colletotrichum sojae is known to infect Fabaceae species worldwide such as Glycine max, Medicago sativa, Phaseolus vulgaris, Atractylodes ovata and Vigna unguiculata (Damm et al. 2019; Talhinhas and Baroncelli 2021), Atractylodes ovata in South Korea (Hassan et al. 2021) and chili pepper in China (Zhanget al. 2023). The first report of C. sojae causing chili anthracnose in South Korea represents a new challenge for chili growers. Integrated disease management strategies need to be developed and implemented to mitigate its impact.

Abstract 4113411: Long Term Outcomes of Hypertension and Antihypertensive Drugs in Young Healthy Adults: A Nationwide Population-based Prospective Cohort Study in Korea

Background: Long term follow-up data on elevated blood pressure (BP) or antihypertensive drugs in young adults are scarce. The effect of hypertension (HTN) and antihypertensive medications on the cardiovascular disease incidence in young healthy adults (20~45 years) was analyzed using a large-scale population medical use database in Korea. Methods: In total, 4,590,597 young Korean adults without comorbidities who underwent regular health examination were included in this study. They were stratified into four groups according to their BP (optimal BP, normal BP, high normal BP, and HTN). The primary outcome was a composite of the incidence of myocardial infarction and ischemic and hemorrhagic stroke, obtained by tracking the medical use data of the first-ever ICD-10 codes. Subgroup analysis was conducted by categorizing the HTN group into two subgroups according to the prescription ratios of the antihypertensive drugs during the follow-up period. Results: The average age was 33.8 years and median follow-up duration was 15.9 years. HTN elevated the incidence risk of major cardiovascular disease by 2.16 times compared to that of the optimal BP group. Dyslipidemia and HTN were the most dominant risk factors for myocardial infarction and stroke, respectively. In the subgroup analysis, antihypertensive medications decreased the incidence of cardiovascular disease by 70% in all diseases. Conclusions: Cardiovascular risk factors, including HTN, contribute to major cardiovascular disease incidence in young adults. The antihypertensive medications decreased the major cardiovascular disease incidence estimates.

Plasma metabolomics profiles and breast cancer risk

BackgroundBreast cancer (BC) is the most common cancer in women and incidence rates are increasing; metabolomics may be a promising approach for identifying the drivers of the increasing trends that cannot be explained by changes in known BC risk factors.MethodsWe conducted a nested case–control study (median followup 6.3 years) within the New York site of the Breast Cancer Family Registry (BCFR) (n = 40 cases and 70 age-matched controls). We conducted a metabolome-wide association study using untargeted metabolomics coupling hydrophilic interaction liquid chromatography (HILIC) and C18 chromatography with high-resolution mass spectrometry (LC-HRMS) to identify BC-related metabolic features.ResultsWe found eight metabolic features associated with BC risk. For the four metabolites negatively associated with risk, the adjusted odds ratios (ORs) ranged from 0.31 (95% confidence interval (CI): 0.14, 0.66) (L-Histidine) to 0.65 (95% CI: 0.43, 0.98) (N-Acetylgalactosamine), and for the four metabolites positively associated with risk, ORs ranged from 1.61 (95% CI: 1.04, 2.51, (m/z: 101.5813, RT: 90.4, 1,3-dibutyl-1-nitrosourea, a potential carcinogen)) to 2.20 (95% CI: 1.15, 4.23) (11-cis-Eicosenic acid). These results were no longer statistically significant after adjusting for multiple comparisons. Adding the BC-related metabolic features to a model, including age, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk score improved the accuracy of BC prediction from an area under the curve (AUC) of 66% to 83%.ConclusionsIf replicated in larger prospective cohorts, these findings offer promising new ways to identify exposures related to BC and improve BC risk prediction.

Public health impact and return on investment of the pediatric National Immunization Program in Italy

ABSTRACT Objectives We conducted a cost–benefit analysis of the pediatric National Immunization Program (NIP) in Italy. Methods An economic model evaluated the benefit–cost ratio (BCR) of the Italian pediatric NIP, including 10 pathogens for mandatory vaccines and 4 pathogens for recommended vaccines for children aged 0–10 years from the healthcare-sector and societal perspectives. Separate decision trees were used to model each vaccine-preventable disease (VPD). The 2020 birth cohort (n = 420,084) was followed over their lifetime; the model projected and compared discounted disease cases, life-years, quality-adjusted life-years (QALYs), and costs (2021 euros) with and without immunization (based on current and pre – vaccine era disease incidence estimates, respectively). Results The pediatric NIP was estimated to prevent 1.8 million cases of VPDs and 3,330 deaths, resulting in 45,900 fewer life-years lost and 57,000 fewer QALYs lost. Vaccination costs of €285 million were offset by disease cost savings of €1.6 billion, resulting in a BCR of 5.6 from a societal perspective (BCR = 1.7 from a healthcare-sector perspective). When QALYs gained were valued, the BCR increased to 15.6. Conclusions The benefits of the Italian pediatric NIP, including averted disease-related morbidity, mortality, and associated costs, highlight the value of continued investment in pediatric immunization.

First report of anthracnose caused by Colletotrichum fructicola on winter jasmine (Jasminum nudiflorum) in China.

Winter jasmine (Jasminum nudiflorum Lindl.) is a medium-sized, deciduous shrub native to China that has become a popular choice among gardeners and landscapers. In 2020 to 2021, symptoms of anthracnose including brown necrotic spots, enlarged irregular lesions and leaf blight were observed on leaves of 20 winter jasmine shrubs in a public garden (22°34'58'' N; 113°56'23'' E) in Shenzhen, China, and with an estimated disease incidence of 65%. Tissues samples (6 × 6 mm2) surrounding the necrotic spots were surface sterilized with 75% ethanol for 30 s, followed by 2% NaClO for 1 min, then rinsed with sterile water for three times and dried with sterile filter paper. Tissues were placed on potato dextrose agar (PDA) medium and incubated at 25℃. After 3 to 7 d, pure cultures were obtained by transferring hyphal tips to new plates and 32 isolates producing Colletotrichum-like colonies were obtained from 40 tissues (isolation frequency=32/(4×10)=80%). Three representative isolates YCH09, YCH23 and YCH32 were selected for further study. Three selected isolates were identical in morphological characteristics. Colonies on PDA after 5 d at 25℃ were white to gray with cottony mycelia and grayish-white on the underside of the culture. Conidia (n = 60) measured 15.4 ± 1.1 µm (13.0 to 17.1 µm) in length and 5.4 ± 0.3 µm (4.9 to 6.0 µm) in width and were hyaline, single-celled, cylindrical with rounded ends. Appressoria (n = 15) measured 7.1 ± 0.1 µm (5.3 to 8.9 µm) in length and 5.2 ± 0.2 µm (4.1 to 6.2 µm) in width and were brown to dark brown, ovoid. These morphological features were aligned with those of Colletotrichum spp. (Weir et al. 2012). Sequences of five genetic markers of representative isolates YCH09, YCH23 and YCH32 including the rDNA internal transcribed spacer region, chitin synthase, partial actin, β-tubulin 2 and Apn2-Mat1-2 intergenic spacer and partial mating type (Mat1-2) region were 99.3 to 100% identical to the ex-type isolate of C. fructicola strain ICMP 18581 (Zhang et al., 2020). From the maximum likelihood phylogenetic tree which was constructed based on concatenated sequences, three representative isolates (YCH09, YCH23 and YCH32) were clustered with other isolates of C. fructicola. The above morphological and molecular characteristics suggest that causal agent was C. fructicola. Pathogenicity was tested using a whole-plant assay. Five healthy plants were inoculated by spraying a conidial suspension (1.5×104 conidia/ml; 20 ml per plant) of the isolate YCH23 onto the foliage (Marshall et al., 2023). Three noninoculated control plants were sprayed with sterile water. All plants were placed in a greenhouse at 25±2℃ with approximately 75% relative humidity. Yellow lesions appeared on leaves of inoculated plants as early as 4 days after inoculation (DAI), and irregularly shaped brown spots similar to those observed in the field were formed on 10 DAI. Noninoculated plants remained asymptomatic. Colletotrichum isolates resembling morphological characters of YCH23 were reisolated from all inoculated plants, then identified as C. fructicola by DNA sequence analysis. C. fructicola is a well-known fungus causing anthracnose on more than 63 plant species including agricultural and horticultural plants worldwide (Talhinhas and Baroncelli, 2021). To our knowledge, this is the first report of C. fructicola infecting J. nudiflorum plants in China. Since its potential risk to other horticultural plant species, precautions may be necessary to minimize the spread of this fungi.

First Report of Pantoea ananatis causing leaf streak disease on wheat (Triticum aestivum) in the United States of America.

Wheat (Triticum aestivum) loses 21.5% yield to pests and diseases annually (Savary et al. 2019). Among the wheat diseases, bacterial leaf streak (BLS) is a growing problem, costing $78.5 million in losses (https://cropprotectionnetwork.org/). In July 2022, we sampled winter wheat leaf samples at Volga (44.30, -96.92), South Dakota, USA with an estimated disease incidence of 40% (n=100). The typical symptoms were water-soaking with large necrotic and chlorotic streaks extending the length of the leaves and were strikingly similar to BLS. To isolate the pathogen, leaves were cut lengthwise into 1 cm pieces and surface-sterilized using a 10% NaOCl solution for 3 min, followed by 70% ethanol for 3 min, and then rinsed with sterile distilled water and placed in 500 ul of sterile distilled water for 5 min and using a sterile loop the water was streaked over a plate of Nutrient Agar (NA). Following Duveiller et al. (1997), the streaked plate was incubated in the dark at 28℃ for 48 h. Observed single colonies were sub-cultured thrice onto fresh NA plates to obtain a pure culture. We named the culture SD101. Bacteria were found to be gram-negative with a colony morphology initially raised, smooth, and white that later turned yellow. DNA was extracted using the Wizard HMW DNA Extraction Kit (Promega, Madison, WI) following the manufacturer's protocol, and sequenced using Nanopore MinION R9.4 (Oxford Nanopore Technology). We used the Rapid Annotation Using Subsystems Technology approach (Aziz eal. 2008) to extract the 16S rDNA, DNA gyrase subunit B (gyrB), and translation initiation factor IF-2 (infB) gene sequences that were deposited in GenBank under accession numbers PP329908.1 for 16S rDNA, PP496481 for infB, and PP328920.1 for gyrB. Homology analysis using CLC Genomics Workbench 22.0.2 (QIAGEN) and BLASTn against the GenBank nucleotide database resulted in a 99.74% match (1543/ 1547 bp) of the 16S sequence, 99.59% match (2674/ 2685 bp) of the infB sequence, and 99.42% match (2396/ 2410 bp) of the gyrB sequence with Pantoea ananatis strain AJ13355 (AP012032). To test pathogenicity, seeds of spring wheat breeding line SD4892 were planted in 30 cm × 30 cm pots in a greenhouse under a 16 h light photoperiod. The inoculum was prepared from 48-h-old NA plates of SD101 rinsed with 1X Phosphate Buffer Saline (PBS buffer), adjusted to an OD600 = 1.0, and amended with two drops of Tween 20 (polyoxyethylene sorbitol ester, Millipore Sigma). PBS with Tween 20 was used as a negative control. The inoculum was sprayed on 15 replicates of 15-day-old seedlings, kept at 95% relative humidity for 48 h, then moved to the greenhouse at 23 to 25°C. The symptoms appeared as water soaking that later turned to necrotic streaks with surrounding chlorosis on all 15 inoculated plants while control plants remained healthy. The pathogen was re-isolated from the leaves as described above. The 16S rDNA, infB, and gyrB sequences amplified and sequenced were identical to the gene sequences from the whole genome sequencing. The experiment was repeated with the same results, completing Koch's postulates. Although P. ananatis is pathogenic on corn, rice, and other plant species in the United States (Coutinho et al. 2009), and was reported pathogenic on wheat in Poland (Krawczyk et al. 2020), this is the first report of its pathogenicity on wheat in the United States. The prevalence, and incidence of BLS disease caused by P. ananatis in wheat is needed to estimate its threat to wheat production and to develop management strategies.

Advancing crop disease early warning in South Asia by complementing expert surveys with internet media scraping

AbstractWheat contributes one‐fifth of the global food supply with an estimated 29% of global production in low and lower‐middle income countries. As production expands across southern Asia, yields are often negatively impacted by outbreaks of fungal rust diseases. A wheat rust early warning and advisory system comprising surveillance, near real‐time disease risk forecasts and advisory dissemination has been established in two target countries in South Asia, including Nepal and Bangladesh. However, as wheat rust spores can be aerially transmitted over long distances, near real‐time estimates of disease incidence are required from sources of infection in neighbouring regions. To address this challenge, we developed and tested a novel algorithm to generate proxy observations of infection sources using online media reports in two neighbouring countries, India and Pakistan. Media sampling could provide an effective alternative where data from ground surveys are not readily available in near real‐time. Our results show that west Nepal was exposed to a substantial inoculum pressure from aerially dispersed stripe rust spores originating from India and Pakistan. There were no outbreaks of stripe rust disease in Bangladesh with only very low levels of cross‐border dispersion and generally unfavourable environmental conditions for infection. We further describe how proxy observations informed farmer decision‐making in near real‐time in Nepal and filled a knowledge gap in identifying early sources of infection for a major outbreak of stripe rust during 2020 in Nepal. Our results highlight the importance of international cooperation in mitigating transboundary plant pathogens.

SARS-CoV-2 viral titer measurements in Ontario, Canada wastewaters throughout the COVID-19 pandemic

During the COVID-19 pandemic, the Province of Ontario, Canada, launched a wastewater surveillance program to monitor SARS-CoV-2, inspired by the early work and successful forecasts of COVID-19 waves in the city of Ottawa, Ontario. This manuscript presents a dataset from January 1, 2021, to March 31, 2023, with RT-qPCR results for SARS-CoV-2 genes and PMMoV from 107 sites across all 34 public health units in Ontario, covering 72% of the province’s and 26.2% of Canada’s population. Sampling occurred 2–7 times weekly, including geographical coordinates, serviced populations, physico-chemical water characteristics, and flowrates. In doing so, this manuscript ensures data availability and metadata preservation to support future research and epidemic preparedness through detailed analyses and modeling. The dataset has been crucial for public health in tracking disease locally, especially with the rise of the Omicron variant and the decline in clinical testing, highlighting wastewater-based surveillance’s role in estimating disease incidence in Ontario.

Limitations in next-generation sequencing-based genotyping of breast cancer polygenic risk score loci

Considering polygenic risk scores (PRSs) in individual risk prediction is increasingly implemented in genetic testing for hereditary breast cancer (BC) based on next-generation sequencing (NGS). To calculate individual BC risks, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) with the inclusion of the BCAC 313 or the BRIDGES 306 BC PRS is commonly used. The PRS calculation depends on accurately reproducing the variant allele frequencies (AFs) and, consequently, the distribution of PRS values anticipated by the algorithm. Here, the 324 loci of the BCAC 313 and the BRIDGES 306 BC PRS were examined in population-specific database gnomAD and in real-world data sets of five centers of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), to determine whether these expected AFs can be reproduced by NGS-based genotyping. Four PRS loci were non-existent in gnomAD v3.1.2 non-Finnish Europeans, further 24 loci showed noticeably deviating AFs. In real-world data, between 11 and 23 loci were reported with noticeably deviating AFs, and were shown to have effects on final risk prediction. Deviations depended on the sequencing approach, variant caller and calling mode (forced versus unforced) employed. Therefore, this study demonstrates the necessity to apply quality assurance not only in terms of sequencing coverage but also observed AFs in a sufficiently large cohort, when implementing PRSs in a routine diagnostic setting. Furthermore, future PRS design should be guided by the technical reproducibility of expected AFs across commonly used genotyping methods, especially NGS, in addition to the observed effect sizes.

The epidemiology of osteochondrosis in an insured Swedish dog population

Osteochondrosis (OC) is a focal disturbance of endochondral ossification due to a failure of blood supply to the epiphyseal growth cartilage. In dogs, OC most commonly affects the shoulder joint, followed by the elbow, tarsal, and stifle joints. The condition is associated with clinical signs such as lameness and pain and the prognosis varies depending on the affected joint. Most epidemiologic studies of OC in dogs were performed over 20 years ago, and updated estimates of disease incidence are lacking. Therefore, the objectives of this study were to provide population-based estimates of the incidence rate, cause-specific mortality rate, and age at diagnosis of appendicular OC (AOC, including OC of the shoulder, elbow, stifle, and tarsal joints) and stifle and tarsal OC separately, using data from Agria Djurförsäkring in Sweden (2011–2016). Further, the study aimed to evaluate the risk of OC in subgroups divided by breed and sex and describe previous, concurrent, and subsequent diagnoses of the affected joint in dogs with stifle or tarsal joint OC. The study population included just over 600,000 dogs, of which 685 were affected by AOC. Stifle joint OC (n = 113) was more common than tarsal joint OC (n = 80). The incidence rate of AOC was 3.77 (95% confidence interval (CI): 3.49–4.07) cases per 10,000 dog-years at risk, while the incidence rate of stifle and joint tarsal OC was 0.64 (95% CI: 0.53–0.77) and 0.43 (95% CI: 0.34–0.54) cases per 10,000 dog-years at risk, respectively. All breeds at increased risk of AOC were large or giant, and male dogs had an increased risk of AOC compared to female dogs (RR 1.76, 95% CI: 1.50–2.07, p < 0.001). The median age at first diagnosis during the study period was 0.74 (0.32–11.5) years for AOC, 2.62 (0.45–8.82) years for stifle joint OC, and 0.73 (0.35–7.35) years for tarsal joint OC. Of the dogs with stifle or tarsal joint OC, 30.2% and 15.0% had a previous diagnosis of stifle/tarsal joint pain or other unspecific clinical signs, respectively, and 13.8% of the dogs with stifle joint OC suffered subsequent cruciate ligament rupture. Osteochondrosis was the most common reason for euthanasia in the affected dogs. In total, 77 dogs were euthanised due to AOC during the study period.

Weighted metrics are required when evaluating the performance of prediction models in nested case–control studies

BackgroundNested case–control (NCC) designs are efficient for developing and validating prediction models that use expensive or difficult-to-obtain predictors, especially when the outcome is rare. Previous research has focused on how to develop prediction models in this sampling design, but little attention has been given to model validation in this context. We therefore aimed to systematically characterize the key elements for the correct evaluation of the performance of prediction models in NCC data.MethodsWe proposed how to correctly evaluate prediction models in NCC data, by adjusting performance metrics with sampling weights to account for the NCC sampling. We included in this study the C-index, threshold-based metrics, Observed-to-expected events ratio (O/E ratio), calibration slope, and decision curve analysis. We illustrated the proposed metrics with a validation of the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in data from the population-based Rotterdam study. We compared the metrics obtained in the full cohort with those obtained in NCC datasets sampled from the Rotterdam study, with and without a matched design.ResultsPerformance metrics without weight adjustment were biased: the unweighted C-index in NCC datasets was 0.61 (0.58–0.63) for the unmatched design, while the C-index in the full cohort and the weighted C-index in the NCC datasets were similar: 0.65 (0.62–0.69) and 0.65 (0.61–0.69), respectively. The unweighted O/E ratio was 18.38 (17.67–19.06) in the NCC datasets, while it was 1.69 (1.42–1.93) in the full cohort and its weighted version in the NCC datasets was 1.68 (1.53–1.84). Similarly, weighted adjustments of threshold-based metrics and net benefit for decision curves were unbiased estimates of the corresponding metrics in the full cohort, while the corresponding unweighted metrics were biased. In the matched design, the bias of the unweighted metrics was larger, but it could also be compensated by the weight adjustment.ConclusionsNested case–control studies are an efficient solution for evaluating the performance of prediction models that use expensive or difficult-to-obtain biomarkers, especially when the outcome is rare, but the performance metrics need to be adjusted to the sampling procedure.

Distribution of pathogenic variants in the CFTR gene in a representative cohort of people with cystic fibrosis in the Kingdom of Bahrain

BackgroundCystic fibrosis (CF) is a rare multi-systemic recessive disorder. The spectrum and the frequencies of CFTR mutations causing CF vary amongst different populations in Europe and the Middle East. In this study, we characterised the distribution of CF-causing mutations (i.e. pathogenic variants in the CFTR gene) in a representative CF cohort from the Kingdom of Bahrain based on a three-decade-long analysis at a single tertiary centre. We aim to improve CF genetic diagnostics, introduce of CF neonatal screening and provide CFTR modulator therapy (CFTRm).MethodsCFTR genotyping and associated clinical information were drawn from a longitudinal cohort. We sequenced 56 people with CF (pwCF) that had one or both CFTR mutations unidentified and carried out comprehensive bioinformatic- and family-based segregation analyses of detected variants, including genotype–phenotype correlations and disease incidence estimates. The study methodology could serve as a basis for other non-European CF populations with a high degree of consanguinity.ResultsAltogether 18 CF-causing mutations were identified, 15 of which were not previously detected in Bahrain, accounting for close to 100% of all population-specific alleles. The most common alleles comprise c.1911delG [2043delG; 22.8%], c.2988+1G > A [3120+1G>A; 16.3%], c.2989-1G>A [3121-1G>A; 14.1%], c.3909C>G [N1303K; 13.0%], and c.1521_1523delCTT [p.PheF508del; 7.6%]. Although the proportion of 1st cousin marriages has decreased to 50%, the frequency of homozygosity in our pwCF is 67.4%, thereby indicating that CF still occurs in large, often related, families. pwCF in Bahrain present with faltering growth, pancreatic insufficiency and classical sino-pulmonary manifestations. Interestingly, two pwCF also suffer from sickle cell disease. The estimated incidence of CF in Bahrain based on data from the last three decades is 1 in 9,880 live births.ConclusionThe most commonCF-causing mutations in Bahraini pwCF were identified, enabling more precise diagnosis, introduction of two-tier neonatal screening and fostering administration of CFTRm.

Abstract 769: Incorporating a cross-ancestry polygenic risk score into a clinical model improved breast cancer risk prediction in women with pathogenic variants

Abstract Introduction. We previously developed and validated a cross-ancestry polygenic risk score (caPRS) to predict risk of developing breast cancer (BC) in women who do not carry pathogenic variants (PVs) in BC susceptibility genes. Here we aimed to expand upon that study by integrating the caPRS with the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model to combine the effects of genetic and clinical factors in carriers of PVs in BRCA1, BRCA2, PALB2, CHEK2 and ATM. Methods. We explored the association of caPRS among 12,525 women from the UK Biobank and the Consortium of Investigators of Modifiers of BRCA1/2. The effect size of the caPRS was evaluated separately for individuals carrying PVs in BRCA1, BRCA2, CHEK2, ATM and PALB2. We used a logistic regression model adjusted for age, first-degree BC family history (FHx) and cohort for BRCA1 and BRCA2 to examine the association of the caPRS with BC. The effect sizes were expressed as standardized odds ratios (ORs) with 95% confidence intervals (CIs). The estimated absolute risks to age 80 of developing BC were calculated for unaffected women by combining the caPRS-based risk with gene-specific clinical risk estimates from the BOADICEA model based on U.S. incidences. Results. The caPRS was significantly associated with BC risk across all PV carrier groups. Using BOADICEA alone, the estimated absolute BC risk by age 80 for an average unaffected 20-year-old female in the U.S. with an unknown FHx ranged from 23.8% for CHEK2 carriers to 79.4% for BRCA2 carriers. Integration of caPRS into BOADICEA, yielded the distribution of risk for each gene. (Table) Gene N OR per SD (95% CI) Absolute risk by BOADICEA Median absolute risk by BOADICEA + caPRS (Range) ATM 2,037 1.46 (1.25 - 1.71) 24.9% 27.1% (0.1 - 70.5) BRCA1 5,794 1.24 (1.18 - 1.31) 76.1% 75.6% (55.6 - 87.7) BRCA2 4,018 1.40 (1.31 - 1.49) 79.4% 78.7% (45.2 - 92.1) CHEK2 372 1.88 (1.41 - 2.55) 23.8% 28.2% (0.0 - 78.4) PALB2 304 1.81 (1.37 - 2.43) 53.9% 56.3% (2.9 - 90.9) Conclusions. The caPRS significantly modified BC risk for carriers of PVs and could help tailor guidelines for women with PVs, particularly in moderate penetrance genes. More data is needed to increase the precision and reach of risk assessment in diverse populations. Citation Format: Placede Tshiaba, Monika Sun, Dariusz Ratman, Jeffrey N. Weitzel, Premal Shah, Matthew Rabinowitz, Akash Kumar, Kate Im. Incorporating a cross-ancestry polygenic risk score into a clinical model improved breast cancer risk prediction in women with pathogenic variants [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 769.

Estimation of age of onset and progression of breast cancer by absolute risk dependent on polygenic risk score and other risk factors.

Genetic, lifestyle, reproductive, and anthropometric factors are associated with the risk of developing breast cancer. However, it is not yet known whether polygenic risk score (PRS) and absolute risk based on a combination of risk factors are associated with the risk of progression of breast cancer. This study aims to estimate the distribution of sojourn time (pre-clinical screen-detectable period) and mammographic sensitivity by absolute breast cancer risk derived from polygenic profile and the other risk factors. The authors used data from a population-based case-control study. Six categories of 10-year absolute risk based on different combinations of risk factors were derived using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm. Women were classified into low, medium, and high-risk groups. The authors constructed a continuous-time multistate model. To calculate the sojourn time, they simulated the trajectories of subjects through the disease states. There was little difference in sojourn time with a large overlap in the 95% confidence interval (CI) between the risk groups across the six risk categories and PRS studied. However, the age of entry into the screen-detectable state varied by risk category, with the mean age of entry of 53.4years (95% CI, 52.2-54.1) and 57.0years (95% CI, 55.1-57.7) in the high-risk and low-risk women, respectively. In risk-stratified breast screening, the age at the start of screening, but not necessarily the frequency of screening, should be tailored to a woman's risk level. The optimal risk-stratified screening strategy that would improve the benefit-to-harm balance and the cost-effectiveness of the screening programs needs to be studied.

First Report of Verticillium Wilt caused by Verticillium dahliae on Chilli in South Korea.

Chili pepper (Capsicum spp.) is an important crop in South Korea and is widely used in Korean cuisine, cultivated across a land area of roughly 29.8 thousand hectares, with a total production of 69 thousand tons (Lee et al., 2005; Statista, 2022). In September 2020, two farmer fields in Samcheok (37.444039°N, 129.135875°E; 37.633738°N, 128.911731°E), Gangwon province, South Korea, it is observed that chili pepper leaves showing yellowing and wilting symptoms, with an estimated disease incidence of approximately 10-15%. To identify the causal agents six affected plants were brought to lab. All the plants exhibited vascular discoloration in stem and root. After surface sterilizing small pieces of discolored tissue in 1% NaOCl for 30 s and rinsing twice in sterile distilled water, the tissue pieces were placed on water agar and incubated at 25°C for 10 days. Six pure isolates with consistent morphological characteristics were obtained by single spore isolation. Two representative isolates, NC17601 and NC20845 were selected for identification based morphological and molecular characters. Colonies on potato dextrose agar (PDA) during 10 days of incubation at 25°C in the dark were cottony white initially but progressively became dark as the formation of melanized microsclerotia. Conidiophores were hyaline, vertically branched or not, and had 2 - 4 phialides per node. Phialides were subulate and tapering from base to tip. The colonies produced abundant conidia, which were hyaline, single celled, smooth walled, cylindrical to oval, clustered on phialides, and 3.8 - 7.2 ×2.1 - 3.9 ㎛(mean ± SD: 5.2 ± 0.7 × 2.8 ± 0.5). Microsclerotia were aggregated form, various size and shape, and brown. These are the typical morphology of Verticillium dahliae (Inderbitiz et al. 2011; Yu et al. 2016). The molecular identification was later confirmed through PCR amplification, and sequencing targeting the translation elongation factor 1 alpha (TEF), actin (ACT), tryptophan synthase (TS), and glyceraldehyde-3-phosphate dehydrogenase (GPD) genes using the primer sets described by Inderbitiz et al. (2011). The resulting sequences were deposited in GenBank with accession numbers LC761935 to LC761942. The maximum likelihood tree based on combined sequences of ACT, GPD, TEF and TS was inferred using RAxML- HPC2 on XSEDE as implemented on the CIPRES web server. The phylogenetic tree showed that the isolates were sit together with V. dahliae isolates (Ex-type PD322, PD227 and PD502). Pathogenicity tests using two isolates (NC17601 and NC20845) were conducted in the greenhouse, where 10 two weeks old seedlings per isolates (cv. Bigstar) were root-tip cut and then soaked in a fungal spore suspension of 107 conidia ml-1 for 1 h, while 10 seedlings were treated with sterile distilled water as a control. All the treated plants were maintained at 25°C (night)/ 25°C (Day) under natural light. After three weeks, all inoculated plants exhibit growth stunting with vascular discoloration in the stem and roots as compared to asymptomatic control plants. The isolates of V. dahliae were consistently re-isolated from discolored root tissues and identified based on morphological characteristics, thus fulfilling Koch's postulates. In South Korea, V. dahliae has been reported to cause wilt disease in various crops, including Kimchi cabbage and radish (Dumin et al. 2020; Choi et al. 2023). To the best of our knowledge, this is the first report that V. dahliae causing Verticillium wilt of chili pepper in South Korea. Overall, Verticillium dahliae is considered to be a significant threat to agriculture in South Korea, and efforts are being made to develop effective control strategies to mitigate its impact on crops.

Variations in Incidence and Prognosis of Stage 4 CKD Among Adults Identified Using Different Algorithms: A Population-Based Cohort Study

Rationale & ObjectiveClinical guidelines define chronic kidney disease (CKD) as abnormalities of kidney structure or function for >3 months. Assessment of the duration criterion may be implemented in different ways, potentially impacting estimates of disease incidence or prevalence in the population, individual diagnosis, and treatment decisions, especially for more severe cases. We investigated differences in incidence and prognosis of CKD G4 identified by one of four algorithms. Study DesignPopulation-based cohort study in Alberta, Canada. Setting & ParticipantsResidents >18 years old with incident CKD G4 (eGFR 15-29 mL/min/1.73 m2) diagnosed between April 1, 2015 and March 31, 2018, based on administrative and laboratory data. ExposuresFour outpatient eGFR-based algorithms, increasing in stringency, for defining cohorts with CKD G4 were evaluated: (1) a single test, (2) first eGFR <30 mL/min/1.73 m2 and a second eGFR 15-29 mL/min/1.73 m2 >90 days apart (two tests), (3) ≥2 eGFR measurements <30 mL/min/1.73 m2 sustained for >90 days (qualifying period) and the last eGFR in the qualifying period of 15-29 mL/min/1.73 m2 (relaxed sustained), (4) ≥2 consecutive measurements 15-29 mL/min/1.73 m2 for >90 days (rigorous sustained). OutcomesTime to the earliest of death, eGFR improvement (a sustained increase in eGFR to ≥30 mL/min/1.73 m2 for >90 days and >25% increase from the index eGFR), or kidney failure. Analytical ApproachFor each of the 4 cohorts, incidence rates and event-specific cumulative incidence functions at 1 year from cohort entry were estimated. ResultsThe incidence rates of CKD G4 decreased as algorithms became more stringent, from 190.7 (single test) to 79.9 (rigorous sustained) per 100,000 person-years. The two cohorts based on sustained reductions in eGFR were of comparable size and 1-year event-specific probabilities. The two cohorts based on a single test and a two-test sequence were larger and experienced higher probabilities of eGFR improvement. LimitationsA short follow-up period of 1 year and a predominantly White population. ConclusionsThe use of more stringent algorithms for defining CKD G4 results in substantially lower estimates of disease incidence, the identification of a group with a lower probability of eGFR improvement, and a higher risk of kidney failure. These findings can inform implementation decisions of disease definitions in clinical reporting systems and research studies.

A Prospective cohort study of zoonotic cutaneous leishmaniasis in tunisia: Clinical and Immunological features and immune correlates of protection.

This study aimed to define immunological markers of exposure to L. major parasites and identify correlates of protection against infection. We analyzed a cohort of 790 individuals at risk of developing ZCL living in endemic areas with varying L. major infection prevalence. One area had a high infection prevalence indicated by high proportions of leishmanin skin test (LST) positive subjects, while the other areas were recent foci with lower infection prevalence. Blood samples were collected before the transmission season to measure Interferon gamma (IFN-γ), Interleukin 10 (IL-10), and Granzyme B (GrB) levels in response to parasite stimulation in peripheral blood mononuclear cells. A one-year follow-up period involved active detection of new ZCL cases to estimate disease incidence after a transmission season and identify immune correlates of protection. The study population showed heterogeneity in parasite contact, evident from specific scars and/or positive LST results, significantly higher in the old focus compared to recent foci. IFN-γ and GrB were markers of parasite exposure and reliable indicators of immunity to L. major. Positive correlations were observed between IFN-γ/IL-10 and GrB/IL-10 ratios and LST results. Unexpectedly, only 29 new ZCL cases (4%) appeared after a transmission season, with 27 cases reported in recent foci and 2 in the oldest focus. Our findings indicate that individuals in L. major endemic areas are likely to develop ZCL regardless of their LST status. We showed that high pre-transmission season levels of IFN-γ and GrB produced by PBMC, along with a high IFN-γ/IL-10 ratio, were associated with protection. This study on a large cohort at risk of ZCL confirmed IFN-γ and GrB as protective factors against the disease. A high IFN-γ/IL-10 ratio, but not GrB/IL-10 ratio was associated with resistance. These results are valuable for developing and evaluating of a vaccine against human leishmaniasis.

Applying a zero-corrected, gravity model estimator reduces bias due to heterogeneity in healthcare utilization in community-scale, passive surveillance datasets of endemic diseases

Data on population health are vital to evidence-based decision making but are rarely adequately localized or updated in continuous time. They also suffer from low ascertainment rates, particularly in rural areas where barriers to healthcare can cause infrequent touch points with the health system. Here, we demonstrate a novel statistical method to estimate the incidence of endemic diseases at the community level from passive surveillance data collected at primary health centers. The zero-corrected, gravity-model (ZERO-G) estimator explicitly models sampling intensity as a function of health facility characteristics and statistically accounts for extremely low rates of ascertainment. The result is a standardized, real-time estimate of disease incidence at a spatial resolution nearly ten times finer than typically reported by facility-based passive surveillance systems. We assessed the robustness of this method by applying it to a case study of field-collected malaria incidence rates from a rural health district in southeastern Madagascar. The ZERO-G estimator decreased geographic and financial bias in the dataset by over 90% and doubled the agreement rate between spatial patterns in malaria incidence and incidence estimates derived from prevalence surveys. The ZERO-G estimator is a promising method for adjusting passive surveillance data of common, endemic diseases, increasing the availability of continuously updated, high quality surveillance datasets at the community scale.