Length Bias Research Articles

Association of Genetic Alterations with Prognosis in Extramammary Paget's Disease: Insights into the Involvement of somatic CDKN2A variants in Poor Prognosis.

Previous studies reported the mutational landscape in extramammary Paget's disease (EMPD); however, the prognostic implications of genetic alterations remain unexplored. While CDKN2A loss is known to be associated with tumor progression or poor prognosis in some types of cancer, its significance in EMPD has not been investigated. To examine the association between common genetic alterations and prognosis in EMPD. This is a retrospective cohort study analyzing EMPD cases registered until January 2024 in the Center for Cancer Genomics and Advanced Therapeutics database, which is a nationwide database recording clinical data and comprehensive genomic profiling (CGP) test results in Japan. A total of 167 cases were recorded in the database, with CDKN2A loss being the most frequent genetic variant. Survival analysis was conducted on 127 cases. Survival from chemotherapy initiation was analyzed with adjusting for length bias inherent in the database using the Kaplan-Meier estimator, an established adjustment method. Cases with BRCA2-mutant tumors (n=18) had a worse prognosis than those with BRCA2-wild-type tumors (n=109; HR=2.97, 95% CI 1.46-6.01, p=0.003). Additionally, CDKN2A-mutant group (n=72) had a significantly worse prognosis than those with CDKN2A-wild-type group (n=55; HR=1.81, 95% CI 1.06-3.07, p=0.029). Most CDKN2A variants were pathogenic, primarily characterized by loss, while most BRCA2 variants were variants of uncertain significance. In the analysis of survival from CGP enrollment based on Eastern Cooperative Oncology Group performance status (ECOG-PS), cases with ECOG-PS 1 at the time of CGP enrollment had significantly poorer prognosis than those with ECOG-PS 0 (p=0.034; median survival time, 531 vs. 259 days). Somatic CDKN2A variant, mainly exhibiting loss, may be associated with poor prognosis in EMPD. Cases with BRCA2-mutant cancer might also have a worse prognosis in EMPD. In addition, CGP testing before PS deteriorates is preferable, considering the observed median survival of individuals undergoing CGP tests in an ECOG-PS-1 condition was less than 9 months.

An sn-2 regioselective lipase with cis-fatty acid preference from Cordyceps militaris: Biochemical characterization and insights into its regioselective mechanism

Lipase with unique regioselectivity is an attractive biocatalyst for elaborate lipid modification. However, the excavation of novel sn-2 regioselective lipases is difficult due to their scarcity in nature, with Candida antarctica lipase A (CALA) being the pronouncedly reported one. Here, we identified a novel CALA-like lipase from Cordyceps militaris (CACML7) via in silico mining. Through chiral-phase high-performance liquid chromatography, we determined that CACML7 displays sn-2 regioselectivity (>68 %) as does CALA, but exhibits distinctive chain length selectivity and bias against unsaturated fats. Notably, the curvature of the acyl-binding tunnel was expected to contribute to the 2.2-fold higher preference for cis-fatty acid (C18:1, cis-Δ9) over trans-fatty acid (C18:1, trans-Δ9) unlike trans-active CALA. Random pose docking of trioleoylglycerol (TOG) into the active site of a lid-truncated mutant of CACML7 revealed that TOG accepts a tuning fork conformation, of which the precise positioning of the reactive ester group towards the catalytic center was only favorable via sn-2 binding mode. The unique active site morphology, which we refer to as an “acyl-binding tunnel with a narrow entrance,” may contribute to the sn-2 regioselectivity of CACML7. Our data provide an attractive model to better understand the mechanism underlying sn-2 regioselectivity.

Forseti: a mechanistic and predictive model of the splicing status of scRNA-seq reads.

Short-read single-cell RNA-sequencing (scRNA-seq) has been used to study cellular heterogeneity, cellular fate, and transcriptional dynamics. Modeling splicing dynamics in scRNA-seq data is challenging, with inherent difficulty in even the seemingly straightforward task of elucidating the splicing status of the molecules from which sequenced fragments are drawn. This difficulty arises, in part, from the limited read length and positional biases, which substantially reduce the specificity of the sequenced fragments. As a result, the splicing status of many reads in scRNA-seq is ambiguous because of a lack of definitive evidence. We are therefore in need of methods that can recover the splicing status of ambiguous reads which, in turn, can lead to more accuracy and confidence in downstream analyses. We develop Forseti, a predictive model to probabilistically assign a splicing status to scRNA-seq reads. Our model has two key components. First, we train a binding affinity model to assign a probability that a given transcriptomic site is used in fragment generation. Second, we fit a robust fragment length distribution model that generalizes well across datasets deriving from different species and tissue types. Forseti combines these two trained models to predict the splicing status of the molecule of origin of reads by scoring putative fragments that associate each alignment of sequenced reads with proximate potential priming sites. Using both simulated and experimental data, we show that our model can precisely predict the splicing status of many reads and identify the true gene origin of multi-gene mapped reads. Forseti and the code used for producing the results are available at https://github.com/COMBINE-lab/forseti under a BSD 3-clause license.

Hook length biases in ordinary and t-regular partitions

In this article, we study hook lengths of ordinary partitions and t-regular partitions. We establish hook length biases for the ordinary partitions and motivated by them we find a few interesting hook length biases in 2-regular partitions. For a positive integer k, let p(k)(n) denote the number of hooks of length k in all the partitions of n. We prove that p(k)(n)≥p(k+1)(n) for all n≥0 and n≠k+1; and p(k)(k+1)−p(k+1)(k+1)=−1 for k≥2. For integers t≥2 and k≥1, let bt,k(n) denote the number of hooks of length k in all the t-regular partitions of n. We find generating functions of bt,k(n) for certain values of t and k. Exploring hook length biases for bt,k(n), we observe that in certain cases biases are opposite to the biases for ordinary partitions. We prove that b2,2(n)≥b2,1(n) for all n>4, whereas b2,2(n)≥b2,3(n) for all n≥0. We also propose some conjectures on biases among bt,k(n).

MDB-81. THE ROLE OF SURVEILLANCE IMAGING IN DETECTING RECURRENCE OF MEDULLOBLASTOMA

Abstract BACKGROUND In patients with medulloblastoma, imaging with magnetic resonance imaging (MRI) of the brain and spine plays an integral role in surveillance following treatment completion. The primary objective of imaging surveillance is to detect early recurrences, possibly leading to better salvage treatment. However, there is a lack of data to demonstrate the utility of imaging with possible demerits associated with increased resource utilization, scan-related anxiety, and lead or length time bias. METHODS Patients with histopathological confirmation of medulloblastoma treated in our institute between 2005 and 2022 were screened to identify patients with image-detected recurrences and corresponding documentation of symptoms and imaging intent (surveillance or directed by symptoms). RESULTS From a cohort of 545 patients treated during the period, 212 had disease recurrence, of which 153 had known symptomatology during the first recurrence. A total of 114 patients (75%) were having recurrence detected prompted by symptoms. Group 4 medulloblastomas were commonly seen to have recurrence detected on surveillance imaging (35%) compared to the SHH subgroup (25%) and group 3 (12%). During the final analysis, 141 of 153 patients had died. The median survival of patients detected to have asymptomatic relapse was 14 months compared to 5 months for symptomatic recurrences (p=0.03). The overall survival (calculated from index diagnosis) was not statistically significant between the two groups, with a 3-year survival of 53% (asymptomatic) vs 46% (symptomatic) (p=0.51). CONCLUSION In most patients, recurrences were detected by unplanned imaging ahead of scheduled surveillance imaging prompted by symptoms. Although the survival after recurrence is better in patients diagnosed on surveillance imaging, the overall survival was not different between the two groups, suggesting the possibility of lead time bias. Prospective studies are warranted to determine the role and appropriate frequency of surveillance imaging in patients with medulloblastoma.

Outcomes of Resected Lung Cancer Diagnosed Through Screening and Incidental Pulmonary Nodule Programs in a Mississippi Delta Cohort

IntroductionEarly lung cancer detection programs improve surgical resection rates and survival but may skew toward more indolent cancers. MethodsHypothesizing that differences in stage-stratified survival indicate differences in biological aggressiveness and possible length-time and overdiagnosis bias, we assessed a cohort who had curative-intent resection, categorized by diagnostic pathways: screening, incidental pulmonary nodule program, and non–program based. Survival was analyzed using Kaplan-Meier plots, log-rank tests, and Cox regression, comparing aggregate and stage-stratified survival across cohorts with Tukey’s method for multiple testing. ResultsOf 1588 patients, 111 patients (7%), 357 patients (22.5%), and 1120 patients (70.5%) were diagnosed through screening, pulmonary nodule, and non–program-based pathways; 0% versus 9% versus 6% were older than 80 years (p = 0.0048); 17%, 23%, and 24% had a Charlson Comorbidity score greater than or equal to 2 (p = 0.0143); 7%, 6%, and 9% had lepidic adenocarcinoma; 26%, 31%, and 34% had poorly or undifferentiated tumors (p = 0.1544); and 93%, 87%, and 77% had clinical stage I (p < 0.0001).Aggregate 5-year survival was 87%, 72%, and 65% (p = 0.0009), including 95%, 74%, and 74% for pathologic stage I. Adjusted pairwise comparisons showed similar survival in screening and nodule program cohorts (p = 0.9905). Nevertheless, differences were significant between screening and non–program-based cohorts (p = 0.0007, adjusted hazard ratio 0.33 [95% confidence interval: 0.18–0.6]) and between nodule and nonprogram cohorts (adjusted hazard ratio 0.77 [95% confidence interval: 0.61–0.99]). Stage I comparisons yielded p = 0.2256, 0.1131, and 0.911. In respective pathways, 0%, 2%, and 2% of patients with stage I disease who were older than 80 years had a Charlson score greater than or equal to 2 (p = 0.3849). ConclusionsNeither length-time nor overdiagnosis bias was evident in NSCLC diagnosed through screening or incidental pulmonary nodule programs.

Hepatocellular Carcinoma Screening in a Contemporary Cohort of At-Risk Patients

Cohort studies demonstrating an association of hepatocellular carcinoma (HCC) screening with reduced mortality are prone to lead-time and length-time biases. To characterize the clinical benefits of HCC screening, adjusting for lead-time and length-time biases, in a diverse, contemporary cohort of at-risk patients. This retrospective cohort study of patients with HCC was conducted between January 2008 and December 2022 at 2 large US health systems. Data analysis was performed from September to November 2023. The primary outcome was screen-detected HCC, defined by abnormal screening-intent abdominal imaging or α-fetoprotein level within 6 months before diagnosis. Cox regression analysis was used to characterize differences in overall survival between patients with screen-detected and non-screen-detected HCC; lead-time and length-time adjustments were calculated using the Duffy parametric formula. Among 1313 patients with HCC (mean [SD] age, 61.7 [9.6] years; 993 male [75.6%]; 739 [56.3%] with Barcelona Clinic Liver Cancer stage 0/A disease), HCC was screen-detected in 556 (42.3%) and non-screen detected in 757 (57.7%). Patients with screen-detected HCC had higher proportions of early-stage HCC (393 patients [70.7%] vs 346 patients [45.7%]; risk ratio [RR], 1.54; 95% CI, 1.41-1.70) and curative treatment receipt (283 patients [51.1%] vs 252 patients [33.5%]; RR, 1.52; 95% CI, 1.34-1.74) compared with patients with non-screen-detected HCC. The screen-detected group had significantly lower mortality, which persisted after correcting for lead-time bias (hazard ratio, 0.75; 95% CI, 0.65-0.87) in fully adjusted models. Both groups had similar tumor doubling times (median [IQR], 3.8 [2.2-10.7] vs 5.6 [1.7-11.4] months) and proportions of indolent tumors (28 patients [35.4%] vs 24 patients [38.1%]; RR, 0.93; 95% CI, 0.60-1.43). Adjustment for length-time bias decreased survival estimates, although 3-year and 5-year survival for patients with screen-detected HCC remained longer than that for patients with non-screen-detected HCC. The findings of this cohort study suggest that HCC screening is associated with reduced mortality even after accounting for lead-time and length-time biases. However, these biases should be considered in future studies.

Differences in molecular sampling and data processing explain variation among single-cell and single-nucleus RNA-seq experiments.

A mechanistic understanding of the biological and technical factors that impact transcript measurements is essential to designing and analyzing single-cell and single-nucleus RNA sequencing experiments. Nuclei contain the same pre-mRNA population as cells, but they contain a small subset of the mRNAs. Nonetheless, early studies argued that single-nucleus analysis yielded results comparable to cellular samples if pre-mRNA measurements were included. However, typical workflows do not distinguish between pre-mRNA and mRNA when estimating gene expression, and variation in their relative abundances across cell types has received limited attention. These gaps are especially important given that incorporating pre-mRNA has become commonplace for both assays, despite known gene length bias in pre-mRNA capture. Here, we reanalyze public data sets from mouse and human to describe the mechanisms and contrasting effects of mRNA and pre-mRNA sampling on gene expression and marker gene selection in single-cell and single-nucleus RNA-seq. We show that pre-mRNA levels vary considerably among cell types, which mediates the degree of gene length bias and limits the generalizability of a recently published normalization method intended to correct for this bias. As an alternative, we repurpose an existing post hoc gene length-based correction method from conventional RNA-seq gene set enrichment analysis. Finally, we show that inclusion of pre-mRNA in bioinformatic processing can impart a larger effect than assay choice itself, which is pivotal to the effective reuse of existing data. These analyses advance our understanding of the sources of variation in single-cell and single-nucleus RNA-seq experiments and provide useful guidance for future studies.

Isolating the effect of confounding from the observed survival benefit of screening participants — a methodological approach illustrated by data from the German mammography screening programme

BackgroundMammography screening programmes (MSP) aim to reduce breast cancer mortality by shifting diagnoses to earlier stages. However, it is difficult to evaluate the effectiveness of current MSP because analyses can only rely on observational data, comparing women who participate in screening with women who do not. These comparisons are subject to several biases: one of the most important is self-selection into the MSP, which introduces confounding and is difficult to control for. Here, we propose an approach to quantify confounding based on breast cancer survival analyses using readily available routine data sources.MethodsUsing data from the Cancer Registry of North Rhine-Westphalia, Germany, we estimate the relative contribution of confounding to the observed survival benefit of participants of the German MSP. This is accomplished by comparing non-participants, participants with screen-detected and participants with interval breast cancers for the endpoints “death from breast cancer” and “death from all causes other than breast cancer” — the latter being assumed to be unrelated to any MSP effect. By using different contrasts, we eliminate the effects of stage shift, lead and length time bias. The association of breast cancer detection mode with survival is analysed using Cox models in 68,230 women, aged 50–69 years, with breast cancer diagnosed in 2006–2014 and followed up until 2018.ResultsThe hazard of dying from breast cancer was lower in participants with screen-detected cancer than in non-participants (HR = 0.21, 95% CI: 0.20–0.22), but biased by lead and length time bias, and confounding. When comparing participants with interval cancers and non-participants, the survival advantage was considerably smaller (HR = 0.62, 95% CI: 0.58–0.66), due to the elimination of stage shift and lead time bias. Finally, considering only mortality from causes other than breast cancer in the latter comparison, length time bias was minimised, but a survival advantage was still present (HR = 0.63, 95% CI: 0.56–0.70), which we attribute to confounding.ConclusionsThis study shows that, in addition to stage shift, lead and length time bias, confounding is an essential component when comparing the survival of MSP participants and non-participants. We further show that the confounding effect can be quantified without explicit knowledge of potential confounders by using a negative control outcome.

Evolving paradigms in breast cancer screening: Balancing efficacy, personalization, and equity

Breast cancer remains a significant global health challenge, with projections indicating a troubling increase in incidence. Breast cancer screening programs have long been hailed as life-saving initiatives, yet their true impact on mortality rates is a subject of ongoing debate. Screening poses the risk of false positives and the detection of indolent tumors, potentially leading to overtreatment. Bias factors, including lead time, length time, and selection biases, further complicate the assessment of screening efficacy. Recent studies suggest that AI-driven image analysis may revolutionize breast cancer screening, maintaining diagnostic accuracy while reducing radiologists' workload. However, the generalizability of these findings to diverse populations is a critical consideration. Personalized screening approaches and equitable access to advanced technologies are essential to mitigate disparities. In conclusion, the breast cancer screening landscape is evolving, emphasizing the need for risk stratification, appropriate imaging modalities, and a personalized approach to reduce overdiagnosis and focus on cancers with the potential to impact lives while prioritizing patient-centered care.

CRISPR Interference-Based Functional Small RNA Genomics.

Small RNAs (sRNAs) are versatile regulators universally present in species across the prokaryotic kingdom, yet their functional characterization remains a major bottleneck. Gene inactivation through random transposon insertion has proven extremely valuable in discovering hidden gene functions. However, this approach is biased toward long genes and usually results in the underrepresentation of sRNA mutants. In contrast, CRISPR interference (CRISPRi) harnesses guide RNAs to recruit cleavage-deficient Cas nucleases to specific DNA loci. The ensuing steric hindrance inhibits RNA polymerase assembly at-or migration along-predefined genes, allowing for targeted knockdown screens without major length bias. In this chapter, we provide a detailed protocol for CRISPRi-based functional screening of bacterial sRNAs. Using the abundant microbiota species Bacteroides thetaiotaomicron as a model, we describe the design and generation of a guide library targeting the full intergenic sRNA repertoire of this organism and its application to identify sRNA knockdown-associated fitness effects. Our protocol is generic and thus suitable for the systematic assessment of sRNA-associated phenotypes in a wide range of bacterial species and experimental conditions. We expect CRISPRi-based functional genomics to boost sRNA research in understudied bacterial taxa, for instance, members of the gut microbiota.

High-risk and silent clonal hematopoietic genotypes in patients with nonhematologic cancer

AbstractClonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer.

Critical view on oligo(dT)-based RNA-seq: bias arising, modeling, and mitigating.

The precise biological interpretation of oligo(dT)-based RNA sequencing (RNA-seq) datasets, particularly in single-cell RNA-seq (scRNA-seq), is invaluable for understanding complex biological systems. However, the presence of biases can lead to misleading results in downstream analysis. This study has now identified two additional biases that are not accounted for in established bias models: poly(A)-tail length bias and fixed-position GC-content bias. These biases have a significant negative impact on the overall quality of oligo(dT)-based RNA-seq data. To address these biases, we have developed a universal bias-mitigating method based on the lower-affinity binding of short and nonanchored oligo(dT) primers to poly(A) tails. This method significantly reduces poly(A) length bias and completely eliminates fixed-position GC bias. Furthermore, the use of short oligo(dT) with impartial binding behavior toward the diverse poly(A) tails renders RNA-seq with more reliable measurements. The findings of this study are particularly beneficial for scRNA-seq datasets, where accurate benchmarking is critical.

Windshield bias is real: 2019 news coverage of pedestrian traffic fatalities in the United States

Framing pedestrian traffic fatalities episodically rather than thematically, attributing responsibility to pedestrians for their own deaths and non-agential descriptions of traffic crashes reflects windshield bias. Pedestrian traffic fatality rates increased dramatically in the U.S. over the previous decade. Findings from this content analysis of 2019 U.S. news coverage supports conclusions that windshield bias is national in scope, varies between cities in the Sun Belt and Frost Belt, and is associated with reduced walkability and greater partisan segregation of cities. The 2016 vote for Republican Donald Trump was also positively associated with episodic framing. An inverse association between word length and windshield bias was also established. The data set analyzed included 366 news articles drawn from 78 news sources in 74 cities located in 30 states.

MicrosatNavigator: exploring nonrandom distribution and lineage-specificity of microsatellite repeat motifs on vertebrate sex chromosomes across 186 whole genomes.

Microsatellites are short tandem DNA repeats, ubiquitous in genomes. They are believed to be under selection pressure, considering their high distribution and abundance beyond chance or random accumulation. However, limited analysis of microsatellites in single taxonomic groups makes it challenging to understand their evolutionary significance across taxonomic boundaries. Despite abundant genomic information, microsatellites have been studied in limited contexts and within a few species, warranting an unbiased examination of their genome-wide distribution in distinct versus closely related-clades. Large-scale comparisons have revealed relevant trends, especially in vertebrates. Here, "MicrosatNavigator", a new tool that allows quick and reliable investigation of perfect microsatellites in DNA sequences, was developed. This tool can identify microsatellites across the entire genome sequences. Using this tool, microsatellite repeat motifs were identified in the genome sequences of 186 vertebrates. A significant positive correlation was noted between the abundance, density, length, and GC bias of microsatellites and specific lineages. The (AC)n motif is the most prevalent in vertebrate genomes, showing distinct patterns in closely related species. Longer microsatellites were observed on sex chromosomes in birds and mammals but not on autosomes. Microsatellites on sex chromosomes of non-fish vertebrates have the lowest GC content, whereas high-GC microsatellites (≥ 50M% GC) are preferred in bony and cartilaginous fishes. Thus, similar selective forces and mutational processes may constrain GC-rich microsatellites to different clades. These findings should facilitate investigations into the roles of microsatellites in sex chromosome differentiation and provide candidate microsatellites for functional analysis across the vertebrate evolutionary spectrum.

Survival analysis of high-grade salivary gland carcinoma adjusted for length bias due to delay in comprehensive genomic profiling.

Survival analysis of high-grade salivary gland carcinoma adjusted for length bias due to delay in comprehensive genomic profiling.

Hook length biases and general linear partition inequalities

Hook length biases and general linear partition inequalities

Impact of thyroid hormone replacement on the risk of second cancer after thyroidectomy: a Korean National Cohort Study

We aimed to investigate the effect of thyroid hormone administration on the risk of second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer. Data were extracted from the medical billing data of the Health Insurance Review and Assessment Service in South Korea. Patients between 19 and 80 years old who underwent thyroid surgery at least once between January 2009 and June 2020 were included. Data of patients with second primary cancer and control patients with matched age, sex, operation date, and follow-up duration were extracted at a ratio of 1:4. A nested case–control analysis was performed to exclude length bias to confirm the correlation between the duration of thyroid hormone administration, dose, and incidence of second primary cancer. Of the 261,598 patients who underwent surgery for thyroid cancer included in the study, 11,790 with second primary cancer and 47,160 without second primary cancer were matched. The average dose of thyroid hormone increased the adjusted odds ratio (OR) for both low (≤ 50 μg, OR 1.29, confidence interval (CI) 1.12–1.48) and high (< 100 μg, OR 1.24, CI 1.12–1.37) doses. Analyzing over time, the adjusted OR of second primary cancer increased, especially in short (≤ 1 year) (OR 1.19; CI 1.06–1.34) and long (> 5 years) duration (OR 1.25; CI 1.10–1.41). In conclusion, insufficient and excessive thyroid hormone replacement might be linked to increased second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer.

Performance and effectiveness of hepatocellular carcinoma screening in individuals with HBsAg seropositivity in China: a multicenter prospective study.

Current guidelines recommend hepatocellular carcinoma (HCC) surveillance for at-risk individuals, including individuals with hepatitis B virus infection. However, the performance and survival benefits of annual screening have not been evaluated through multicenter prospective studies in a Chinese population. Between 2017 and 2021, we included 14,426 participants with hepatitis B surface antigen seropositivity in an annual HCC screening study in China using a multicenter prospective design with ultrasonography and serum alpha-fetoprotein. After four rounds of screening and follow-up, the adjusted hazard ratios of death after correction for lead-time and length-time biases for screen-detected cancers at the prevalent and incident rounds were 0.74 (95% confidence interval = 0.60-0.91) and 0.52 (95% confidence interval = 0.40-0.68), respectively. A meta-analysis demonstrated that HCC screening was associated with improved survival after adjusting for lead-time bias. Our findings highlight the 'real-world' feasibility and effectiveness of annual HCC screening in community settings for the early detection of HCC and to improve survival.

SOI FinFET Design Optimization for Radiation Hardening and Performance Enhancement

This work proposes Total Ionizing Dose (TID) hardening techniques compatible with conventional 14-nm-node silicon-on-insulator (SOI) FinFETsf process flows through performing 3-dimensional (3-D) simulations based on technology computer-aided design (TCAD) tools. The simulation results reveal a significantly critical TID impact induced by trapped charges in the buried oxide (BOX) and the spacer with calibration against 14 nm SOI FinFETfs experimental data (error < 6%). Inspired by the physical interpretation, an optimization technique featuring an optimized gate structure, spacer length, and substrate bias is designed. The optimized gate structure is utilized to enhance the local gate-to-channel coupling at the bottom and reduce the generation and capture of electron-hole pairs. By reducing the spacer length, a lower sensitive volume in the spacer can effectively suppress the TID response. The setting of the negative substrate bias greatly improves the subthreshold characteristics, weakening the TID effect in the BOX. By adopting the combined optimization including these techniques, the threshold voltage shift (VTH) induced by a 5 Mrad(SiO2) irradiation can be reduced to 21 mV, whereas VTH is 45 mV with only gate structure optimized and 97 mV without hardening. Meanwhile, the ION/IOFF after radiation increases to 1 × 107, which is at least four orders of magnitude better than the original device. Meanwhile, subthreshold swing (SS) is reduced from 81 mV/dec to 71 mV/dec, and Drain Induced Barrier Lowering (DIBL) is reduced from 120 mV/V to 99 mV/V, respectively. The combined optimization design is demonstrated as an effective method to improve the tolerance against TID irradiation without compromising performance, promoting 14 nm SOI FinFET’s application in future harsh space environments.