Survival Genie: A web platform for single cell data, gene ratio, and cell composition based survival analyses across adult and pediatric cancers

Immune Cell ◽

Molecular Profile ◽

Pediatric Cancers ◽

Gene Sets ◽

Correlate Gene

The genomics data-driven identification of gene signatures and pathways has been routinely explored for predicting cancer survival and making decisions related to targeted treatments. A large number of packages and tools have been developed to correlate gene expression/mutations to the clinical outcome but lack the ability to perform such analysis based on pathways, gene sets, and gene ratios. Furthermore, in this single cell omics era, the cluster markers from cancer single cell transcriptomics studies remain an underutilized prognostic option. Additionally, no bioinformatics online tool evaluates the associations between the enrichment of canonical cell types and survival across cancers. Here we have developed Survival Genie, a web tool to perform survival analysis on single cell RNA-seq (scRNA-Seq) data and a variety of other molecular inputs such as gene sets, genes ratio, tumor infiltrating immune cells proportion, gene expression profile scores, and tumor mutation burden. For a comprehensive analysis, Survival Genie contains 53 datasets of 27 distinct malignancies from 11 different cancer programs related to adult and pediatric cancers. Users can upload scRNA-Seq data or gene sets and select a gene expression partitioning method (i.e., mean, median, quartile, cutp) to determine the effect of expression levels on survival outcomes. The tool provides comprehensive results including box plots of low and high-risk groups, Kaplan-Meier plots with univariate Cox proportional hazards model, and correlation of immune cell enrichment and molecular profile. The analytical options and comprehensive collection of cancer datasets make Survival Genie a unique resource to correlate gene sets, pathways, cellular enrichment, and single-cell signatures to clinical outcomes to assist in developing next-generation prognostic and therapeutic biomarkers. Survival Genie is open-source and available online at https://bbisr.shinyapps.winship.emory.edu/SurvivalGenie/.

Fibroblast growth factor receptor 3 (FGFR3), peroxisome proliferator-activated receptor gamma (PPARg), and outcomes with nivolumab (nivo) in metastatic urothelial cancer (UC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.511 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 511-511 ◽

Cited By ~ 4

Author(s):

Matt D. Galsky ◽

Abdel Saci ◽

Peter Szabo ◽

Li Wang ◽

Jun Zhu ◽

...

Keyword(s):

Gene Expression ◽

Peroxisome Proliferator ◽

Metastatic Urothelial Cancer ◽

Pearson's R ◽

Pparg Gene ◽

Pparg Expression ◽

Pearson’S R

511 Background: Prior studies have correlated FGFR3 mutations (mut) and increased PPARg expression with decreased T-cell infiltration raising the possibility that these might represent mediators of PD-1/PD-L1 blockade resistance in luminal UC and targets for combination strategies. The causality of these associations remains unclear and the clinical relevance in PD-1/PD-L1 blockade treated patients has been underexplored. Methods: Archival tumor specimens from patients enrolled on CheckMate 275, a phase 2 trial of nivo in patients with platinum-resistant metastatic UC, underwent whole exome sequencing (WES) and gene expression profiling (HTG EdgeSeq). CD8 expression was determined by immunohistochemistry. Results: WES and gene expression data was available for 139 and 217 patients, respectively; the baseline characteristics and outcomes of both cohorts were similar to the full CheckMate 275 cohort. FGFR3mut were detected in 15 patients (11%) and correlated with higher FGFR3 gene expression. Neither FGFR3mut nor FGFR gene expression correlated with CD8 expression (Pearson's r -0.13; p=0.16) or with response rate (RR), progression-free survival (PFS), or overall survival (OS); RR in FGFRmut vs. FGFRwt = 20% vs 20%. PPARg gene expression was inversely correlated with CD8 (Pearson’s r -0.44; P <0.001) and IFNg gene expression (Pearson’s r -0.52; P <0.001). Higher PPARg gene expression was associated with inferior outcomes (Table); RR in PPARg highest vs lowest tertile = 15% vs 24%. Conclusions: FGFR3 alterations (mut/increased expression) do not preclude response to nivo and were not associated with decreased CD8. Higher PPARg expression was associated with decreased CD8, lower RR to nivo, and significantly shorter PFS and OS. These data support exploring therapeutic modulation of PPARg or downstream mediators in an effort to overcome resistance to PD-1/PD-L1 blockade. Cox proportional hazards model. [Table: see text]

Biomarker analyses from the phase III CheckMate 214 trial of nivolumab plus ipilimumab (N+I) or sunitinib (S) in advanced renal cell carcinoma (aRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.5009 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 5009-5009 ◽

Cited By ~ 6

Author(s):

Robert J. Motzer ◽

Toni K. Choueiri ◽

David F. McDermott ◽

Thomas Powles ◽

Jin Yao ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Objective Response ◽

Gene Signature ◽

Gene Set Enrichment Analysis ◽

Phase Iii ◽

Mesenchymal Transition ◽

Gene Sets

5009 Background: In CheckMate 214 (NCT02231749), N+I demonstrated superior clinical outcomes vs S in patients (pts) with aRCC. Here, we report exploratory biomarker analyses of pretreatment tumor samples relative to outcomes. Methods: Formalin-fixed, paraffin-embedded aRCC samples were characterized by immunohistochemistry (tumor programmed death ligand 1 [PD-L1], n = 992; PD-L1 combined positive score [CPS], n = 980), whole exome sequencing (WES; tumor mutational burden, indel burden, HLA class I zygosity, and PBRM1 mutation status; n = 481), and RNAseq (n = 213). Gene signature scores were calculated as the median value of Z-scored expression for transcripts. Association with outcome was tested using Fisher’s exact test and Cox proportional hazards model. With ≥ 42 mo follow-up, prolonged progression-free survival (PFS) with N+I ( < or ≥ 18 mo; n = 82 vs 27, respectively) was analyzed by limma and gene set enrichment analysis of Hallmark gene sets (MSigDB). Results: PD-L1 CPS did not have improved predictive power over tumor PD-L1. The WES-derived biomarkers were not associated with outcomes in pts treated with N+I or S. For the RNAseq cohort, objective response rates (ORR) for pts with ≥ median scores, and hazard ratios (HR) relative to < median are shown (Table). A higher angiogenesis (Angio) gene signature score was associated with higher ORR and PFS for S; lower Angio score was associated with higher ORR in N+I. Immune signature scores were not predictive for ORR in N+I. Prolonged PFS with N+I (≥ 18 mo, n = 27) was associated with higher expression of Hallmark inflammatory response and Hallmark epithelial mesenchymal transition (EMT) gene sets (both adjusted P = 0.002). Conclusions: The Angio gene signature was associated with ORR for S (high score) and N+I (low score). Prolonged PFS in 27 pts receiving N+I was linked with inflammation (consistent with findings from PD-1 blockade monotherapy), but associated with EMT-related transcripts (in contrast with findings in other tumor types). Further validation of these exploratory analyses will be required. Clinical trial information: NCT02231749 . [Table: see text]

Age at Exposure to Parental Suicide and the Subsequent Risk of Suicide in Young People

Crisis ◽

10.1027/0227-5910/a000468 ◽

2018 ◽

Vol 39 (1) ◽

pp. 27-36 ◽

Cited By ~ 5

Author(s):

Kuan-Ying Lee ◽

Chung-Yi Li ◽

Kun-Chia Chang ◽

Tsung-Hsueh Lu ◽

Ying-Yeh Chen

Keyword(s):

Young People ◽

Proportional Hazards ◽

Birth Registry ◽

Data Set ◽

Parental Suicide ◽

The Impact ◽

Age At Exposure

Abstract. Background: We investigated the age at exposure to parental suicide and the risk of subsequent suicide completion in young people. The impact of parental and offspring sex was also examined. Method: Using a cohort study design, we linked Taiwan's Birth Registry (1978–1997) with Taiwan's Death Registry (1985–2009) and identified 40,249 children who had experienced maternal suicide (n = 14,431), paternal suicide (n = 26,887), or the suicide of both parents (n = 281). Each exposed child was matched to 10 children of the same sex and birth year whose parents were still alive. This yielded a total of 398,081 children for our non-exposed cohort. A Cox proportional hazards model was used to compare the suicide risk of the exposed and non-exposed groups. Results: Compared with the non-exposed group, offspring who were exposed to parental suicide were 3.91 times (95% confidence interval [CI] = 3.10–4.92 more likely to die by suicide after adjusting for baseline characteristics. The risk of suicide seemed to be lower in older male offspring (HR = 3.94, 95% CI = 2.57–6.06), but higher in older female offspring (HR = 5.30, 95% CI = 3.05–9.22). Stratified analyses based on parental sex revealed similar patterns as the combined analysis. Limitations: As only register-based data were used, we were not able to explore the impact of variables not contained in the data set, such as the role of mental illness. Conclusion: Our findings suggest a prominent elevation in the risk of suicide among offspring who lost their parents to suicide. The risk elevation differed according to the sex of the afflicted offspring as well as to their age at exposure.

Proliferation-dominant high-grade astrocytoma: survival benefit associated with extensive resection of FLAIR abnormality region

Journal of Neurosurgery ◽

10.3171/2018.12.jns182775 ◽

2020 ◽

Vol 132 (4) ◽

pp. 998-1005 ◽

Cited By ~ 4

Author(s):

Haihui Jiang ◽

Yong Cui ◽

Xiang Liu ◽

Xiaohui Ren ◽

Mingxiao Li ◽

...

Keyword(s):

Survival Benefit ◽

Proportional Hazards ◽

Characteristic Curve ◽

Extent Of Resection ◽

High Grade ◽

Extensive Resection ◽

High Grade Astrocytoma

OBJECTIVEThe aim of this study was to investigate the relationship between extent of resection (EOR) and survival in terms of clinical, molecular, and radiological factors in high-grade astrocytoma (HGA).METHODSClinical and radiological data from 585 cases of molecularly defined HGA were reviewed. In each case, the EOR was evaluated twice: once according to contrast-enhanced T1-weighted images (CE-T1WI) and once according to fluid attenuated inversion recovery (FLAIR) images. The ratio of the volume of the region of abnormality in CE-T1WI to that in FLAIR images (VFLAIR/VCE-T1WI) was calculated and a receiver operating characteristic curve was used to determine the optimal cutoff value for that ratio. Univariate and multivariate analyses were performed to identify the prognostic value of each factor.RESULTSBoth the EOR evaluated from CE-T1WI and the EOR evaluated from FLAIR could divide the whole cohort into 4 subgroups with different survival outcomes (p < 0.001). Cases were stratified into 2 subtypes based on VFLAIR/VCE-T1WIwith a cutoff of 10: a proliferation-dominant subtype and a diffusion-dominant subtype. Kaplan-Meier analysis showed a significant survival advantage for the proliferation-dominant subtype (p < 0.0001). The prognostic implication has been further confirmed in the Cox proportional hazards model (HR 1.105, 95% CI 1.078–1.134, p < 0.0001). The survival of patients with proliferation-dominant HGA was significantly prolonged in association with extensive resection of the FLAIR abnormality region beyond contrast-enhancing tumor (p = 0.03), while no survival benefit was observed in association with the extensive resection in the diffusion-dominant subtype (p=0.86).CONCLUSIONSVFLAIR/VCE-T1WIis an important classifier that could divide the HGA into 2 subtypes with distinct invasive features. Patients with proliferation-dominant HGA can benefit from extensive resection of the FLAIR abnormality region, which provides the theoretical basis for a personalized resection strategy.

Association of time to surgery with leg pain after lumbar discectomy: is delayed surgery detrimental?

Journal of Neurosurgery Spine ◽

10.3171/2019.8.spine19613 ◽

2020 ◽

Vol 32 (2) ◽

pp. 160-167 ◽

Cited By ~ 2

Author(s):

Alessandro Siccoli ◽

Victor E. Staartjes ◽

Marlies P. de Wispelaere ◽

Marc L. Schröder

Keyword(s):

Rating Scale ◽

Lumbar Discectomy ◽

Neurological Deficits ◽

Leg Pain ◽

Specific Method ◽

Time To Surgery ◽

Patient Reported

OBJECTIVEWhile it has been established that lumbar discectomy should only be performed after a certain waiting period unless neurological deficits are present, little is known about the association of late surgery with outcome. Using data from a prospective registry, the authors aimed to quantify the association of time to surgery (TTS) with leg pain outcome after lumbar discectomy and to identify a maximum TTS cutoff anchored to the minimum clinically important difference (MCID).METHODSTTS was defined as the time from the onset of leg pain caused by radiculopathy to the time of surgery in weeks. MCID was defined as a minimum 30% reduction in the numeric rating scale score for leg pain from baseline to 12 months. A Cox proportional hazards model was utilized to quantify the association of TTS with MCID. Maximum TTS cutoffs were derived both quantitatively, anchored to the area under the curve (AUC), and qualitatively, based on cutoff-specific MCID rates.RESULTSFrom a prospective registry, 372 patients who had undergone first-time tubular microdiscectomy were identified; 308 of these patients (83%) obtained an MCID. Attaining an MCID was associated with a shorter TTS (HR 0.718, 95% CI 0.546–0.945, p = 0.018). Effect size was preserved after adjustment for potential confounders. The optimal maximum TTS was estimated at 23.5 weeks based on the AUC, while the cutoff-specific method suggested 24 weeks. Discectomy after this cutoff starts to yield MCID rates under 80%. The 24-week cutoff also coincided with the time point after which the specificity for MCID first drops below 50% and after which the negative predictive value for nonattainment of MCID first surpasses ≥ 20%.CONCLUSIONSThe study findings suggest that late lumbar discectomy is linked with poorer patient-reported outcomes and that—in accordance with the literature—a maximum TTS of 6 months should be aimed for.

Survival of people living with AIDS with or without tuberculosis in Sao Paulo, Brazil

European Journal of Public Health ◽

10.1093/eurpub/ckaa166.835 ◽

2020 ◽

Vol 30 (Supplement_5) ◽

Author(s):

M V Tancredi ◽

S Sakabe ◽

C S B Domingues ◽

G F M Pereira² ◽

E A Waldman

Keyword(s):

Universal Access ◽

Sao Paulo ◽

Capital City ◽

São Paulo ◽

Aids Patients ◽

Probability Of Survival ◽

Aids Diagnosis

Abstract Background To estimate median survival time of AIDS patients, with and without tuberculosis (TB), in a cohort in Sao Paulo, Brazil, and to investigate survival predictors. Methods Retrospective cohort study of AIDS patients above 12 years old, registered at the Ministry of Health AIDS surveillance system between 2003-2007, and followed until 2014. Survival analysis used the Kaplan-Meier method and Cox proportional hazards model to estimate hazard ratios (HR), with respective 95% confidence intervals (CI = 95%). Results 35,515 patients were included, being 4,581 (12.9%) co-infected with TB. Among the latter, probability of survival 12 years after AIDS diagnosis was 95.2%, 82.9%, and 21.9%, respectively for patients receiving at least one third line ARV (HAART2), receiving triple therapy (HAART1) and the last one not on ARV. In the same period, the probability of survival for patients without TB, in the same order as for the therapeutic regimens, was 95.2%, 90.5%, and 40.9%, respectively. The main factors associated with survival, adjusted for the year of diagnosis, were: Living in the city of Sao Paulo (HR = 1,16;IC95% 1,01-1,32), living away from the capital city (HR = 1.43; 95%CI 1.25-1.62); or on the coast (HR = 1.49; 95%CI 1.21-1.82); having TB (HR = 1.70; 95%CI 1.49-1.87); above 49 years old (HR = 1.35; 95%CI 1.18-1.54); black (HR = 1.27; 95%CI 1.12-1.45); IV drug use (HR = 1.73; 95%CI 1.49-2.02); CD4+ below 200 cell/mm³ at AIDS diagnosis (HR = 2.31; 95%CI 1.97-2.72); viral load above 500 copies at AIDS diagnosis (HR = 1.99; 95%CI 1.72-2.30); HAART1 scheme (HR = 1.94; 95%CI 1.47-2.55); no ARV (HR = 8.22; 95%CI 2.95-22.87). Conclusions A large proportion of patients did not receive ARVs or were late diagnosed with AIDS, especially those with TB, whose survival was shorter. Survival is heterogeneous in the state, being lower in regions with higher TB rates. The results point to the need for specific strategies for patients with TB-HIV co-infection. Key messages Tuberculosis is the main cause of death among HIV-infected people, being responsible for one third of deaths in this group and causing a great impact on the survival of this population. The Brazilian policy of universal access to ARV and treatment for TB has increased the survival of AIDS-TB from 22% to 95% and in patients without TB from 50% to 95% up to 12 years after diagnosis.

Adapting the Default Weighted Survival Analysis Modelling Approach to Model IFRS 9 LGD

Risks ◽

10.3390/risks9060103 ◽

2021 ◽

Vol 9 (6) ◽

pp. 103

Author(s):

Morne Joubert ◽

Tanja Verster ◽

Helgard Raubenheimer ◽

Willem D. Schutte

Keyword(s):

Survival Analysis ◽

Financial Reporting ◽

Proportional Hazards ◽

Survival Curve ◽

Reporting Standard ◽

International Financial Reporting Standard ◽

Ifrs 9

Survival analysis is one of the techniques that could be used to predict loss given default (LGD) for regulatory capital (Basel) purposes. When using survival analysis to model LGD, a proposed methodology is the default weighted survival analysis (DWSA) method. This paper is aimed at adapting the DWSA method (used to model Basel LGD) to estimate the LGD for International Financial Reporting Standard (IFRS) 9 impairment requirements. The DWSA methodology allows for over recoveries, default weighting and negative cashflows. For IFRS 9, this methodology should be adapted, as the estimated LGD is a function of in the expected credit losses (ECL). Our proposed IFRS 9 LGD methodology makes use of survival analysis to estimate the LGD. The Cox proportional hazards model allows for a baseline survival curve to be adjusted to produce survival curves for different segments of the portfolio. The forward-looking LGD values are adjusted for different macro-economic scenarios and the ECL is calculated for each scenario. These ECL values are probability weighted to produce a final ECL estimate. We illustrate our proposed IFRS 9 LGD methodology and ECL estimation on a dataset from a retail portfolio of a South African bank.

Risk factors associated with major adverse cardiac and cerebrovascular events following percutaneous coronary intervention: a 10-year follow-up comparing random survival forest and Cox proportional-hazards model

BMC Cardiovascular Disorders ◽

10.1186/s12872-020-01834-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Maryam Farhadian ◽

Sahar Dehdar Karsidani ◽

Azadeh Mozayanimonfared ◽

Hossein Mahjub

Keyword(s):

Proportional Hazards ◽

Coronary Intervention ◽

Hazards Model ◽

Cerebrovascular Events ◽

Long Term Follow Up ◽

Stent Length

Abstract Background Due to the limited number of studies with long term follow-up of patients undergoing Percutaneous Coronary Intervention (PCI), we investigated the occurrence of Major Adverse Cardiac and Cerebrovascular Events (MACCE) during 10 years of follow-up after coronary angioplasty using Random Survival Forest (RSF) and Cox proportional hazards models. Methods The current retrospective cohort study was performed on 220 patients (69 women and 151 men) undergoing coronary angioplasty from March 2009 to March 2012 in Farchshian Medical Center in Hamadan city, Iran. Survival time (month) as the response variable was considered from the date of angioplasty to the main endpoint or the end of the follow-up period (September 2019). To identify the factors influencing the occurrence of MACCE, the performance of Cox and RSF models were investigated in terms of C index, Integrated Brier Score (IBS) and prediction error criteria. Results Ninety-six patients (43.7%) experienced MACCE by the end of the follow-up period, and the median survival time was estimated to be 98 months. Survival decreased from 99% during the first year to 39% at 10 years' follow-up. By applying the Cox model, the predictors were identified as follows: age (HR = 1.03, 95% CI 1.01–1.05), diabetes (HR = 2.17, 95% CI 1.29–3.66), smoking (HR = 2.41, 95% CI 1.46–3.98), and stent length (HR = 1.74, 95% CI 1.11–2.75). The predictive performance was slightly better by the RSF model (IBS of 0.124 vs. 0.135, C index of 0.648 vs. 0.626 and out-of-bag error rate of 0.352 vs. 0.374 for RSF). In addition to age, diabetes, smoking, and stent length, RSF also included coronary artery disease (acute or chronic) and hyperlipidemia as the most important variables. Conclusion Machine-learning prediction models such as RSF showed better performance than the Cox proportional hazards model for the prediction of MACCE during long-term follow-up after PCI.

Elevated plasma growth and differentiation factor 15 predicts incident anemia in older adults aged 60 years and older

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa324 ◽

2020 ◽

Author(s):

Yuko Yamaguchi ◽

Marta Zampino ◽

Toshiko Tanaka ◽

Stefania Bandinelli ◽

Yusuke Osawa ◽

...

Keyword(s):

Older Adults ◽

Proportional Hazards ◽

Differentiation Factor ◽

Hazards Model ◽

Increased Risk ◽

The Relationship

Abstract Background Anemia is common in older adults and associated with greater morbidity and mortality. The causes of anemia in older adults have not been completely characterized. Although elevated circulating growth and differentiation factor 15 (GDF-15) has been associated with anemia in older adults, it is not known whether elevated GDF-15 predicts the development of anemia. Methods We examined the relationship between plasma GDF-15 concentrations at baseline in 708 non-anemic adults, aged 60 years and older, with incident anemia during 15 years of follow-up among participants in the Invecchiare in Chianti (InCHIANTI) Study. Results During follow-up, 179 (25.3%) participants developed anemia. The proportion of participants who developed anemia from the lowest to highest quartile of plasma GDF-15 was 12.9%, 20.1%, 21.2%, and 45.8%, respectively. Adults in the highest quartile of plasma GDF-15 had an increased risk of developing anemia (Hazards Ratio 1.15, 95% Confidence Interval 1.09, 1.21, P<.0001) compared to those in the lower three quartiles in a multivariable Cox proportional hazards model adjusting for age, sex, serum iron, soluble transferrin receptor, ferritin, vitamin B12, congestive heart failure, diabetes mellitus, and cancer. Conclusions Circulating GDF-15 is an independent predictor for the development of anemia in older adults.

Mortality of Japanese Olympic athletes in 1964 Tokyo Olympic Games

BMJ Open Sport & Exercise Medicine ◽

10.1136/bmjsem-2020-000896 ◽

2021 ◽

Vol 7 (1) ◽

pp. e000896

Author(s):

Taro Takeuchi ◽

Yuri Kitamura ◽

Soya Ishizuka ◽

Sachiko Yamada ◽

Hiroshi Aono ◽

...

Keyword(s):

Women Athletes ◽

Japanese Population ◽

Female Athletes ◽

Olympic Games ◽

Handgrip Strength ◽

Smoking History ◽

Male Athletes

ObjectivesTo compare the mortality of Japanese athletes in the 1964 Tokyo Olympic Games with that of the Japanese population, and to elucidate factors associated with their mortality.MethodsWe obtained from the Japan Sport Association study subjects’ biographical information, information on lifestyles and medical data. Missing data were obtained from online databases. Standardised mortality ratio (SMR) was calculated to compare athletes’ mortality with the Japanese population. Cox proportional hazards model was applied to estimate the HR for each category of body mass index (BMI), smoking history and handgrip strength. This analysis was limited to male athletes due to the small number of female athletes.ResultsAmong 342 (283 men, 59 women) athletes, deaths were confirmed for 70 (64 men, 6 women) athletes between September 1964 and December 2017. Total person years was 15 974.8, and the SMR was 0.64 (95% CI 0.50 to 0.81). Multivariate analysis performed on 181 male athletes. Mortality was significantly higher for BMI≥25 kg/m2 than for 21–23 kg/m2 (HR: 3.03, 95% CI 1.01 to 9.07). We found no statistically significant associations between smoking history and mortality; the HR (95% CI) for occasional and daily smokers were 0.82 (0.26 to 2.57) and 1.30 (0.55 to 3.03) compared with never smokers. We also found no statistically significant associations between handgrip strength and mortality (P for trend: 0.51).ConclusionJapanese athletes in the 1964 Tokyo Olympic Games lived longer than the Japanese population. BMI≥25 kg/m2 was associated with higher mortality, but smoking history and handgrip strength were not associated with mortality.