Background: Pulmonary rehabilitation (PR) can improve muscle strength and balance in individuals with advanced lung cancer. Typically, exercise instructions are provided through brochures; however, these lack engagement. Augmented reality (AR) applications can integrate users into digital interfaces, potentially increasing their motivation to exercise. However, no AR-based PR currently exists for individuals with advanced lung cancer. Methods: Fifty participants with advanced lung cancer were enrolled in this study. Thirty participants received AR-based therapy and 20 received paper-based PR. The PR program, including strength, balance, and breathing training, was performed 3 times daily during hospitalization until the participants were discharged. The primary outcomes were improvements in grip strength, balance, and degree of dyspnea. Results: Quadriceps strength, balance function, and dyspnea significantly improved after PR in the total cohort during hospitalization, while grip strength showed no significant change. Between-group differences were not statistically significant. The questionnaire survey revealed reduced clinical workload and more efficient communication for the nursing staff when implementing AR-based PR. Participants also reported that AR-based pR was associated with higher motivation. Conclusion: AR-based PR was feasible for hospitalized individuals with advanced lung cancer and demonstrated short-term improvements comparable to paper-based PR. Furthermore, AR-based PR was associated with higher participant motivation and lower nursing workload, thus supporting its potential utility as an innovative complementary approach within conventional in-hospital rehabilitation.

Introduction:Transformed small-cell lung cancer (tSCLC) is a clinically important resistance mechanism to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer. This study characterizes clinical features, treatment outcomes, and biomarker profiles in patients with tSCLC. Methods:Data from 45 patients with EGFR-mutant NSCLC who developed tSCLC between 2014 and 2023 were analyzed. Demographic characteristics, treatment histories, and delta-like ligand 3 (DLL3) and B7-H3 expression were collected. Objective response rate, progression-free survival (PFS), and posttransformation survival (PTS) were assessed. Spatial transcriptomic profiling was performed in selected cases. Results:Most patients were women (60%) and never-smokers (75.6%). Exon 19 deletion was the predominant EGFR mutation (57.8%). Median PFS and PTS were 3.3 and 9.2 months, respectively. Etoposide plus platinum (EP) was the predominant first-line regimen (69.8%), with 23.2% of the patients receiving EP plus immune checkpoint or tyrosine kinase inhibitors. EP-based combination regimens yielded a numerically higher objective response rate and a significantly longer PFS than EP alone (7.5 versus 2.8 months, p = 0.002). PTS was longer with EP-based regimens than with other regimens (10.4 versus 6.4 months, p = 0.035). DLL3 and B7-H3 were expressed in 87.5% and 66.7% of tumors, respectively, without prognostic significance. Multivariable analysis identified brain metastasis and liver progression at transformation as adverse prognostic factors. Spatial transcriptomic analysis revealed neuroendocrine lineage reprogramming, stromal depletion, and immune exclusion. Conclusions:tSCLC remains an aggressive resistance phenotype with poor outcomes. EP-based combination strategies may provide clinical benefit, whereas frequent DLL3 expression supports further evaluation of targeted therapies.

BACKGROUND:Immune checkpoint inhibitors (ICIs) have demonstrated survival benefits when combined with platinum and etoposide (EP) in first-line (1L) treatment for extensive-stage small-cell lung cancer (ES-SCLC). We investigated the real-world outcomes, adverse events (AEs), and prognostic factors of Taiwanese patients with ES-SCLC receiving 1L ICI + EP. METHODS:We analyzed the clinical characteristics, objective response rates, disease control rates (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related AEs of patients with ES-SCLC who received ICI + EP or EP alone as 1L treatment. RESULTS:A total of 33 patients received ICI + EP, and 199 received EP alone. The 1L ICI + EP group had longer OS than did the 1L EP group (median: 13.9 months vs 8.5 months; p = 0.003). Baseline liver metastasis was associated with shorter 1L PFS, whereas undergoing consolidative thoracic radiotherapy (cTRT) was associated with longer 1L PFS. Baseline liver metastasis, severe hematological AEs (grade ≥ 3), and a neutrophil-to-lymphocyte ratio (NLR) of ≥4 were associated with shorter OS. CONCLUSION:Adding ICIs to 1L chemotherapy provides survival benefits in ES-SCLC, while close monitoring for AEs is required. cTRT enhances local tumor control and improves PFS. Liver metastasis is associated with shorter PFS and OS. Severe hematological AEs and an elevated NLR predict poor OS in patients with ES-SCLC undergoing immunochemotherapy.

Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options, especially after the failure of first-line (1L) platinum-based chemotherapy. This study evaluated the treatment patterns and survival outcomes of Taiwanese patients with SCLC following 1L treatment failure, focusing on the effects of treatment-free interval (TFI). This retrospective study enrolled 287 patients with SCLC from 2012 to 2021. Data on clinical characteristics, systemic treatments after 1L failure, and survival status were collected. Progression-free survival (PFS) and overall survival (OS) were examined in analyses stratified by TFI. TFI < 90 days and ≥ 90 days denoted resistant relapse and sensitive relapse, respectively. Second-line (2L) and third-line (3L) chemotherapy was administered to 76

BACKGROUND:Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), penetrates the blood-brain barrier and provides intracranial tumor control in non-small-cell lung cancer (NSCLC). This study investigated whether combining osimertinib with intracranial radiotherapy (RT) improved outcomes in the patients with EGFR-mutant lung adenocarcinoma and brain metastases. METHODS:This is a retrospective analysis included patients who took osimertinib accompanying with or without RT between 2014 and 2022 from a single tertiary medical center. At least one session of magnetic resonance imaging and clinical follow-up after treatment. Outcomes assessed were intracranial local control, intracranial distant control, and overall survival (OS). Kaplan-Meier curves were used for outcome demonstration. Cox regression analysis was also used to identify independent predictors from age, gender, smoking, characteristics of brain metastases, KPS, gene types (presence of T790M), and radiation modalities. RESULTS:A total of 567 brain metastases from 69 patients were enrolled: TKI alone (n = 38) and TKI + RT (n = 31). Intracranial local control was significantly higher with TKI+RT compared with TKI alone (77% vs 23%; p < 0.01) at 3-year follow-up. Intracranial distant control was also longer in the TKI + RT group (23.2 vs 8.7 months in median; p < 0.01). No significant difference in OS was observed between the two groups ( p = 0.27). Multivariable analysis demonstrated that the presence of T790M mutation ( p = 0.01) and TKI + RT ( p = 0.01) were associated with improved intracranial local control, while TKI + RT was also associated with improved intracranial distant control ( p = 0.03). CONCLUSION:The addition of RT to osimertinib enhanced intracranial local and distant control in the patients with EGFR-mutant lung adenocarcinoma and brain metastases, although no survival benefit was observed. Prospective studies are warranted to validate these findings.

Tarlatamab is a bispecific T-cell engager (BiTE®) immunotherapy that binds delta-like ligand 3 on the surface of small cell lung cancer (SCLC) cells and CD3 on T cells, facilitating T cell-mediated cancer cell lysis. In the primary analysis of the phase 2 DeLLphi-301 study (NCT05060016), tarlatamab showed a favourable benefit-to-risk profile with durable objective responses and promising survival outcomes in patients with previously treated SCLC. Here, phase 2 data for the Asia region subgroup are presented. Patients with previously treated, advanced SCLC received 10 mg tarlatamab every 2 weeks. The primary endpoint was objective response rate (ORR) by blinded independent central review (RECIST version 1.1). Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. The present analysis includes patients enrolled at sites in Asia. A total of 43 patients were enrolled at sites in Asia. ORR was 46.3

BACKGROUND:Limited information is available regarding the clinical features and outcomes of advanced human epidermal growth factor receptor 2 ( HER2 )-mutant non-small cell lung cancer (NSCLC) in Taiwan, despite expanding treatment options for this distinct subtype. This study aimed to investigate the clinical characteristics and outcomes of HER2-mutant NSCLC in a real-world setting. METHODS:Relevant data were collected from patients with advanced or recurrent HER2 -mutant NSCLC who received systemic therapy between 2011 and 2021 and were followed up until 2022 at two medical centers in Taiwan. Clinical features, treatment responses, and survival-related factors were analyzed. RESULTS:This study included 45 patients (median age: 59.7 [range: 41.3-78.7] years). A775_G776insYVMA was the most common HER2 mutation subtype (57.8%), followed by G778_P780dup (11.1%). Approximately 53.3% of the patients received first-line platinum-based chemotherapy (PC) alone, whereas 13.3% received PC combined with an immune checkpoint inhibitor (ICI). The median overall survival (OS) and progression-free survival (PFS) after first-line therapy were 25.8 and 4.4 months, respectively. The objective response rate was generally higher in patients receiving first-line PC + ICI than those receiving PC alone (33.3% vs 12.5%; p = 0.269). Furthermore, patients receiving PC + ICI had longer PFS than those receiving PC alone (9.5 vs 4.4 months; p = 0.131) and those receiving tyrosine kinase inhibitor/ICI monotherapy (9.5 vs 0.5 months; p = 0.015). Compared with patients having other NSCLC subtypes, those carrying HER2 exon 20 insertion mutations had shorter median PFS (17.3 vs 2.9 months; p = 0.043) and OS (not reached vs 19 months; p = 0.031). CONCLUSION:This study highlights the clinical features and outcomes of advanced HER2 -mutant NSCLC in Taiwan. PC + ICI may be more effective than other regimens as first-line therapy. The prognostic impact of HER2 exon 20 insertion mutations warrants further investigation.

Small cell lung cancer (SCLC) is associated with high mortality and limited therapeutic options. There is increasing recognition that SCLC harbors molecular heterogeneity. Using a new liquid biopsy assay, it is demonstrated that SCLC subtypes, as determined by patient tumor tissue staining and cell lines, can be accurately identified by measuring the mRNA expression of subtype transcription factors (ASCL1, POU2F3, and NEUROD1) in circulating exosome-rich extracellular vesicles (Exo). Additionally, upregulation of Delta-like ligand 3 (DLL3) mRNA in Exo and its membrane protein (mProtein) in extracellular vesicles associated with tumor (tEV) may distinguish both limited- and extensive-stage SCLC patients from high-risk smokers, with AUC/ROC values of 0.836 and 0.839, respectively. By incorporating Exo-ASCL1 and Exo-POU2F3 mRNA expression with DLL3 Exo-mRNA/tEV-mProtein expression, the classifier enhances the AUC/ROC to 0.912 and 0.963 for limited- and extensive-stage SCLC patients, respectively.

PURPOSE:Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment for advanced EGFR-mutant non-small cell lung cancer (NSCLC). Despite this, most patients experience tumor progression. The optimal immunotherapy (IO)-based strategy and its timing after EGFR-TKI failure remains under debate. MATERIALS AND METHODS:A retrospective analysis was performed to assess the outcomes for patients with EGFR-mutant NSCLC who were treated with either IO alone or in combination with chemotherapy (C/T) following disease progression. Data from January 2014 to December 2022 at Taipei Veterans General Hospital were reviewed. The Kaplan-Meier method was used to evaluate overall survival (OS) and time to treatment failure (TTF), while a Cox proportional hazards model evaluated the impact of clinical factors on survival. RESULTS:This study enrolled 107 patients with advanced EGFR-mutant NSCLC, all of whom had previously been treated with first- to second-generation EGFR-TKIs. The IO alone group included 33 patients, while 74 patients were in the IO combined with chemotherapy (IO+C/T) group. The median number of prior treatment lines before immunotherapy was 2. The IO+C/T group demonstrated a trend toward longer OS compared to the IO alone group (OS: 20 vs. 16 months, P=0.70). Patients with more than four lines of treatment before IO-based therapy had significantly worse OS (6 vs. 29 months, P<0.001) and TTF (2 vs. 5, P=0.018) than those less than 4 lines of treatment. Multivariate analysis revealed that patients who had undergone more than 4 lines of treatment before IO-based therapy had poorer OS (HR 2.21, 95% CI 1.16-4.21, P=0.01) and TTF (HR 1.89, 95% CI 1.11-3.19, P=0.019) compared to those with fewer than 4 lines of treatment. The HRs for OS were 4.32 (95% CI 1.95-9.61, P<0.001) for patients with more than 4 lines of treatment and 2.05 (95% CI 1.04-4.05, P=0.038) for those with 2-4 lines of treatment, in comparison to patients who had 0-1 lines of treatment. CONCLUSION:This study highlights the potential benefits of early initiation of IO-based regimens in advanced EGFR-mutant NSCLC following EGFR-TKI failure. Combination therapy with chemotherapy showed a trend toward improved survival compared to IO monotherapy, although not statistically significant. Moreover, poorer outcomes associated with multiple prior treatments underscore the importance of timely implementation of IO-based strategies to optimize clinical benefit in this patient population.

Introduction Predictive markers for chemotherapy and immunotherapy response in advanced NSCLC are limited, and no objective tool exists to assess immune function, which is critical for treatment outcomes. This study prospectively evaluated the interferon gamma (IFN-γ) release assay (IGRA) as a potential predictor of treatment response and a tool for assessing immune function. Methods We enrolled patients with stage IV NSCLC undergoing first-line chemotherapy, EGFR tyrosine kinase inhibitor (TKI) therapy, or any line of single-agent immunotherapy, alongside stage I controls. Peripheral blood samples were collected pre- and post-treatment for IGRA testing using the QuantiFERON-TB Gold In-Tube (QFT-GIT) kit. Phytohemagglutinin-stimulated IFN-γ (PSIG) responses were measured by both QFT-GIT and in-house enzyme-linked immunosorbent assay, with stage IV patients categorized into high- and low-PSIG response groups based on median pretreatment values. Results A total of 117 patients were analyzed (32 surgery, 30 EGFR TKI, 25 chemotherapy, 30 immunotherapy). The median PSIG response was significantly higher in stage I patients than stage IV (1420 pg/mL versus 960 pg/mL; p = 0.032). In stage IV, those with driver mutations had higher pretreatment PSIG responses (1278 pg/mL versus 288 pg/mL; p = 0.004). Kaplan–Meier analysis suggested a trend toward longer progression-free and overall survival in the EGFR TKI and immunotherapy groups with higher PSIG responses, though not statistically significant. Conclusions Patients with advanced-stage NSCLC exhibited reduced lymphocyte function, and patients with driver mutations correlated to less exhausted lymphocyte. IGRA demonstrates potential as a clinical tool for assessing immune function in these patients.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis and accounts for approximately 11% of all lung cancers. Owing to the complex and aggressive nature of the disease, clinical management of SCLC is challenging. Many SCLC regional guidelines, including those from East Asia, have been developed in light of potential regional variations in socioeconomic conditions and healthcare infrastructure. However, less is known about the potential implications of the inherent population/regional differences in clinical management and the emerging treatment landscape in SCLC. Here, we review variations in the real-world patient characteristics and in diagnosis and treatment guidelines in SCLC between East Asia and Europe/North America. We also consider similarities and differences in real-world treatment patterns, as well as clinical outcomes between regions, to explore the need to adapt clinical management in SCLC.

Predicting complex disease risks on the basis of individual genomic profiles is an advancing field in human genetics1,2. However, most genetic studies have focused on populations of European ancestry, creating a global imbalance in precision medicine and underscoring the need for genomic research in non-European groups3,4. The Taiwan Precision Medicine Initiative recruited more than half a million Taiwanese residents, providing a large dataset of genetic profiles and electronic medical record data for people with Han Chinese ancestry. Using extensive phenotypic data, we conducted comprehensive genomic analyses across the medical phenome with individuals genetically similar to Han Chinese reference populations. These analyses identified population-specific genetic risk variants and new findings for various complex traits. We developed polygenic risk scores, demonstrating strong predictive performance for conditions such as cardiometabolic diseases, autoimmune disorders, cancers and infectious diseases. We observed consistent findings in an independent dataset, Taiwan Biobank, and among people of East Asian ancestry in the UK Biobank and the All of Us Project. The identified genetic risks accounted for up to 10.3% of the overall health variation in the Taiwan Precision Medicine Initiative cohort. Our approach of characterizing the phenome-wide genomic landscape, developing population-specific risk-prediction models, assessing their performance and identifying the genetic effect on health serves as a model for similar studies in other diverse study populations.

BackgroundPulmonary infections are a crucial health concern for patients with advanced non–small-cell lung cancer (NSCLC). Whether the clinical outcome of pulmonary infection is influenced by immunotherapy(IO) remains unclear. By evaluating immune signatures, this study investigated the post-immunotherapy risk of pulmonary infection in patients with lung cancer and identified circulating biomarkers that predict post-immunotherapy infection.MethodsBlood specimens were prospectively collected from patients with NSCLC before and after chemotherapy(C/T) and/or IO to explore dynamic changes in immune signatures. Real-world clinical data were extracted from medical records for outcome evaluation. Mass cytometry and ELISA were employed to analyze immune signatures and cytokine profiles to reveal potential correlations between immune profiles and the risk of infection.ResultsThe retrospective cohort included 283 patients with advanced NSCLC. IO was associated with a lower risk of pneumonia (odds ratio=0.46, p=0.012). Patients receiving IO and remained pneumonia-free exhibited the most favorable survival outcomes compared with those who received C/T or developed pneumonia (p<0.001). The prospective cohort enrolled 30 patients. The proportion of circulating NK cells significantly increased after treatment in IO alone (p<0.001) and C/T+IO group (p<0.01). An increase in cell densities of circulating PD-1+CD8+(cytotoxic) T cells (p<0.01) and PD-1+CD4+ T cells (p<0.01) were observed in C/T alone group after treatment. In IO alone group, a decrease in cell densities of TIM-3+ and PD-1+ cytotoxic T cells (p<0.05), and PD-1+CD4+ T cells (p<0.01) were observed after treatment. In C/T alone and C/T+IO groups, cell densities of circulating PD-1+ cytotoxic T cells significantly increased in patients with pneumonia after treatment(p<0.05). However, in IO alone group, cell density of PD-1+ cytotoxic T cells significantly decreased in patients without pneumonia after treatment (p<0.05). TNF-α significantly increased after treatment with IO alone (p<0.05) but decreased after C/T alone (p<0.01).ConclusionsOur results indicate that the incorporation of immunotherapy into treatment regimens may potentially offer protective effects against pulmonary infection. Protective effects are associated with reduction of exhausted T-cells and augmentation of TNF-α and NK cells. Exhausted T cells, NK cells, and TNF-α may play crucial roles in immune responses against infections. These observations highlight the potential utility of certain circulating biomarkers, particularly exhausted T cells, for predicting post-treatment infections.

Background: Programmed cell death protein 1 ligand 1 (PD-L1) expression alone may not be the optimal predictor of immunotherapy (IO) efficacy in advanced non-small cell lung cancer (NSCLC). Evaluation of circulating immune signatures using mass cytometry is a promising technique for predicting IO response and prognosis. The utility of circulating immune signatures for efficacy prediction after IO in advanced NSCLC remains to be elucidated. Objectives: To assess the feasibility of circulating immune cells and cytokines in predicting tumor response to IO in advanced NSCLC. Design: A prospective observational study. Methods: To investigate dynamic changes in immune signatures, blood specimens were prospectively collected from patients with NSCLC at baseline and following chemotherapy (C/T) and/or IO. Mass cytometry and enzyme-linked immunosorbent assay were used to characterize immune signatures and cytokine patterns to identify correlations between immune profiles and treatment efficacy. Results: The study enrolled 45 patients. The proportion of circulating natural killer (NK) cells and CD8 + T cells significantly increased after IO alone treatment. Cell levels of PD-1 + CD8 + T cells, PD-1 + CD4 + T cells, TIM-3 + CD8 + T cells, LAG-3 + NK cells, and LAG-3 + CD8 + T cells significantly decreased in patients with treatment response to IO alone. Tumor necrosis factor-alpha (TNF-α) levels significantly increased after IO alone treatment. Patients with high PD-1 + CD8 + T cells before IO alone treatment had lower overall survival (OS) compared to those with low levels. Patients with high LAG-3 + CD8 + T cells before chemotherapy plus immunotherapy treatment had lower OS compared to those with low levels. Conclusion: Responses to IO in NSCLC were correlated with declines in specific exhausted T cells, suggesting that IO may exert therapeutical efficacy by decreasing circulating exhausted T cells, which were associated with poorer survival, while also increasing TNF-α. These results highlight the prognostic value of monitoring changes in circulating exhausted T cells to predict IO response and survival outcomes in advanced lung cancer.

Objectives Molecular subtyping of small cell lung cancer (SCLC) tumors based on the expression of four transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) using immunohistochemical (IHC) staining has recently emerged as a proposed approach. This study was aimed to examine this subtyping method in Asian patients with SCLC and investigate its correlation with treatment efficacy. Materials and methods Seventy-two tumor samples from patients with SCLC, including de novo cases and those transformed from EGFR-mutant tumors, were analyzed. IHC staining was used to measure the expression of the four transcription factors and conventional SCLC markers. Subtypes were defined based on relative expression levels. The treatment response and outcome of patients receiving immune checkpoint inhibitors and chemotherapy were also reviewed. Results ASCL1 was the most common subtype, observed in 55.2 % of the samples, followed by NEUROD1 (26.9 %) and POU2F3 (9 %). No tumor exhibited predominant YAP1 positivity, while 41.8 % of the samples demonstrated positivity for two subtype markers. Approximately 50 % of the patients experienced a subtype switch after disease progression. Patients with the ASCL1/NEUROD1 (SCLC-A/N) subtype had similar progression-free survival (PFS) compared to non-SCLC-A/N patients after treatment with immune checkpoint inhibitors plus chemotherapy. Transformed SCLC patients had significantly worse PFS than de novo SCLC patients after chemoimmunotherapy. (2.1 vs. 5.4 months, P = 0.023) Conclusions This study revealed the challenges associated with using IHC alone for molecular subtyping, highlighting the frequent co-expression of subtypes and temporal changes following treatment. Further research is warranted to explore the prognostic and therapeutic implications of IHC subtyping in patients with SCLC.

Predicting complex disease risks based on individual genomic profiles is an advancing field in human genetics. However, most genetic studies have focused on European populations, creating a global imbalance in precision medicine and underscoring the need for genomic research in non-European groups. The Taiwan Precision Medicine Initiative (TPMI) recruited over half a million Taiwanese residents, providing the largest datasets of genetic profiles and electronic medical records for the Han Chinese. Using extensive phenotypic data, we conducted the largest genomic analyses of Han Chinese across the medical phenome. These analyses identified population-specific genetic risk variants and novel findings on the genetic architecture of complex traits. We developed polygenic risk scores, demonstrating strong predictive performance for conditions such as cardiometabolic diseases, autoimmune disorders, cancers, and infectious diseases. We observed consistent findings in an independent dataset, Taiwan Biobank, and among East Asians in the UK Biobank and the All of Us Project. The identified genetic risks accounted for up to 9.1% of the disease burden variance in Taiwan. Our approach of characterizing the phenome-wide genomic landscape, developing population-specific risk prediction models, assessing their performance, and identifying the genetic impact on health, serves as a model for similar studies in other diverse study populations. ### Competing Interest Statement SDHH is a founder, shareholder, and serves on the Board of Directors of Genomic Prediction, Inc. (GP). EW is an employee and shareholder of GP. ### Funding Statement This study was funded in part by the Academia Sinica (40-05-GMM, AS-GC-110-MD02, and 236e-1100202 to P.-Y.K. and J.-Y.W.) and the National Development Fund, Executive Yuan (NSTC 111-3114-Y-001-001 to P.-Y.K.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Institutional Review Boards of Taipei Veterans General Hospital (2020-08-014A), National Taiwan University Hospital (201912110RINC), Tri-Service General Hospital (2-108-05-038), Chang Gung Memorial Hospital (201901731A3), Taipei Medical University Healthcare System (N202001037), Chung Shan Medical University Hospital (CS19035), Taichung Veterans General Hospital (SF19153A), Changhua Christian Hospital (190713), Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUHIRB-SV(II)-20190059), Hualien Tzu Chi Hospital (IRB108-123-A),Far Eastern Memorial Hospital (110073-F), Ditmanson Medical Foundation Chia-Yi Christian Hospital (IRB2021128), Taipei City Hospital (TCHIRB-10912016), Koo Foundation Sun Yat-Sen Cancer Center (20190823A), Cathay General Hospital (CGH-P110041), Fu Jen Catholic University Hospital (FJUH109001) and Academia Sinica (AS-IRB01-18079), Taiwan. Written informed consent was obtained from the subjects in accordance with institutional requirements and the Declaration of Helsinki principles. All collected information was de-identified before statistical data analysis. The analysis with Health and Welfare Data Science Center (HWDC) was approved by Institutional Review Boards of Academia Sinica (AS-IRB-BM-23056). This research has been conducted using the UK Biobank Resource under UK Biobank Main Application 15326. Work with All of Us data was performed using the All of Us Researcher Workbench under the workspace, Duplicate of Prediction of Polygenic Traits. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The genotyping and electronic medical record (EMR) data analyzed in this study are from the Taiwan Precision Medicine Initiative (TPMI) with proper approval from the TPMI Data Access Committee. In compliance with the confidentiality laws governing genetic and health data in Taiwan, the de-identified TPMI data are kept in a secure server at the Academia Sinica and not released to the public.