Stacking Ensemble of Disproportionality Indicators for Adverse Vaccine Reactions Detection-An Empirical Study on Predicting Adverse Reactions of COVID-19 Vaccines.

Vaccine safety is a critical issue for public health, which has recently become more crucial than ever since COVID-19 started to spread worldwide in 2020. Many COVID-19 vaccines have been developed and used without following the traditional three clinical trial stages. Instead, most COVID-19 vaccines were approved through emergency use approval (EUA) within one year, significantly raising the risk of rare and severe adverse events. Reporting systems like the Vaccine Adverse Event Reporting System (VAERS) have been established worldwide to detect unknown and severe adverse reactions as early as possible. Although experts and researchers have been working hard to find ways to detect adverse vaccine event (AVE) signals from VAERS data, most of the contemporary methods are statistical methods based on measuring the disproportionality between vaccine-induced events and non-vaccine-induced events. This paper proposes a novel ensemble AVE detection method, which adopts a stacking ensemble of various disproportionality indicators, fusing dual-scale contingency values measured in single and cumulative yearly duration, and embraces the concept of feature concatenation. Experiments conducted on US VAERS data to predict AVE caused by COVID-19 vaccines show that our proposed method is effective. We observed that: (1) Stacking ensemble of various disproportionality indicators is superior to any single disproportionality indicator and voting ensemble method; (2) Fusing dual-scale contingency values and feature concatenation brings synergy to our proposed stacking ensemble AVE detection. Compared to the best disproportionality metric in this study, our top-performing ensemble version exhibited a 34% improvement in accuracy, 71% in precision, 29% in recall, and 77% in F-measure, with a slight decrease (8%) in specificity.

Adjuvant probiotic Bifidobacterium animalis subsp. lactis CP-9 improve phototherapeutic treatment outcomes in neonatal jaundice among full-term newborns: A randomized double-blind clinical study.

BACKGROUND: Probiotics had been used to decreased bilirubin level in neonatal jaundice (NJ) without being further studied mechanism and stratification. The intestinal pathogen Escherichia coli produced ß-glucuronidase would increase enterohepatic circulation and elevate serum bilirubin levels (SBLs) which might worsen the disease process of NJ. STUDY OBJECTIVE: We hypothesized that some probiotics could decrease bilirubin level through inhibiting the growth of E. coli. It's assumed that adjuvant probiotic intervention might accelerate the phototherapy for NJ and alleviate the severity of the NJ. Besides, it's further study the efficacy of the probiotic intervention in NJ among the full-term and preterm newborns. MATERIALS AND METHODS: Firstly, the Bifidobacterium animalis subsp. lactis CP-9 was screened for its anti-E. coli activity. Then, it was orally administered to newborns with NJ in combination with conventional phototherapy (wavelength 425-457 nm) to determine its efficacy. 83 neonatal patients whose serum bilirubinemia was at a concentration of ≥ 15 mg/dL were participated the double-blind randomized trial and conducted in the neonatal ward of China Medical University Children's Hospital (CMUCH, Taichung, Taiwan). The test was conducted in 2 groups: experimental group: phototherapy + B. animalis subsp. lactis CP-9 (n = 43; 5 × 109 CFU/capsule) and control group: phototherapy + placebo (n = 40). The SBL and total phototherapy duration were measured. RESULTS: The experimental group showed improved serum bilirubin decline rate (-0.16 ±â€…0.02 mg/dL/h; P = .009, 95% CI -0.12 to -0.2), particularly in the first 24 hour of in-hospital care, and reduced total phototherapy duration (44.82 ±â€…3.23 h; P = .011, 95% CI: 51.3-38.2) compared with the control group. Especially, probiotics had a significant therapeutic effect (serum bilirubin decline rate: -0.18 ±â€…0.02 mg/dL/h, 95% CI -0.12 to -0.23, P = .014; phototherapy duration: 43.17 ±â€…22.72 h, 95% CI 51.9-34.3, P = .019) in the low-risk subgroup (full-term newborns). CONCLUSIONS: In conclusion, B. animalis subsp. lactis CP-9 synergistically improves treatment outcomes of NJ during in-hospital phototherapy including reduced total phototherapy duration and improved serum bilirubin decline rate, particularly in full-term newborns.

Combinatorial Inactivation of Tumor Suppressors Efficiently Initiates Lung Adenocarcinoma with Therapeutic Vulnerabilities.

Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type, and the discovery of oncogene mutations has led to the development of targeted therapies that have improved clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens using quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Generation of hundreds of diverse combinations of tumor suppressor alterations demonstrates that inactivation of suppressors of the RAS and PI3K pathways drives the development of oncogene-negative lung adenocarcinoma. Human genomic data and histology identified RAS/MAPK and PI3K pathway activation as a common feature of an event in oncogene-negative human lung adenocarcinomas. These Onc-negativeRAS/PI3K tumors and related cell lines are vulnerable to pharmacologic inhibition of these signaling axes. These results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma. SIGNIFICANCE: To address the large fraction of lung adenocarcinomas lacking mutations in proto-oncogenes for which targeted therapies are unavailable, this work uncovers driver pathways of oncogene-negative lung adenocarcinomas and demonstrates their therapeutic vulnerabilities.

Impact of the food grade heat-killed probiotic and postbiotic oral lozenges in oral hygiene.

The oral cavity plays a crucial role in food digestion and immune protection. Thus, maintaining oral health is necessary. Postbiotic and heat-killed probiotic cells have shown increased antibacterial potential with stable viability compared with live strains. However, clinical evidence regarding their effect on oral health is insufficient. Therefore, in this study, we tested postbiotic lozenges of Lactobacillus salivarius subsp. salicinius AP-32, L. paracasei ET-66, and L. plantarum LPL28 and heat-killed probiotic lozenges of L. salivarius subsp. salicinius AP-32 and L. paracasei ET-66 for their effect on oral health. In total, 75 healthy individuals were blindly and randomly divided into placebo, postbiotic lozenge, and heat-killed probiotic lozenge groups and were administered the respective lozenge type for 4 weeks. Postbiotic and heat-killed probiotic lozenge groups demonstrated antibacterial activities with a considerable increase in L. salivarius in their oral cavity. Furthermore, their salivary immunoglobulin A, Lactobacillus, and Bifidobacterium increased. Subjective questionnaires completed by the participants indicated that participants in both the experimental groups developed better oral health and intestinal conditions than those in the placebo group. Overall, our study revealed that a food additive in the form of an oral postbiotic or heat-killed probiotic lozenge may effectively enhance oral immunity, inhibit the growth of oral pathogens, and increase the numbers of beneficial oral microbiota.

Probiotic Strains Isolated from an Olympic Woman's Weightlifting Gold Medalist Increase Weight Loss and Exercise Performance in a Mouse Model.

Obesity is a worldwide health problem. Calorie-restricted diets constitute a common intervention for treating obesity. However, an improper calorie-restricted diet can lead to malnutrition, fatigue, poor concretion, muscle loss, and reduced exercise performance. Probiotics have been introduced as an alternative treatment for obesity. In the present study, we tested the weight loss and exercise performance enhancement effectiveness of probiotic strains of different origins, including four isolated from an Olympic weightlifting gold medalist (Bifidobacterium longum subsp. longum OLP-01, Lactobacillus plantarum PL-02, Lactobacillus salivarius subsp. salicinius SA-03, and Lactococcus lactis subsp. lactis LY-66). A high-fat diet (HFD) was used to induce obesity in 16 groups of mice (n = 8/group). The mice were administered probiotic supplements at a dosage of 4.1 × 109 CFU/kg/day for 10 weeks. All probiotic supplementation groups showed a significant reduction in body weight and fat mass compared with the HFD group. TYCA06, CS-773, BLI-02, PL-02, bv-77, and OLP-01 were the most effective in facilitating weight loss and fat reduction, which may be due to fatty-acid absorbing activity. PL-02, LY-66, TYCA06, CS-773, and OLP-01 elevated the animals' grip strength and exhaustive running duration. PL-02, LY-66, and OLP-01 increased tissue glycogen (liver and muscle) levels and muscle capillary density and reduced blood lactate production levels after exercise. In conclusion, OLP-01, PL-02, LY-66, TYCA06, and CS-773 were highly effective in enhancing weight loss and exercise performance. This study should be repeated on humans in the future to further confirm the findings.

Adjuvant Probiotics of Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 Attenuate Glycemic Levels and Inflammatory Cytokines in Patients With Type 1 Diabetes Mellitus.

Introduction: Type 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of pancreatic ß cells. Previous study has discovered that probiotic strains residing in the gut play essential roles in host immune regulation. However, few clinical results demonstrated probiotic would actually benefit in attenuating glycated hemoglobin (HbA1c) along with inflammatory cytokine levels of the T1DM patients and analyzed their gut microbiota profile at the same time. In this clinical trial, we evaluated the therapeutic efficacy of probiotics on HbA1c along with inflammatory cytokine levels of T1DM patients to determine an alternative administration mode for T1DM medication. The probiotics changed T1DM gut microbiota profile will be measured by next-generation sequencing (NGS). Research Design and Methods: A randomized, double-blind, placebo-controlled trial was performed at China Medical University Hospital. T1DM patients between 6 and 18 years of age were enrolled. 27 patients were administered regular insulin therapy plus capsules containing probiotic strains Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 daily for 6 months, and 29 patients were administered insulin therapy without extra probiotic supplement as placebo group. The variations of fasting blood glucose and HbA1c in these patients were analyzed. In addition, serum levels of inflammatory cytokines and anti-inflammatory cytokine were assessed using enzyme-linked immunosorbent assay. Patients' stool microbiota were all subjects to NGS analysis. Results: NGS data showed elevated populations of Bifidobacterium animalis, Akkermansia muciniphila and Lactobacillus salivarius in the gut of patients with T1DM who were taking probiotics. Patients with T1DM who were administered probiotics showed significantly reduced fasting blood glucose levels compared with the before-intervention levels. The HbA1c levels of the patients also improved after administration of probiotics. The concentrations of IL-8, IL-17, MIP-1ß, RANTES, and TNF-α were significantly reduced and were associated with an increased TGF-ß1 expression after probiotic intervention. The persistence effect of glycemic control and immunomodulation were observed even 3 months after discontinuation of the probiotics. Conclusions: Here, we found that conventional insulin therapy plus probiotics supplementation attenuated T1DM symptoms than receiving insulin treatment only. Probiotics supplementation with insulin treatment changed gut microbiota and revealed better outcome in stabilizing glycemic levels and reducing HbA1c levels in patients with T1DM through beneficial regulation of immune cytokines. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03880760.

Probiotics and their Metabolites Reduce Oxidative Stress in Middle-Aged Mice.

Aging is an irreversible physiological degradation of living organisms. Accumulated oxidative stress and dysbiosis accelerate aging. Probiotics such as Lactobacillus and Bifidobacterium and their fermented metabolites (postbiotics) have been discovered to exhibit antioxidative activities that regulate oxidative stress and protect cells from oxidative damage. We screened selected Lactobacillus and Bifidobacterium strains and their postbiotics for potential antioxidative activity by using DPPH (2,2-Diphenyl-1-picrylhydrazyl) assay. Strains with their metabolites were selected for mixed formula in experiments involving aging mice. The aged groups presented higher oxidative stress in the brain, liver, heart, and kidney than did young mice. However, treatment with probiotic strains and their postbiotics elevated antioxidative levels, especially in the high-dose probiotics plus postbiotics group. Next-generation sequencing data revealed positive microbiota alterations of Lactobacillus and Bifidobacterium and Akkermansia in the gut. Lactobacillus johnsonii and Akkermansia muciniphila exhibited effective enlargement of relative abundance. Besides, high-dose probiotics and high-dose probiotics plus postbiotics showed significant elevation in serum SCFAs, especially in butyrate. In conclusion, the formula containing Bifidobacterium animalis subsp. infantis BLI-02, Bifidobacterium breve Bv889, Bifidobacterium bifidum VDD088, B. animalis subsp. lactis CP-9, and Lactobacillus plantarum PL-02 and their metabolites may benefit aged people's health.

Lozenges with probiotic strains enhance oral immune response and health.

OBJECTIVE: Probiotics participate in regulating oral microbiota and reducing the prevalence of oral diseases; however, clinical research on probiotics is insufficient. Therefore, in this study, we performed in vitro screening of potential oral protective probiotic strains and then evaluated the clinical efficacy of the selected strains on maintaining oral health. MATERIALS AND METHODS: Fifty healthy individuals were recruited and randomly assigned into the placebo group and probiotics group, which included three strains of probiotics, Lactobacillus salivarius subs. salicinius AP-32, Lactobacillus paracasei ET-66, and Lactobacillus plantarum LPL28. Each group was blindly administered placebo or probiotics for four weeks. RESULTS: Next-generation sequencing results showed that the oral microbiota of Lactobacillus salivarius in the oral cavity were significantly increased in subjects supplemented with mixed probiotic lozenges. The anti-bacterial activities of viable probiotics were observed within two weeks. Both IgA levels and Lactobacillus and Bifidobacterium abundances in the oral cavity were significantly increased in the experimental groups, along with a reduced formation of plaque. Most participants reported that their oral health conditions and intestinal symptoms had improved. CONCLUSIONS: Overall, our clinical study suggests that oral probiotic lozenges may enhance oral immunity, modulate oral microbiota, and improve oral health.

Effectiveness of human-origin Lactobacillus plantarum PL-02 in improving muscle mass, exercise performance and anti-fatigue.

Gut microbiota is very important for energy metabolism and regulation, which in turn affect the health and physiological functions of the host, and provide energy required for exercise. Supplementation with probiotics may be one of the ways to change the gut microbiota. In recent years, many studies have shown that probiotic supplementation can effectively improve sports performance. In this study, we screened Lactobacillus plantarum (PL-02), a probiotic of human-origin, from the intestines of 2008 Olympic women's 48 kg weightlifting gold medalist and explored the role of PL-02 in improved exercise endurance performance, reduced fatigue biochemical parameters, and changes in body composition. Male Institute of Cancer Research (ICR) mice were assigned to 0, 2.05 × 109, 4.10 × 109 and 1.03 × 1010 CFU/kg/day groups and were fed by oral gavage once daily for 4 weeks. The results showed that 4 weeks of PL-02 supplementation could significantly increase muscle mass, muscle strength and endurance performance, and hepatic and muscular glycogen storage. Furthermore, PL-02 could significantly decrease lactate, blood urea nitrogen (BUN), ammonia, and creatine kinase (CK) levels after exercise (p < 0.05). We believe that PL-02 can be used as a supplement to improve exercise performance and for its anti-fatigue effect.

Privacy-Preserving Anonymity for Periodical Releases of Spontaneous Adverse Drug Event Reporting Data: Algorithm Development and Validation.

BACKGROUND: Spontaneous reporting systems (SRSs) have been increasingly established to collect adverse drug events for fostering adverse drug reaction (ADR) detection and analysis research. SRS data contain personal information, and so their publication requires data anonymization to prevent the disclosure of individuals' privacy. We have previously proposed a privacy model called MS(k, θ*)-bounding and the associated MS-Anonymization algorithm to fulfill the anonymization of SRS data. In the real world, the SRS data usually are released periodically (eg, FDA Adverse Event Reporting System [FAERS]) to accommodate newly collected adverse drug events. Different anonymized releases of SRS data available to the attacker may thwart our single-release-focus method, that is, MS(k, θ*)-bounding. OBJECTIVE: We investigate the privacy threat caused by periodical releases of SRS data and propose anonymization methods to prevent the disclosure of personal privacy information while maintaining the utility of published data. METHODS: We identify potential attacks on periodical releases of SRS data, namely, BFL-attacks, mainly caused by follow-up cases. We present a new privacy model called PPMS(k, θ*)-bounding, and propose the associated PPMS-Anonymization algorithm and 2 improvements: PPMS+-Anonymization and PPMS++-Anonymization. Empirical evaluations were performed using 32 selected FAERS quarter data sets from 2004Q1 to 2011Q4. The performance of the proposed versions of PPMS-Anonymization was inspected against MS-Anonymization from some aspects, including data distortion, measured by normalized information loss; privacy risk of anonymized data, measured by dangerous identity ratio and dangerous sensitivity ratio; and data utility, measured by the bias of signal counting and strength (proportional reporting ratio). RESULTS: The best version of PPMS-Anonymization, PPMS++-Anonymization, achieves nearly the same quality as MS-Anonymization in both privacy protection and data utility. Overall, PPMS++-Anonymization ensures zero privacy risk on record and attribute linkage, and exhibits 51%-78% and 59%-82% improvements on information loss over PPMS+-Anonymization and PPMS-Anonymization, respectively, and significantly reduces the bias of ADR signal. CONCLUSIONS: The proposed PPMS(k, θ*)-bounding model and PPMS-Anonymization algorithm are effective in anonymizing SRS data sets in the periodical data publishing scenario, preventing the series of releases from disclosing personal sensitive information caused by BFL-attacks while maintaining the data utility for ADR signal detection.

Viable and Heat-Killed Probiotic Strains Improve Oral Immunity by Elevating the IgA Concentration in the Oral Mucosa.

Oral-nasal mucosal immunity plays a crucial role in protecting the body against bacterial and viral invasion. Safe probiotic products have been used to enhance human immunity and oral health. In this study, we verified the beneficial effects of mixed viable probiotic tablets, consisting of Lactobacillus salivarius subsp. salicinius AP-32, Bifidobacterium animalis subsp. lactis CP-9, and Lactobacillus paracasei ET-66, and heat-killed probiotic tablets, consisting of L. salivarius subsp. salicinius AP-32 and L. paracasei ET-66, on oral immunity among 45 healthy participants. Participants were randomly divided into viable probiotic, heat-killed probiotic, and placebo groups. The administration of treatment lasted for 4 weeks. Saliva samples were collected at Weeks 0, 2, 4, and 6, and Lactobacillus, Bifidobacterium and Streptococcus mutans populations and IgA concentration were measured. IgA concentrations, levels of TGF-beta and IL-10 in PBMCs cells were quantified by ELISA method. Results showed that salivary IgA levels were significantly increased on administration of both the viable (119.30 ± 12.63%, ***P < 0.001) and heat-killed (116.78 ± 12.28%, ***P < 0.001) probiotics for 4 weeks. Among three probiotic strains, AP-32 would effectively increase the levels of TGF-beta and IL-10 in PBMCs. The oral pathogen Streptococcus mutans was significantly reduced on viable probiotic tablet administration (49.60 ± 31.01%, ***P < 0.001). The in vitro antibacterial test confirmed that viable probiotics effectively limited the survival rate of oral pathogens. Thus, this clinical pilot study demonstrated that oral probiotic tablets both in viable form or heat-killed form could exert beneficial effects on oral immunity via IL-10, TGB-beta mediated IgA secretion. The effective dosage of viable probiotic content in the oral tablet was 109 CFUs/g and the heat-killed oral tablet was 1 × 1010 cells/g.

Quantitative In Vivo Analyses Reveal a Complex Pharmacogenomic Landscape in Lung Adenocarcinoma.

The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most critical gaps in enabling the effective use of cancer therapies. Here, we couple a multiplexed and quantitative experimental platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. The complex map of genotype-specific treatment responses uncovered that over 20% of possible interactions show significant resistance or sensitivity. Known and novel interactions were identified, and one of these interactions, the resistance of KEAP1-mutant lung tumors to platinum therapy, was validated using a large patient response data set. These results highlight the broad impact of tumor suppressor genotype on treatment responses and define a strategy to identify the determinants of precision therapies. SIGNIFICANCE: An experimental and analytical framework to generate in vivo pharmacogenomic maps that relate tumor genotypes to therapeutic responses reveals a surprisingly complex map of genotype-specific resistance and sensitivity.

Multi-strain probiotic supplement attenuates streptozotocin-induced type-2 diabetes by reducing inflammation and ß-cell death in rats.

Probiotics are health beneficial bacterial populations colonizing the human gut and skin. Probiotics are believed to be involved in immune system regulation, gut microbiota stabilization, prevention of infectious diseases, and adjustments of host metabolic activities. Probiotics such as Lactobacillus and Bifidobacterium affect glycemic levels, blood lipids, and protein metabolism. However, the interactions between probiotics and metabolic diseases as well as the underlying mechanisms remain unclear. We used streptozotocin (STZ)-induced diabetic animal models to study the effect of ProbiogluTM, a multi-strain probiotic supplement including Lactobaccilus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, L. reuteri GL-104, and Bifidobacterium animalis subsp. lactis CP-9, on the regulation of physiochemical parameters related to type-2 diabetes. Experimental rats were randomly assigned into five groups, control group, streptozotocin (STZ)-treated rats (STZ group), STZ + 1× ProbiogluTM group, STZ + 5× ProbiogluTM group, and STZ + 10× ProbiogluTM group, and physiological data were measured at weeks 0, 2, 4, 6, and 8. Our results indicate that supplementation with ProbiogluTM significantly improved glucose tolerance, glycemic levels, insulin levels, and insulin resistance (HOMA-IR). Furthermore, we observed reduction in urea and blood lipid levels, including low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC). ProbiogluTM administration increased the ß-cell mass in STZ-induced diabetic animal models, whereas it reduced the levels of proinflammatory cytokines TNF-α, IL-6, and IL-1ß. In addition, the enhancement of oxidative stress biomarkers and superoxide dismutase (SOD) activities was associated with a decrease in malondialdehyde (MDA) levels. We conclude that ProbiogluTM attenuates STZ-induced type-2 diabetes by protecting ß-cells, stabilizing glycemic levels, and reducing inflammation. Among all probiotic treating groups, the 10×ProbiogluTM treatment revealed the best results. However, these experimental results still need to be validated by different animal models of type-2 diabetes and human clinical trials in the future.

Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo.

In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2-the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.This article is highlighted in the In This Issue feature, p. 1601.

A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer.

Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. SIGNIFICANCE: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS-driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models.This article is highlighted in the In This Issue feature, p. 1601.

Impact of patient-related factors on successful autologous fat injection laryngoplasty in thyroid surgical treated related unilateral vocal fold paralysis- observational study.

The aim of this study was to compare major voice indicators in different sub-categories, the outcome of lipoinjection for patients might be refined and some voice prognostic factors could be more particularized in specific sub-groups. This is an observational study, and sub-grouped UVFP patients into 3 categories: male vs female, BMI ≥ 24 vs BMI < 24, Age ≥ 60 vs Age < 60 for more detailed exploring whether sub-categories affected voice diagnostic and prognostic parameters. Patients' voice data is recorded before and after the autologous fat injection laryngoplasty by a multidimensional voice program. Overall, 73 patients' voice performance were improved 12 months later by vocal fold lipoinjection. In the comparison of the male with female revealed female obtained better Jita than male by surgery (Female: 174.50 ±â€Š100.58 Hz; Male: 294.82 ±â€Š253.65 Hz; P < .05). BMI ≥ 24 vs BMI < 24 showed no statistical difference. Patients aged under 60 demonstrated better Highest F0, lowest F0, NHR and ShdB than elder ones 12 months after receiving vocal fold lipoinjection. Thus, Noise-to-harmonics ratio (NHR), voice turbulence index (VTI), and ShdB (Absolute shimmer, dB) may be the major post-operative evaluating markers of patients' age under 60. Voice parameters showed no significant correlation with BMI. Female patients performed lower Jita (Absolute jitter, µsec) than male patients 1 year after receiving treatment. The experimental results in this study showed UVFP patients' gender and age may stand as significant categories on analyzing clinical voice prognostic indicators, ShdB and Jita of autologous injection laryngoplasty.

On Anonymizing Medical Microdata with Large-Scale Missing Values - A Case Study with the FAERS Dataset.

As big data analysis becomes one of the main driving forces for productivity and economic growth, the concern of individual privacy disclosure increases as well, especially for applications accessing medical or health data that contain personal information. Most contemporary techniques for privacy preserving data publishing follow a simple assumption-the data of concern is complete, i.e., containing no missing values, which however is not the case in the real world. This paper presents our endeavors on inspecting the effect of missing values upon medical data privacy. In particular, we inspected the US FAERS dataset, a public dataset containing adverse drug events released by US FDA. Following the presumption of current anonymization paradigm-the data should contain no missing values, we investigated three intuitive strategies, including or excluding missing values or executing imputation, to anonymize the FAERS dataset. Our results demonstrate the awkwardness of these intuitive strategies in handling data with a massive amount of missing values. Accordingly, we propose a new strategy, consolidation, and the corresponding privacy protection model and anonymization algorithm. Experimental results show that our method can prevent privacy disclosure and sustain the data utility for ADR signal detection.

Using Innovative Acoustic Analysis to Predict the Postoperative Outcomes of Unilateral Vocal Fold Paralysis.

Objective. Autologous fat injection laryngoplasty is ineffective for some patients with iatrogenic vocal fold paralysis, and additional laryngeal framework surgery is often required. An acoustically measurable outcome predictor for lipoinjection laryngoplasty would assist phonosurgeons in formulating treatment strategies. Methods. Seventeen thyroid surgery patients with unilateral vocal fold paralysis participated in this study. All subjects underwent lipoinjection laryngoplasty to treat postsurgery vocal hoarseness. After treatment, patients were assigned to success and failure groups on the basis of voice improvement. Linear prediction analysis was used to construct a new voice quality indicator, the number of irregular peaks (NIrrP). It compared with the measures used in the Multi-Dimensional Voice Program (MDVP), such as jitter (frequency perturbation) and shimmer (perturbation of amplitude). Results. By comparing the [i] vowel produced by patients before the lipoinjection laryngoplasty (AUC = 0.98, 95% CI = 0.78-0.99), NIrrP was shown to be a more accurate predictor of long-term surgical outcomes than jitter (AUC = 0.73, 95% CI = 0.47-0.91) and shimmer (AUC = 0.63, 95% CI = 0.37-0.85), as identified by the receiver operating characteristic curve. Conclusions. NIrrP measured using the LP model could be a more accurate outcome predictor than the parameters used in the MDVP.

Privacy preserving data anonymization of spontaneous ADE reporting system dataset.

BACKGROUND: To facilitate long-term safety surveillance of marketing drugs, many spontaneously reporting systems (SRSs) of ADR events have been established world-wide. Since the data collected by SRSs contain sensitive personal health information that should be protected to prevent the identification of individuals, it procures the issue of privacy preserving data publishing (PPDP), that is, how to sanitize (anonymize) raw data before publishing. Although much work has been done on PPDP, very few studies have focused on protecting privacy of SRS data and none of the anonymization methods is favorable for SRS datasets, due to which contain some characteristics such as rare events, multiple individual records, and multi-valued sensitive attributes. METHODS: We propose a new privacy model called MS(k, θ (*) )-bounding for protecting published spontaneous ADE reporting data from privacy attacks. Our model has the flexibility of varying privacy thresholds, i.e., θ (*) , for different sensitive values and takes the characteristics of SRS data into consideration. We also propose an anonymization algorithm for sanitizing the raw data to meet the requirements specified through the proposed model. Our algorithm adopts a greedy-based clustering strategy to group the records into clusters, conforming to an innovative anonymization metric aiming to minimize the privacy risk as well as maintain the data utility for ADR detection. Empirical study was conducted using FAERS dataset from 2004Q1 to 2011Q4. We compared our model with four prevailing methods, including k-anonymity, (X, Y)-anonymity, Multi-sensitive l-diversity, and (α, k)-anonymity, evaluated via two measures, Danger Ratio (DR) and Information Loss (IL), and considered three different scenarios of threshold setting for θ (*) , including uniform setting, level-wise setting and frequency-based setting. We also conducted experiments to inspect the impact of anonymized data on the strengths of discovered ADR signals. RESULTS: With all three different threshold settings for sensitive value, our method can successively prevent the disclosure of sensitive values (nearly all observed DRs are zeros) without sacrificing too much of data utility. With non-uniform threshold setting, level-wise or frequency-based, our MS(k, θ (*))-bounding exhibits the best data utility and the least privacy risk among all the models. The experiments conducted on selected ADR signals from MedWatch show that only very small difference on signal strength (PRR or ROR) were observed. The results show that our method can effectively prevent the disclosure of patient sensitive information without sacrificing data utility for ADR signal detection. CONCLUSIONS: We propose a new privacy model for protecting SRS data that possess some characteristics overlooked by contemporary models and an anonymization algorithm to sanitize SRS data in accordance with the proposed model. Empirical evaluation on the real SRS dataset, i.e., FAERS, shows that our method can effectively solve the privacy problem in SRS data without influencing the ADR signal strength.

Rough-set-based ADR signaling from spontaneous reporting data with missing values.

Spontaneous reporting systems of adverse drug events have been widely established in many countries to collect as could as possible all adverse drug events to facilitate the detection of suspected ADR signals via some statistical or data mining methods. Unfortunately, due to privacy concern or other reasons, the reporters sometimes may omit consciously some attributes, causing many missing values existing in the reporting database. Most of research work on ADR detection or methods applied in practice simply adopted listwise deletion to eliminate all data with missing values. Very little work has noticed the possibility and examined the effect of including the missing data in the process of ADR detection. This paper represents our endeavor towards the exploration of this question. We aim at inspecting the feasibility of applying rough set theory to the ADR detection problem. Based on the concept of utilizing characteristic set based approximation to measure the strength of ADR signals, we propose twelve different rough set based measuring methods and show only six of them are feasible for the purpose. Experimental results conducted on the FARES database show that our rough-set-based approach exhibits similar capability in timeline warning of suspicious ADR signals as traditional method with missing deletion, and sometimes can yield noteworthy measures earlier than the traditional method.