A hierarchical statistical modeling approach to analyze proteomic isobaric tag for relative and a... more A hierarchical statistical modeling approach to analyze proteomic isobaric tag for relative and absolute quantitation data
American journal of Alzheimer's disease and other dementias, Jan 30, 2018
Pregnancy is associated with improvement in immunoregulation that persists into the geriatric pha... more Pregnancy is associated with improvement in immunoregulation that persists into the geriatric phase. Impaired immunoregulation is implicated in Alzheimer's disease (AD) pathogenesis. Hence, we investigate the relationship between pregnancy and AD. Cross-sectional cohort of British women (N = 95). Cox proportional hazards modeling assessed the putative effects of cumulative months pregnant on AD risk and the mutually adjusted effects of counts of first and third trimesters on AD risk. Cumulative number of months pregnant, was associated with lower AD risk (β = -1.90, exp(β) = 0.15, P = .02). Cumulative number of first trimesters was associated with lower AD risk after adjusting for third trimesters (β = -3.83, exp(β) = 0.02, P < .01), while the latter predictor had no significant effect after adjusting for the former. Our observation that first trimesters (but not third trimesters) conferred protection against AD is more consistent with immunologic effects, which are driven by...
Background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to ... more Background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to optimise their use. Methods: Blood samples were collected during and following treatment and, where appropriate, upon progression from ovarian cancer patients in ICON7, a randomised phase III trial of carboplatin and paclitaxel with or without bevacizumab. Plasma concentrations of 15 circulating angio-biomarkers were measured using a validated multiplex ELISA, analysed through a novel network analysis and their relevance to the PFS then determined. Results: Samples (n ¼ 650) were analysed from 92 patients. Bevacizumab induced correlative relationships between Ang1 and Tie2 plasma concentrations, which reduced after initiation of treatment and remained decreased until progressive disease occurred. A 50% increase from the nadir in the concentration of circulating Tie2 (or the product of circulating Ang1 and Tie2) predicted tumour progression. Combining Tie2 with GCIG-defined Ca125 data yielded a significant improvement in the prediction of progressive disease in patients receiving bevacizumab in comparison with Ca125 alone (74.1% vs 47.3%, Po1 Â 10 À 9). Conclusions: Tie2 is a vascular progression marker for bevacizumab-treated ovarian cancer patients. Tie2 in combination with Ca125 provides superior information to clinicians on progressive disease in patients with VEGFi-treated ovarian cancers. Ovarian cancer accounts for 22 000 lives annually in the United States (Jelovac and Armstrong, 2011) and 7000 each year in the UK (Jayson et al, 2014). For decades, the combination of surgery and platinum-based cytotoxic chemotherapy has been used to control advanced ovarian cancer (Vergote et al, 2010), resulting in response rates of approximately 70% in advanced disease. As recurrent disease usually occurs within the first 2 years in the majority of patients who present with advanced disease,
Clinical cancer research : an official journal of the American Association for Cancer Research, 2014
Randomized ovarian cancer trials, including ICON7, have reported improved progression-free surviv... more Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab. Pretreatment training (n=91) and validation (n=114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Our statistical approach adopted PFS as the primary outcome measure and involved (i) searching for biomarkers with prognostic relevance or which related to between-individual variation in bevacizumab effect; (ii) unbiased determination of cutoffs for putative biomarker values; (iii) investigation of biologically meaningfully predictive combinations of putative biomarkers; and (iv) replicating the analysis on candidate biomarkers in the validation dataset. The combined values of circulating Ang1 (angiopoietin 1) and Tie2 (Tunica in...
We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and c... more We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations 1-4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (41% allele frequency) and none met the pre-specified threshold for replication (P o 10 À3). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.
Atherosclerotic lesions within the graft are considered to be a major cause of interstitial fibro... more Atherosclerotic lesions within the graft are considered to be a major cause of interstitial fibrosis/tubular atrophy (IF/TA). We evaluated the factors that influence the development of IF/TA and three- and five-yr graft survival including nitric oxide synthase (eNOS) and angiotensin II type 1 and type 2 receptor gene polymorphism. Seventy-one male and 35 female patients (age: 34.9 ± 11.2 yr) who underwent living-related renal transplantation were included. Angiotensin type 1 and type 2 receptor gene polymorphisms and eNOS intron 4 gene polymorphism were analyzed. The pre- and post-transplant laboratory data, patient characteristics, acute rejection episodes, and presence of IF/TA were evaluated. Patients with the bb allele of eNOS gene had a lower prevalence of post-transplant third year (12.6% and 38.5%, p = 0.005) and fifth year IF/TA (46.6% and 82.3%, p = 0.02) and a lower incidence of five-yr graft failure (35.4% and 55.6%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.005). The eNOS gene polymorphism was independent and was the most prominent factor associated with third and fifth year IF/TA (p = 0.01, RR: 29.72, and p = 0.03, RR: 4.1, respectively). No significant relationship existed when angiotensin II gene polymorphisms were considered. We concluded that recipient eNOS gene polymorphism can predict IF/TA, and the presence of the bb allele is associated with better graft outcome.
Background— We investigated the association between 9 polymorphisms of genes encoding hemostasis ... more Background— We investigated the association between 9 polymorphisms of genes encoding hemostasis factors and myocardial infarction in a large sample of young patients chosen because they have less coronary atherosclerosis than older patients, and thus their disease is more likely to be related to a genetic predisposition to a prothrombotic state. Methods and Results— This nationwide case-control study involved 1210 patients who had survived a first myocardial infarction at an age of <45 years who underwent coronary arteriography in 125 coronary care units and 1210 healthy subjects matched for age, sex, and geographical origin. None of the 9 polymorphisms of genes encoding proteins involved in coagulation (G-455A β-fibrinogen: OR, 1.0; CI, 0.8 to 1.2; G1691A factor V: OR, 1.1; CI, 0.6 to 2.1; G20210A factor II: OR, 1.0; CI, 0.5 to 1.9; and G10976A factor VII: OR, 1.0; CI, 0.8 to 1.3), platelet function (C807T glycoprotein Ia: OR, 1.1; CI, 0.9 to 1.3; and C1565T glycoprotein IIIa: ...
Motivation: Isobaric tag for relative and absolute quantitation (iTRAQ) is a widely used method i... more Motivation: Isobaric tag for relative and absolute quantitation (iTRAQ) is a widely used method in quantitative proteomics. A robust data analysis strategy is required to determine protein quantification reliability, i.e. changes due to biological regulation rather than technical variation, so that proteins that are differentially expressed can be identified. Methods: Samples were created by mixing 5, 10, 15 and 20 μg Escherichia coli cell lysate with 100 μg of cell lysate from mouse, corresponding to expected relative fold changes of one for mouse proteins and from 0.25 to 4 for E.coli proteins. Relative quantification was carried out using eight channel isobaric tagging with iTRAQ reagent, and proteins were identified using a TripleTOF 5600 mass spectrometer. Technical variation inherent in this iTRAQ dataset was systematically investigated. Results: A hierarchical statistical model was developed to use quantitative information at peptide level and protein level simultaneously to ...
We continue the discussion of sequential data-gathering and decision-making processes, started in... more We continue the discussion of sequential data-gathering and decision-making processes, started in the preceding chapter in this volume. The archetypical context is that of a sequence of medical decisions, taken at different time points during the follow-up of the patient, each decision involving choice of a treatment in the light of any interim responses or adverse
Our Bayesian approach to Mendelian Randomisation uses multiple instruments to assess the putative... more Our Bayesian approach to Mendelian Randomisation uses multiple instruments to assess the putative causal effect of an exposure on an outcome. The approach is robust to violations of the (untestable) Exclusion Restriction condition, and hence it does not require instruments to be independent of the outcome conditional on the exposure and on the confounders of the exposure-outcome relationship. The Bayesian approach offers a rigorous handling of the uncertainty (e.g. about the estimated instrument-exposure associations), freedom from asymptotic approximations of the null distribution and the possibility to elaborate the model in any direction of scientific relevance. We illustrate the last feature with the aid of a study of the metabolic mediators of the disease-inducing effects of obesity, where we elaborate the model to investigate whether the causal effect of interest interacts with a covariate. The proposed model contains a vector of unidentifiable parameters, $\beta$, whose $j$th...
From a cohort of 1352 consecutive patients admitted with coronavirus disease (Covid-19) to Papa G... more From a cohort of 1352 consecutive patients admitted with coronavirus disease (Covid-19) to Papa Giovanni XXIII Hospital in Bergamo, Italy, between February and April 2020, we selected and studied 688 patients with arterial hypertension (254 deaths) to assess whether use of renin-angiotensin system inhibitors (RASIs) prior to hospital admission affects mortality from Covid-19. Prior use of RASIs was associated with a lower mortality in the over-68 group of patients, whereas no evidence of a similar effect (whether protective or adverse) was found in the younger group. There was positive relative excess due to a statistically significant (p =0.001) interaction between prior RASI exposure and an age greater than 68 years, corresponding to a positive relative excess risk. Next we used the subgroup of 411 hypertensive patients older than 68 yrs to separately assess the effects prior use of two RASI drug subclasses, angiotensin-converting enzyme inhibitors (ACEIs) and angiogiotensin recep...
Background In a study performed on multiplex Multiple Sclerosis (MS) Sardinian families to identi... more Background In a study performed on multiplex Multiple Sclerosis (MS) Sardinian families to identify disease causing plasma proteins, application of Mendelian Randomization (MR) methods encounters difficulties due to relatedness of individuals, correlation between finely mapped genotype instrumental variables (IVs) and presence of missing exposures. Method We specialize the method of Berzuini et al (2018) to deal with these difficulties. The proposed method allows pedigree structure to enter the specification of the outcome distribution via kinship matrix, and treating missing exposures as additional parameters to be estimated from the data. It also acknowledges possible correlation between instruments by replacing the originally proposed independence prior for IV-specific pleiotropic effect with a g-prior. Based on correlated (r2< 0.2) IVs, we analysed the data of four candidate MS-causing proteins by using both the independence and the g-prior. Results 95% credible intervals for...
The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antih... more The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWAS) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting hypertensive patients. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
ObjectivesBeing able to predict which patients with COVID-19 are going to deteriorate is importan... more ObjectivesBeing able to predict which patients with COVID-19 are going to deteriorate is important to help identify patients for clinical and research practice. Clinical prediction models play a critical role in this process, but current models are of limited value because they are typically restricted to baseline predictors and do not always use contemporary statistical methods. We sought to explore the benefits of incorporating dynamic changes in routinely measured biomarkers, non-linear effects and applying ‘state-of-the-art’ statistical methods in the development of a prognostic model to predict death in hospitalised patients with COVID-19.DesignThe data were analysed from admissions with COVID-19 to three hospital sites. Exploratory data analysis included a graphical approach to partial correlations. Dynamic biomarkers were considered up to 5 days following admission rather than depending solely on baseline or single time-point data. Marked departures from linear effects of cov...
Background Mendelian randomization (MR) has been widely applied to causal inference in medical re... more Background Mendelian randomization (MR) has been widely applied to causal inference in medical research. It uses genetic variants as instrumental variables (IVs) to investigate putative causal relationship between an exposure and an outcome. Traditional MR methods have mainly focussed on a two-sample setting in which IV-exposure association study and IV-outcome association study are independent. However, it is not uncommon that participants from the two studies fully overlap (one-sample) or partly overlap (overlapping-sample). Methods We proposed a Bayesian method that is applicable to all the three sample settings. In essence, we converted a two- or overlapping- sample MR to a one-sample MR where data were partly unmeasured. Assume that all study individuals were drawn from the same population and unmeasured data were missing at random. Then the missing data were treated au pair with the model parameters as unknown quantities, and thus, were imputed iteratively conditioning on the ...
Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-def... more Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning t...
We define mechanistic interaction between the effects of two variables on an outcome in terms of ... more We define mechanistic interaction between the effects of two variables on an outcome in terms of departure of these effects from a generalized noisy-OR model in a stratum of the population. We develop a fully probabilistic framework for the observational identification of this type of interaction via excess risk or superadditivity, one novel feature of which is its applicability when the interacting variables have been generated by arbitrarily dichotomizing continuous exposures. The method allows for stochastic mediators of the interacting effects. The required assumptions are provided in the form of conditional independencies between the problem variables, which may relate to a causal-graph representation of the problem. We also develop a theory of mechanistic interaction between effects associated with specific paths of the causal graph.
We propose a general Bayesian network model for application in a wide class of problems of therap... more We propose a general Bayesian network model for application in a wide class of problems of therapy monitoring. We discuss the use of stochastic simulation as a computational approach to inference on the proposed class of models. As an illustration we present an application to the monitoring of cytotoxic chemotherapy in breast cancer.
Multiple genome screens have been performed to identify regions in linkage or association with Mu... more Multiple genome screens have been performed to identify regions in linkage or association with Multiple Sclerosis (MS, OMIM 126200), but little overlap has been found among them. This may be, in part, due to a low statistical power to detect small genetic effects and to genetic heterogeneity within and among the studied populations. Motivated by these considerations, we studied a very special population, namely that of Nuoro, Sardinia, Italy. This is an isolated, old, and genetically homogeneous population with high prevalence of MS. Our study sample includes both nuclear families and unrelated cases and controls. A multi-stage study design was adopted. In the first stage, microsatellites were typed in the 17q11.2 region, previously independently found to be in linkage with MS. One significant association was found at microsatellite D17S798. Next, a bioinformatic screening of the region surrounding this marker highlighted an interesting candidate MS susceptibility gene: the Amiloride-sensitive Cation Channel Neuronal 1 (ACCN1) gene. In the second stage of the study, we resequenced the exons and the 39 untranslated (UTR) region of ACCN1, and investigated the MS association of Single Nucleotide Polymorphisms (SNPs) identified in that region. For this purpose, we developed a method of analysis where complete, phase-solved, posteriorweighted haplotype assignments are imputed for each study individual from incomplete, multi-locus, genotyping data. The imputed assignments provide an input to a number of proposed procedures for testing association at a microsatellite level or of a sequence of SNPs. These include a Mantel-Haenszel type test based on expected frequencies of pseudocase/pseudocontrol haplotypes, as well as permutation based tests, including a combination of permutation and weighted logistic regression analysis. Application of these methods allowed us to find a significant association between MS and the SNP rs28936 located in the 39 UTR segment of ACCN1 with p = 0.0004 (p = 0.002, after adjusting for multiple testing). This result is in tune with several recent experimental findings which suggest that ACCN1 may play an important role in the pathogenesis of MS.
We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously un... more We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.
A hierarchical statistical modeling approach to analyze proteomic isobaric tag for relative and a... more A hierarchical statistical modeling approach to analyze proteomic isobaric tag for relative and absolute quantitation data
American journal of Alzheimer's disease and other dementias, Jan 30, 2018
Pregnancy is associated with improvement in immunoregulation that persists into the geriatric pha... more Pregnancy is associated with improvement in immunoregulation that persists into the geriatric phase. Impaired immunoregulation is implicated in Alzheimer's disease (AD) pathogenesis. Hence, we investigate the relationship between pregnancy and AD. Cross-sectional cohort of British women (N = 95). Cox proportional hazards modeling assessed the putative effects of cumulative months pregnant on AD risk and the mutually adjusted effects of counts of first and third trimesters on AD risk. Cumulative number of months pregnant, was associated with lower AD risk (β = -1.90, exp(β) = 0.15, P = .02). Cumulative number of first trimesters was associated with lower AD risk after adjusting for third trimesters (β = -3.83, exp(β) = 0.02, P < .01), while the latter predictor had no significant effect after adjusting for the former. Our observation that first trimesters (but not third trimesters) conferred protection against AD is more consistent with immunologic effects, which are driven by...
Background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to ... more Background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to optimise their use. Methods: Blood samples were collected during and following treatment and, where appropriate, upon progression from ovarian cancer patients in ICON7, a randomised phase III trial of carboplatin and paclitaxel with or without bevacizumab. Plasma concentrations of 15 circulating angio-biomarkers were measured using a validated multiplex ELISA, analysed through a novel network analysis and their relevance to the PFS then determined. Results: Samples (n ¼ 650) were analysed from 92 patients. Bevacizumab induced correlative relationships between Ang1 and Tie2 plasma concentrations, which reduced after initiation of treatment and remained decreased until progressive disease occurred. A 50% increase from the nadir in the concentration of circulating Tie2 (or the product of circulating Ang1 and Tie2) predicted tumour progression. Combining Tie2 with GCIG-defined Ca125 data yielded a significant improvement in the prediction of progressive disease in patients receiving bevacizumab in comparison with Ca125 alone (74.1% vs 47.3%, Po1 Â 10 À 9). Conclusions: Tie2 is a vascular progression marker for bevacizumab-treated ovarian cancer patients. Tie2 in combination with Ca125 provides superior information to clinicians on progressive disease in patients with VEGFi-treated ovarian cancers. Ovarian cancer accounts for 22 000 lives annually in the United States (Jelovac and Armstrong, 2011) and 7000 each year in the UK (Jayson et al, 2014). For decades, the combination of surgery and platinum-based cytotoxic chemotherapy has been used to control advanced ovarian cancer (Vergote et al, 2010), resulting in response rates of approximately 70% in advanced disease. As recurrent disease usually occurs within the first 2 years in the majority of patients who present with advanced disease,
Clinical cancer research : an official journal of the American Association for Cancer Research, 2014
Randomized ovarian cancer trials, including ICON7, have reported improved progression-free surviv... more Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab. Pretreatment training (n=91) and validation (n=114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Our statistical approach adopted PFS as the primary outcome measure and involved (i) searching for biomarkers with prognostic relevance or which related to between-individual variation in bevacizumab effect; (ii) unbiased determination of cutoffs for putative biomarker values; (iii) investigation of biologically meaningfully predictive combinations of putative biomarkers; and (iv) replicating the analysis on candidate biomarkers in the validation dataset. The combined values of circulating Ang1 (angiopoietin 1) and Tie2 (Tunica in...
We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and c... more We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations 1-4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (41% allele frequency) and none met the pre-specified threshold for replication (P o 10 À3). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.
Atherosclerotic lesions within the graft are considered to be a major cause of interstitial fibro... more Atherosclerotic lesions within the graft are considered to be a major cause of interstitial fibrosis/tubular atrophy (IF/TA). We evaluated the factors that influence the development of IF/TA and three- and five-yr graft survival including nitric oxide synthase (eNOS) and angiotensin II type 1 and type 2 receptor gene polymorphism. Seventy-one male and 35 female patients (age: 34.9 ± 11.2 yr) who underwent living-related renal transplantation were included. Angiotensin type 1 and type 2 receptor gene polymorphisms and eNOS intron 4 gene polymorphism were analyzed. The pre- and post-transplant laboratory data, patient characteristics, acute rejection episodes, and presence of IF/TA were evaluated. Patients with the bb allele of eNOS gene had a lower prevalence of post-transplant third year (12.6% and 38.5%, p = 0.005) and fifth year IF/TA (46.6% and 82.3%, p = 0.02) and a lower incidence of five-yr graft failure (35.4% and 55.6%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.005). The eNOS gene polymorphism was independent and was the most prominent factor associated with third and fifth year IF/TA (p = 0.01, RR: 29.72, and p = 0.03, RR: 4.1, respectively). No significant relationship existed when angiotensin II gene polymorphisms were considered. We concluded that recipient eNOS gene polymorphism can predict IF/TA, and the presence of the bb allele is associated with better graft outcome.
Background— We investigated the association between 9 polymorphisms of genes encoding hemostasis ... more Background— We investigated the association between 9 polymorphisms of genes encoding hemostasis factors and myocardial infarction in a large sample of young patients chosen because they have less coronary atherosclerosis than older patients, and thus their disease is more likely to be related to a genetic predisposition to a prothrombotic state. Methods and Results— This nationwide case-control study involved 1210 patients who had survived a first myocardial infarction at an age of <45 years who underwent coronary arteriography in 125 coronary care units and 1210 healthy subjects matched for age, sex, and geographical origin. None of the 9 polymorphisms of genes encoding proteins involved in coagulation (G-455A β-fibrinogen: OR, 1.0; CI, 0.8 to 1.2; G1691A factor V: OR, 1.1; CI, 0.6 to 2.1; G20210A factor II: OR, 1.0; CI, 0.5 to 1.9; and G10976A factor VII: OR, 1.0; CI, 0.8 to 1.3), platelet function (C807T glycoprotein Ia: OR, 1.1; CI, 0.9 to 1.3; and C1565T glycoprotein IIIa: ...
Motivation: Isobaric tag for relative and absolute quantitation (iTRAQ) is a widely used method i... more Motivation: Isobaric tag for relative and absolute quantitation (iTRAQ) is a widely used method in quantitative proteomics. A robust data analysis strategy is required to determine protein quantification reliability, i.e. changes due to biological regulation rather than technical variation, so that proteins that are differentially expressed can be identified. Methods: Samples were created by mixing 5, 10, 15 and 20 μg Escherichia coli cell lysate with 100 μg of cell lysate from mouse, corresponding to expected relative fold changes of one for mouse proteins and from 0.25 to 4 for E.coli proteins. Relative quantification was carried out using eight channel isobaric tagging with iTRAQ reagent, and proteins were identified using a TripleTOF 5600 mass spectrometer. Technical variation inherent in this iTRAQ dataset was systematically investigated. Results: A hierarchical statistical model was developed to use quantitative information at peptide level and protein level simultaneously to ...
We continue the discussion of sequential data-gathering and decision-making processes, started in... more We continue the discussion of sequential data-gathering and decision-making processes, started in the preceding chapter in this volume. The archetypical context is that of a sequence of medical decisions, taken at different time points during the follow-up of the patient, each decision involving choice of a treatment in the light of any interim responses or adverse
Our Bayesian approach to Mendelian Randomisation uses multiple instruments to assess the putative... more Our Bayesian approach to Mendelian Randomisation uses multiple instruments to assess the putative causal effect of an exposure on an outcome. The approach is robust to violations of the (untestable) Exclusion Restriction condition, and hence it does not require instruments to be independent of the outcome conditional on the exposure and on the confounders of the exposure-outcome relationship. The Bayesian approach offers a rigorous handling of the uncertainty (e.g. about the estimated instrument-exposure associations), freedom from asymptotic approximations of the null distribution and the possibility to elaborate the model in any direction of scientific relevance. We illustrate the last feature with the aid of a study of the metabolic mediators of the disease-inducing effects of obesity, where we elaborate the model to investigate whether the causal effect of interest interacts with a covariate. The proposed model contains a vector of unidentifiable parameters, $\beta$, whose $j$th...
From a cohort of 1352 consecutive patients admitted with coronavirus disease (Covid-19) to Papa G... more From a cohort of 1352 consecutive patients admitted with coronavirus disease (Covid-19) to Papa Giovanni XXIII Hospital in Bergamo, Italy, between February and April 2020, we selected and studied 688 patients with arterial hypertension (254 deaths) to assess whether use of renin-angiotensin system inhibitors (RASIs) prior to hospital admission affects mortality from Covid-19. Prior use of RASIs was associated with a lower mortality in the over-68 group of patients, whereas no evidence of a similar effect (whether protective or adverse) was found in the younger group. There was positive relative excess due to a statistically significant (p =0.001) interaction between prior RASI exposure and an age greater than 68 years, corresponding to a positive relative excess risk. Next we used the subgroup of 411 hypertensive patients older than 68 yrs to separately assess the effects prior use of two RASI drug subclasses, angiotensin-converting enzyme inhibitors (ACEIs) and angiogiotensin recep...
Background In a study performed on multiplex Multiple Sclerosis (MS) Sardinian families to identi... more Background In a study performed on multiplex Multiple Sclerosis (MS) Sardinian families to identify disease causing plasma proteins, application of Mendelian Randomization (MR) methods encounters difficulties due to relatedness of individuals, correlation between finely mapped genotype instrumental variables (IVs) and presence of missing exposures. Method We specialize the method of Berzuini et al (2018) to deal with these difficulties. The proposed method allows pedigree structure to enter the specification of the outcome distribution via kinship matrix, and treating missing exposures as additional parameters to be estimated from the data. It also acknowledges possible correlation between instruments by replacing the originally proposed independence prior for IV-specific pleiotropic effect with a g-prior. Based on correlated (r2< 0.2) IVs, we analysed the data of four candidate MS-causing proteins by using both the independence and the g-prior. Results 95% credible intervals for...
The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antih... more The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWAS) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting hypertensive patients. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
ObjectivesBeing able to predict which patients with COVID-19 are going to deteriorate is importan... more ObjectivesBeing able to predict which patients with COVID-19 are going to deteriorate is important to help identify patients for clinical and research practice. Clinical prediction models play a critical role in this process, but current models are of limited value because they are typically restricted to baseline predictors and do not always use contemporary statistical methods. We sought to explore the benefits of incorporating dynamic changes in routinely measured biomarkers, non-linear effects and applying ‘state-of-the-art’ statistical methods in the development of a prognostic model to predict death in hospitalised patients with COVID-19.DesignThe data were analysed from admissions with COVID-19 to three hospital sites. Exploratory data analysis included a graphical approach to partial correlations. Dynamic biomarkers were considered up to 5 days following admission rather than depending solely on baseline or single time-point data. Marked departures from linear effects of cov...
Background Mendelian randomization (MR) has been widely applied to causal inference in medical re... more Background Mendelian randomization (MR) has been widely applied to causal inference in medical research. It uses genetic variants as instrumental variables (IVs) to investigate putative causal relationship between an exposure and an outcome. Traditional MR methods have mainly focussed on a two-sample setting in which IV-exposure association study and IV-outcome association study are independent. However, it is not uncommon that participants from the two studies fully overlap (one-sample) or partly overlap (overlapping-sample). Methods We proposed a Bayesian method that is applicable to all the three sample settings. In essence, we converted a two- or overlapping- sample MR to a one-sample MR where data were partly unmeasured. Assume that all study individuals were drawn from the same population and unmeasured data were missing at random. Then the missing data were treated au pair with the model parameters as unknown quantities, and thus, were imputed iteratively conditioning on the ...
Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-def... more Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning t...
We define mechanistic interaction between the effects of two variables on an outcome in terms of ... more We define mechanistic interaction between the effects of two variables on an outcome in terms of departure of these effects from a generalized noisy-OR model in a stratum of the population. We develop a fully probabilistic framework for the observational identification of this type of interaction via excess risk or superadditivity, one novel feature of which is its applicability when the interacting variables have been generated by arbitrarily dichotomizing continuous exposures. The method allows for stochastic mediators of the interacting effects. The required assumptions are provided in the form of conditional independencies between the problem variables, which may relate to a causal-graph representation of the problem. We also develop a theory of mechanistic interaction between effects associated with specific paths of the causal graph.
We propose a general Bayesian network model for application in a wide class of problems of therap... more We propose a general Bayesian network model for application in a wide class of problems of therapy monitoring. We discuss the use of stochastic simulation as a computational approach to inference on the proposed class of models. As an illustration we present an application to the monitoring of cytotoxic chemotherapy in breast cancer.
Multiple genome screens have been performed to identify regions in linkage or association with Mu... more Multiple genome screens have been performed to identify regions in linkage or association with Multiple Sclerosis (MS, OMIM 126200), but little overlap has been found among them. This may be, in part, due to a low statistical power to detect small genetic effects and to genetic heterogeneity within and among the studied populations. Motivated by these considerations, we studied a very special population, namely that of Nuoro, Sardinia, Italy. This is an isolated, old, and genetically homogeneous population with high prevalence of MS. Our study sample includes both nuclear families and unrelated cases and controls. A multi-stage study design was adopted. In the first stage, microsatellites were typed in the 17q11.2 region, previously independently found to be in linkage with MS. One significant association was found at microsatellite D17S798. Next, a bioinformatic screening of the region surrounding this marker highlighted an interesting candidate MS susceptibility gene: the Amiloride-sensitive Cation Channel Neuronal 1 (ACCN1) gene. In the second stage of the study, we resequenced the exons and the 39 untranslated (UTR) region of ACCN1, and investigated the MS association of Single Nucleotide Polymorphisms (SNPs) identified in that region. For this purpose, we developed a method of analysis where complete, phase-solved, posteriorweighted haplotype assignments are imputed for each study individual from incomplete, multi-locus, genotyping data. The imputed assignments provide an input to a number of proposed procedures for testing association at a microsatellite level or of a sequence of SNPs. These include a Mantel-Haenszel type test based on expected frequencies of pseudocase/pseudocontrol haplotypes, as well as permutation based tests, including a combination of permutation and weighted logistic regression analysis. Application of these methods allowed us to find a significant association between MS and the SNP rs28936 located in the 39 UTR segment of ACCN1 with p = 0.0004 (p = 0.002, after adjusting for multiple testing). This result is in tune with several recent experimental findings which suggest that ACCN1 may play an important role in the pathogenesis of MS.
We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously un... more We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.
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Papers by Carlo Berzuini