Congenital extrahepatic portosystemic shunts (Abernethy malformation): An international observational study

Congenital extrahepatic portosystemic shunt (CEPS) or Abernethy malformation is a rare condition in which splanchnic venous blood bypasses the liver draining directly into systemic circulation through a congenital shunt. Patients may develop hepatic encephalopathy (HE), pulmonary hypertension (PaHT), or liver tumors, among other complications. However, the actual incidence of such complications is unknown, mainly because of the lack of a protocolized approach to these patients. This study characterizes the clinical manifestations and outcome of a large cohort of CEPS patients with the aim of proposing a guide for their management. This is an observational, multicenter, international study. Sixty-six patients were included; median age at the end of follow-up was 30 years. Nineteen patients (28%) presented HE. Ten-, 20-, and 30-year HE incidence rates were 13%, 24%, and 28%, respectively. No clinical factors predicted HE. Twenty-five patients had benign nodular lesions. Ten patients developed adenomas (median age, 18 years), and another 8 developed HCC (median age, 39 years). Of 10 patients with dyspnea, PaHT was diagnosed in 8 and hepatopulmonary syndrome in 2. Pulmonary complications were only screened for in 19 asymptomatic patients, and PaHT was identified in 2. Six patients underwent liver transplantation for hepatocellular carcinoma or adenoma. Shunt closure was performed in 15 patients with improvement/stability/cure of CEPS manifestations. Conclusion: CEPS patients may develop severe complications. Screening for asymptomatic complications and close surveillance is needed. Shunt closure should be considered both as a therapeutic and prophylactic approach

Ecografia Doppler de l'artèria hepàtica en el post-trasplantament immediat

[cat] La complicació vascular més greu després del trasplantament hepàtic és la trombosi de l'artèria hepàtica. Quan aquesta complicació se sospita clínicament es realitza una ecografia Doppler amb la finalitat d'establir el diagnòstic. Tanmateix, donats els resultats de la present tesi, és possible, mitjançant l'ecografia Doppler, establir el diagnòstic de trombosi de l'artèria hepàtica abans que apareixi la sospita clínica. Aquest fet augmenta les probabilitats de revascularitzar amb èxit l'artèria hepàtica i millora significativament el pronòstic dels pacients tractats, reduint la morbimortalitat i la taxa de retrasplantaments. Per poder realitzar el diagnòstic en fases pre-clíniques és necessari establir un protocol que inclogui la pràctica d'ecografies Doppler de rutina, almenys durant les primeres 72 hores posteriors al trasplantament. Tanmateix, la interpretació del registre Doppler arterial en aquest periode és complexa ja que amb freqüència existeix una elevació transitòria de les resistències hepàtiques que contribueixen a alterar l'ona Doppler. Segons els resultats obtinguts en el present treball d'investigació, aquesta elevació de les resistències post-trasplantament estan en relació amb l'edat avançada del donant i amb l'antecedent d'un temps d'isquèmia prolongat; sense que això tingui valor pronòstic, ja que no implica repercussió clínica precoç ni tampoc a llarg plaç. Per altra banda, ha quedat demostrat que el contrast ecogràfic d'última generació (SonoVue®) és de gran utilitat en l'estudi de permeabilitat de l'artèria hepàtica en el periode immediat posterior al trasplantament, ja que augmenta la sensibilitat de l'ecografia Doppler, escurça la duració de l'exploració ecogràfica i disminueix el nombre d'arteriografies diagnòstiques necessàries. A més, permet establir el diagnòstic de sospita de la síndrome de robatori de l'artèria esplènica mitjançant ecografia ja que permet constatar els criteris angiogràfics descrits pel diagnòstic d'aquesta complicació. Les troballes ecogràfiques que permetrien sospitar una síndrome de robatori serien la presència d'una artèria hepàtica permeable amb fluxe molt escàs constituït per petits pics sistòlics (de vegades indetectable a l'estudi Doppler sense contrast), ompliment simultani de l'artèria hepàtica i la vena porta a l'estudi contrastat i disminució mantinguda de la perfusió de les branques distals de l'artèria hepàtica.[eng] "DOPPLER SONOGRAPHY OF THE HEPATIC ARTERY IN THE IMMEDIATE POST-TRASPLANT PERIOD" TEXT: Hepatic artery thrombosis is one of the most important and devastating complications following orthotopic liver transplantation. Doppler ultrasonography is the initial imaging test in patients in whom hepatic artery thrombosis is suspected. However, according to the results of this doctoral thesis, Doppler ultrasound may allow a presymptomatic detection of early hepatic artery thrombosis. This fact permits an early repermeabilization of the hepatic artery before liver damage, reducing the morbidity and the necessity of retransplantation, improving the prognosis of these patients. In order to allow a prompt diagnosis of this complication in presymptomatic stage it is necessary to establish a surveillance Doppler program which includes at least a routine Doppler sonography in the first 72-hours after liver transplantation. However, the interpretation of the Doppler arterial waveform in this early period is difficult, because of the frequent high resistance flow which contributes to alter the Doppler waveform. The results obtained in the present investigation work show that the increase of the arterial resistances immediately after liver transplantation are in relation with the old-age liver donor and a long ischemic time. However, this is a finding without clinical repercussion at early and long-term follow-up. Contrast-enhanced ultrasound using a second generation contrast agent (SonoVue®) is very useful in the study of the hepatic artery permeability in the immediate post-operative period because it improves significantly the flow visualization in hepatic artery, decreases scanning time and reduces the frequency of arteriographics studies. Moreover, microbubble ultrasound contrast helps to establish the diagnosis of the splenic arterial steal syndrome. The sonographic findings that point to the diagnosis of this syndrome are the presence of a patent hepatic artery with slowly flow constituted by low velocity systolic peaks (sometimes only detectable after contrast injection), simultaneous filling contrast of the hepatic artery and the portal vein and diminished perfusion of the distal hepatic arteries

BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update

There have been major advances in the armamentarium for hepatocellular carcinoma (HCC) since the last official update of the Barcelona Clinic Liver Cancer prognosis and treatment strategy published in 2018. Whilst there have been advances in all areas, we will focus on those that have led to a change in strategy and we will discuss why, despite being encouraging, data for select interventions are still too immature for them to be incorporated into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that are required to make clinical decisions for individual patients, considering all of the parameters that must be considered to deliver personalised clinical management

Incidence and factors predictive of recurrent thrombosis in patients with non-cirrhotic portal vein thrombosis.

BACKGROUND AND AIMS Clinical guidelines do not recommend long-term anticoagulation in non-cirrhotic splanchnic vein thrombosis (NC-SVT) without underlying thrombophilia because it is assumed that there is a very low risk of recurrent thrombosis (RT). Our first aim was to describe the incidence of RT in patients with NC-SVT without indication for long-term anticoagulation. The second aim was to identify RT risk factors and afterwards verify them in a validation cohort. METHODS Multicenter retrospective observational study evaluating risk factors for RT in 64 patients with NC-SVT of idiopathic/local etiology. In a subgroup of 48 patients the potential value of additional thrombophilic parameters to predict RT was analyzed. Findings were validated in 70 independent patients with idiopathic/local NC-SVT. RESULTS Of the 64 patients, 17 (26%) presented splanchnic and/or extra-splanchnic RT (overall-RT) during follow-up (cumulative incidence: 2%, 10%, 19% and 34% at 1, 2, 5 and 10 years). 53% of splanchnic RT were asymptomatic. No clinical or biochemical parameters predicted overall-RT. However, in the 48 patients with additional comprehensive thrombophilic study, factor VIII ≥ 150% was the only independent factor predicting overall-RT (HR 7.10 (CI 2.17 - 23.17) p 150% (HR 3.71 (1.31 - 10.5), p < 0.01). The predictive value of factor VIII was confirmed both in patients with idiopathic and with local etiology. CONCLUSIONS Patients with idiopathic/local NC-SVT are at risk of overall-RT. Splanchnic RT can be asymptomatic and requires screening for its detection. Values of factor VIII ≥ 150% may help identify patients at high risk of overall-RT who could benefit from long-term anticoagulation. LAY SUMMARY Patients with idiopathic/isolated local factor non cirrhotic splanchnic vein thrombosis (NC-SVT) were previously thought to be at minimal risk of rethrombosis. Our results show a 25% incidence of rethrombosis and support the indication of close follow-up to identify new thrombotic events, specially in patients with factor VIII >150%

Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors.

BACKGROUND & AIMS Portal vein thrombosis (PVT) is a relatively frequent event in patients with cirrhosis. While different risk factors for PVT have been reported, such as decreased portal blood flow velocity (PBFV) and parameters related with severity of portal hypertension, these are based on retrospective studies assessing only a discrete number of parameters. The aim of the current study was to evaluate the incidence and risks factors for non-tumoral PVT development in a large prospective cohort of patients with cirrhosis. METHODS We performed an exhaustive evaluation of clinical, biochemical, inflammatory and acquired/hereditary hemostatic profiles in 369 patients with cirrhosis without PVT who were prospectively followed-up. Doppler ultrasound was performed at baseline and every 6 months or whenever clinically indicated. PVT development was always confirmed by computed tomography. RESULTS Twenty-nine patients developed non-tumoral PVT, with an incidence of 1.6%, 6% and 8.4% at 1, 3 and 5 years, respectively. Low platelet count, PBFV <15 cm/sec and history of variceal bleeding were factors independently associated with a high PVT risk. No relationship between PVT development and any other clinical biochemical, inflammatory and acquired or hereditary hemostatic parameter was found. CONCLUSIONS In patients with cirrhosis, the factors predictive of PVT development were mainly those related to the severity of portal hypertension. Our results do not support the role of hemostatic alterations (inherited or acquired) and inflammatory markers in the prediction of PVT in patients with cirrhosis. LAY SUMMARY Patients with cirrhosis and more severe portal hypertension are at higher risk of non-tumoral portal vein thrombosis development. Acquired or inherited hemostatic disorders, as well as inflammatory status, do not seem to predict the development of portal vein thrombosis in patients with cirrhosis

Datasets related to a study aimed to identify genetic markers of CDA by subphenotypes associated with cardiotoxicity

Who produced the data? The data has been created by the authors listed above. Is the title specific enough? "Datasets related to a study aimed to identify genetic markers of CDA by subphenotypes associated with cardiotoxicity." Why has the data been created? These datasets are supplementary material with which the principal and supplementary figures and tables of our indicated work were generated. What limitations do the data have (for example, sensitive data has been deleted)? All confidential patient information is not present. We have not had access to that information, following current legal regulations. How should the data be interpreted? These data sets should not be separated from the main article in which they were utilized. Thus, to better understand their context, researchers should see them in the global scenario of our work. Are there gaps in the data, or do they give a complete picture of the topic studied? As indicated above, data should be considered and interpreted in the global context of our study. What processes have generated the data? The processes that generated the data are indicated in the summary of the data above and individually for each of them. Thus, each dataset is accompanied by a legend within the document. What does the data measure in the columns of the files? As indicated, each dataset individually shows the information contained in the legend of each dataset. What software is required to be able to read the data? The datasets are in Excel format. How should the data be quoted? Researchers should cite the data in the context of the work they belong to once it is published and free of the embargo. Can the data be reused? What use licenses are assigned to you? In principle, yes. If additional clinical information is required, these data were previously published by some of us, and the references are included in our manuscript. These data are available from the principal investigators of the references listed in our work upon reasonable request. Are there more versions of the data? Where? I do not think so beyond our files and copies. Have the technical terms and acronyms referenced by the data been defined? A legend with the appropriate descriptions accompanies each dataset. Have the geographic and chronological parameters of the data been qualified? The authors of the work have generated the data. Elsewhere, we indicate the authors of the work, their contributions, and affiliations. Are keywords sufficiently data-specific? Are they based on any thesaurus? Keywords are based on our study. We include cardiotoxicity due to anthracyclines, missing heritability, subphenotype, pathophenotype, complex trait. What is the name of the research project in which the data are framed? The main research project in which the data is prepared is: Títle: "Chemotherapy cardiotoxicity in the elderly: a translational and personnel approach." Ref.: PIE14/00066 Who has financed data production and management? Each of the authors of the study has its funding. The grants are included in the acknowledgments section of our manuscript.Here we present a series of supplemental datasets that complement our study entitled "A Systems Genetics approach to identify genetic markers of cardiotoxicity due to anthracyclines in cancer patients." The datasets presented here were used to generate the main and supplementary figures and tables of the indicated study. The study consists of the identification of genetic markers of cardiotoxicity due to anthracyclines (CDA). CDA is a complex genesis disease or complex trait, and because of this, there is a component of missing heritability. Therefore, it is not possible to identify genetic markers associated with CDA risk. Here, we propose that molecular subphenotypes associated with the CDA may be a strategy for identifying some of this missing heritability and risk markers associated with it. A similar strategy could be applied to identify markers of other diseases of complex genesis. This study is done using a genetically heterogeneous cohort of mice that developed breast cancer and was treated with doxorubicin or a combined treatment of doxorubicin and docetaxel. The mouse cohort was generated by backcrossing, so each mouse is genetically unique. Post-chemotherapy heart damage was assessed by quantifying fibrosis's cardiac area and the thickness of myocardial fibers. The genetic regions associated with CDA were assessed by massive genotyping and genetic linkage analysis. Several molecular subphenotypes were quantified in the myocardium, and their association with the CDA was evaluated. Subsequently, we identified which of them were most statistically associated with CDA in multivariate models. Moreover, which complex trait loci (QTLs) associated with molecular subphenotypes best explained CDA. This strategy served to identify in the cohort of mice genes whose allelic forms could be candidates for the risk of CDA. Allelic variants of these genes were evaluated in four cohorts of cancer patients treated with anthracyclines and whose CDA was evaluated by echocardiography or cardiac magnetic resonance imaging (CMR).JPL laboratory was partially supported by the European Regional Development Fund (ERDF) and the Ministry of Science, Innovation, and Universities (SAF2014-56989-R, SAF2017-88854R), the Carlos III Health Institute (PIE14/00066), "Proyectos Integrados IBSAL 2015" (IBY15/00003), the Regional Government of Castile and Leon (CSI234P18), and "We can be heroes" Foundation. AGN laboratory and human patients' study are supported by funds from the ISCIII project grant (PI18/01242). The Human Genotyping unit is a member of CeGen, PRB3, and is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. SCLL was the recipient of a Ramón y Cajal research contract from the Spanish Ministry of Economy and Competitiveness, and the work was supported by MINECO/FEDER research grants (RTI2018-094130-B-100). The Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019/0023, of the PE I + D + I 2017-2020, funded by ISCIII and FEDER. RCC is funded by fellowships from the Spanish Regional Government of Castile and León. NGS is a recipient of an FPU fellowship (MINECO/FEDER). hiPSC-CM studies were funded in part by the "la Caixa" Banking Foundation under the project code HR18-00304" and Severo Ochoa CNIC Intramural Project (Expediente 12-2016 IGP) to JJ.Supplemental Dataset 1: CDA pathophenotypes after doxorubicin treatment. We treated 71 mice carrying breast cancer with doxorubicin. Each mouse was generated by backcrossing; thus, each one is genetically unique. Cardiotoxicity due to anthracyclines (CDA) was evaluated by automatically quantifying the heart fibrosis area and the average area of myocardial fibers as pathophenotypes of cardiotoxicity using the Ariol slide scanner. The histopathological damage was evaluated in the subendocardium and subepicardium from five randomly chosen regions of each sample (averages in μm2 are shown).-- Supplemental Dataset 2: CDA pathophenotypes after the combined therapy. We treated 61 mice carrying breast cancer with the combined therapy with doxorubicin and docetaxel. Each mouse was generated by backcrossing; thus, each one is genetically unique. Cardiotoxicity due to anthracyclines (CDA) was evaluated by automatically quantifying the heart fibrosis area and the average area of myocardial fibers as pathophenotypes of cardiotoxicity using the Ariol slide scanner. The histopathological damage was evaluated in the subendocardium and subepicardium from five randomly chosen regions of each sample (averages in μm2 are shown).-- Supplemental Dataset 3: CDA subphenotypes after doxorubicin therapy. Myocardium molecular subphenotypes after doxorubicin therapy. Proteins were quantified by a multiplex bead array (Luminex). TGFβ units are shown in pg/mL. The rest of the protein levels are shown in molecular fluorescence intensity (MFI) Units. The telomeric length was quantified by QPCR (RQ units). miRNAs were quantified by QPCR (RQ units). QPCR analyses were assessed by the ΔΔCT method; we show the averages of triplicates.-- Supplemental Dataset 4: CDA subphenotypes after the combined therapy. Myocardium molecular subphenotypes after the combined therapy with doxorubicin and docetaxel. Proteins were quantified by a multiplex bead array (Luminex). TGFβ units are shown in pg/mL. The rest of the protein levels are shown in molecular fluorescence intensity (MFI) Units. The telomeric length was quantified by QPCR (RQ units). miRNAs were quantified by QPCR (RQ units). QPCR analyses were assessed by the ΔΔCT method; we show the averages of triplicates.-- Supplemental Dataset 5: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after doxorubicin therapy in all mice.-- Supplemental Dataset 6: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after doxorubicin therapy in young mice. Correlation of Spearman.-- Supplemental Dataset 7: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after doxorubicin therapy in old mice. Correlation of Spearman.-- Supplemental Dataset 8: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after the combined therapy in all mice. Correlation of Spearman.-- Supplemental Dataset 9: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after the combined therapy in young mice. Correlation of Spearman.-- Supplemental Dataset 10: Correlations identified between molecular subphenotype levels in the myocardium and pathophenotypes of cardiotoxicity due to anthracyclines (CDA) after the combined therapy in old mice. Correlation of Spearman.-- Supplemental Dataset 11: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after doxorubicin therapy in all mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 12: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after doxorubicin therapy in young mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 13: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after doxorubicin therapy in old mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 14: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after the combined therapy in all mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 15: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after the combined therapy in young mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 16: Linkage analysis of molecular subphenotype levels quantified in the myocardium. Lod scores after the combined therapy in old mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 17: Massive genotyping of mouse cohort treated with doxorubicin. The genome-wide scan was carried out at the Spanish National Centre of Genotyping (CeGEN) at the Spanish National Cancer Research Centre (CNIO, Madrid, Spain). The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution.-- Supplemental Dataset 18: Massive genotyping of mouse cohort treated with the combined therapy. The genome-wide scan was carried out at the Spanish National Centre of Genotyping (CeGEN) at the Spanish National Cancer Research Centre (CNIO, Madrid, Spain). The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution.-- Supplemental Dataset 19: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after doxorubicin therapy in all mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 20: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after doxorubicin therapy in young mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 21: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after doxorubicin therapy in old mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 22: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after the combined therapy in all mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 23: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after the combined therapy in young mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 24: Linkage analysis of CDA pathophenotypes quantified in the myocardium. Lod scores after the combined therapy in old mice. The Illumina Mouse Medium Density Linkage Panel Assay was used to genotype 130 F1BX mice at 1449 single nucleotide polymorphisms (SNPs). Genotypes were classified as FVB/FVB (F/F) or FVB/C57BL/6 (F/B). Ultimately, 806 SNPs are informative from the FVB and C57BL/6 mice; the average genomic distance between these SNPs was 9.9 Mb. The genotype proportion among the F1BX mice showed a normal distribution. Linkage analysis was carried out using interval mapping with the expectation-maximization (EM) algorithm and R/QTL software. The criteria for significant and suggestive linkages for single markers were chosen based on Lander and Kruglyak (see methods section of our manuscript).-- Supplemental Dataset 25: Human breast cancer cohort-1 genotyping. The association of genetic variants with CDA was evaluated in four patient cohorts p