Association between ABO blood group and recurrence of venous thrombosis in middle-aged patients: Insights from a weighted Cox analysis dedicated to an ambispective design BMC Medical Research Methodology

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martha research

This work was motivated by the identification of genetic risk factors for VT recurrence in the MARseille Thrombosis Association (MARTHA) study. [25, 26]MARTHA included 2,837 unrelated VT patients presented between 1994 and 2012 at the Thrombosis Center of La Timone Hospital, Marseille (France). Have at least 1 documented VT, no chronic disease, homozygosity for Leiden factor V or factor II 20210A, protein C, protein S and antithrombin deficiency, lupus anticoagulant, etc. All patients without identified genetic risk factors were eligible. As an ancillary genetic study, a subsample of 1,592 of her MARTHA patients was typed by high-density genotyping array, henceforth referred to as the MARTHA GWAS subsample (GWAS stands for Genome Wide Association Study). [27]The MARTHA GWAS substudy was further extended over the period 2013-2018 and patients were re-contacted to collect information on VT events after enrollment.

MARTHA GWAS substudy and VT recurrence

Previous application of standard quality control procedures to the genome-wide genotype data of MARTHA participants selected 1,542 VT patients for genetic analysis. [27]From these remaining individuals, we further excluded patients with autoimmune disease or cancer at the time of inclusion, or those lacking information on time to VT recurrence in patients of concern. Finally, 1,518 VT patients were left for VT recurrence analysis. Of these patients, 411 had already experienced at least one VT recurrence prior to inclusion. The date of first VT and first recurrence, type (DVT or PE), and induced characters were collected. During the period 2013–2018, patients were re-contacted through telephone, email questionnaires, or medical visits to collect information on post-inclusion VT. Of 1,107 patients with unique VT at inclusion, 846 (76%) were recontactable and 160 additional first relapses were identified. At the end of the second stage, information on the vital status of non-responders was obtained through the Répertoire National d’Identification des Personnes Physiques (RNIPP) or medical data. Vital status was eventually available for 1,380 people, including 73 fatalities.

Ambispective design

The current project is Abo Genetic polymorphisms for recurrence risk after first VT can distinguish four different types of MARTHA participants (Figure 1). Case 1 corresponds to a patient who had a single VT prior to inclusion in the study and was followed up during the recontact phase in which no recurrent events were observed. Case 2 represents a patient who had a single VT prior to inclusion and experienced a recurrent event collected during the recontact phase. Case 3 corresponds to a patient with a single VT prior to inclusion for whom no follow-up information was collected during the recontact phase (i.e., failed follow-up). Finally, case 4 represents a patient who experienced both a first VT and a relapse before inclusion in the study. For each of these four situations, the risk period, which is an important factor in the analysis of recurrence data representing the period contributing to the estimation of recurrence risk, is shown in gray in Fig. 1.

Figure 1
Figure 1

Illustration of four scenarios of patients included in the MARTHA study. Case 1: A patient who had a single VT prior to inclusion in the study and was followed up during the recontact period with no observed recurrent events. Case 2: A patient who had one VT before inclusion and experienced recurrent events collected during the recontact phase. Case 3: Patient with a single VT at enrollment for whom no follow-up information was collected during the recontact phase (i.e., failed follow-up). Case 4: A patient who experienced both a first VT and a recurrence before inclusion in the study. For all four situations, the period at risk is shown in gray, the post-inclusion period is dotted, and the retrospective period is dashed

In a standard cohort analysis, only the post-enrollment period for patients in Cases 1 and 2 (represented by the dotted line), thenprospective sample”, used to investigate risk factors for recurrence. However, since genetic polymorphisms are fixed at birth, all cases of patients can contribute to the analysis of genetic susceptibility to VT recurrence if the first VT is considered as the starting point for the analysis (non-solid line). This last comment also applies to non-genetic variables available at the time of first VT that are fixed over time, such as sex and age at first VT. Below,Ambispective sample” [28] When the four situations are considered simultaneously, it includes both pre- and post-inclusion VT recurrences, i.e. recurrences occurring before or within the observation window.

Finally, Martha prospective sample Consisting of 846 patients, including 160 VT recurrences, Ambispective sample 1,518 patients were involved, including 571 recurrent VT.

Statistical modeling of recurrent events using weighted Cox models

The Cox proportional hazards model is a general semiparametric model proposed by Cox in 1972. [29]. The relationship between the instantaneous risk function (or hazard function) and the vector associated with the occurrence of an event \(Z\) The explanatory variables for can be written as: \({\lambda \left(t,Z,\beta \right)= \lambda }_{0}\left(t\right)\mathrm{exp}({\beta }^{\top }Z)\ ) where \(\beta\) is the vector of regression coefficients and \({\lambda}_{0}
Abo Genetic determination of blood type

Five Abo Polymorphisms were investigated to infer Abo blood type.Follow recent recommendations [12]rs8176719-delG was used for tagging O1, rs41302905-T allele for O2, rs2519093-T for A1, rs1053878-A for A2 and rs8176743-T allele for B.

MARTHA and MEGA participants were typed by high-throughput genotyping array and imputed to the 1000G Phase I Consolidated Release Version 2 haplotype, and were therefore inferred using the best-inferred genotype from imputation data Abo blood type [27, 36]Note that for MARTHA and MEGA all five polymorphs have an imputation quality greater than 0.9.guessed Abo Unambiguous haplotypes and haplotype pairs in 1,504 (99.1%) and 1,248 (99.5%) MARTHA and MEGA participants, respectively.Finally, Martha prospective sample Expanded MARTHA consisting of 839 individuals including 159 relapses Ambispective sample 1,504 were included, of whom 565 relapses were observed, and the MEGA sample consisted of 1,248, including 428 relapses. A detailed flowchart of the MARTHA subsample is shown in Supplementary Fig. S1.

modeling strategy

Association of Abo First recurrence blood group was tested assuming an additive effect of Abo Use the O1 group as a reference to tag polymorphisms. Analyzes included sex, precipitating condition for first VT (corresponding to the presence of risk factors that transiently predispose to VT, such as pregnancy or surgery), age at first VT, type of first VT (DVT or PE), and adjusted for the first VT.Four principal components derived from GWAS genotype data according to the literature [8].

finally, Abo Association parameters from MARTHA ambitious MEGA analyzes were meta-analyzed using a fixed-effects model (Mantel-Haenszel methodology) to emphasize observed trends [37].



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