Biology subjects

Thorand, B.

Publications and source records attributed to Thorand, B..

3 recordsLinked to original sources

bioRxiv2024

The Interpretable Multimodal Machine Learning (IMML) framework reveals pathological signatures of distal sensorimotor polyneuropathy

Distal sensorimotor polyneuropathy (DSPN) is a common neurological disorder in elderly adults and people with obesity, prediabetes and diabetes and is associated with high morbidity and premature mortality. DSPN is a multifactorial disease and not fully understood yet. Here, we developed the Interpretable Multimodal Machine Learning (IMML) framework for predicting DSPN prevalence and incidence based on sparse multimodal data. Exploiting IMMLs interpretability further empowered biomarker identification. We leveraged the population-based KORA F4/FF4 cohort including 1,091 participants and their deep multimodal characterisation, i.e. clinical data, genomics, methylomics, transcriptomics, proteomics, inflammatory proteins and metabolomics. Clinical data alone is sufficient to stratify individuals with and without DSPN (AUROC = 0.752), whilst predicting DSPN incidence 6.5{+/-}0.2 years later strongly benefits from clinical data complemented with two or more molecular modalities (improved {Delta}AUROC >0.1, achieved AUROC of 0.714). Important and interpretable features of incident DSPN prediction include up-regulation of proinflammatory cytokines, down-regulation of SUMOylation pathway and essential fatty acids, thus yielding novel insights in the disease pathophysiology. These may become biomarkers for incident DSPN, guide prevention strategies and serve as proof of concept for the utility of IMML in studying complex diseases.

bioinformatics↗

bioRxiv2020

Multi-platforms approach for plasma proteomics: complementarity of Olink PEA technology to mass spectrometry-based protein profiling

The plasma proteome is the ultimate target for biomarker discovery. It stores an endless amount of information on the pathophysiological status of a living organism, which is however still difficult to comprehensively access. The high structural complexity of the plasma proteome can be addressed by either a system-wide and unbiased tool such as mass spectrometry (LC-MS/MS) or a highly sensitive targeted immunoassay such as the Proximity Extension Assays (PEA). In order to address relevant differences and important shared characteristics, we tested the performance of LC-MS/MS in data-dependent and -independent acquisition modes and PEA Olink to measure circulating plasma proteins in 173 human plasma samples from a Southern German population-based cohort. We demonstrated the measurement of more than 300 proteins with both LC-MS/MS approaches applied, mainly including high abundance plasma proteins. By the use of the PEA technology, we measured 728 plasma proteins, covering a broad dynamic range with high sensitivity down to pg/ml concentrations. In a next step, we quantified 35 overlapping proteins with all three analytical platforms, verifying the reproducibility of data distributions, measurement correlation and gender-based differential expression. Our work highlights the limitations and the advantages of both, targeted and untargeted approaches, and prove their complementary strengths. We demonstrated a significant gain in proteome coverage depth and subsequent biological insight by platforms combination - a promising approach for future biomarker and mechanistic studies.

biochemistry↗

bioRxiv2019

Investigation of an LPA KIV-2 nonsense mutation in 11,000 individuals: the importance of linkage disequilibrium structure in LPA genetics.

ObjectiveElevated Lp(a) plasma concentrations are determined mainly genetically by the LPA gene locus, but up to 70% of the coding sequence is located in the so-called "kringle IV type 2" (KIV-2) copy number variation. This region is not resolved by common genotyping technologies and large epidemiological studies on this region are therefore missing. The Arg21Ter variant (R21X, variant frequency {approx}2%) is a functional variant in this region, but it has never been analyzed in large cohorts and is it unknown whether it is captured by genome-wide association studies. Approach and ResultsWe developed a highly sensitive allele-specific qPCR assay and genotyped R21X in 10,910 individuals from three populations (GCKD, KORA F3, KORA F4). R21X carriers showed significantly lower mean Lp(a) concentrations (-11.7 mg/dL [-15.5;-7.82], p=3.39e-32). Of particular note, virtually all R21X carriers also carried the splice mutation rs41272114 (D=0.957, R2=0.275), as confirmed by pulsed-field gel electrophoresis and long-range haplotyping. This proposes that the R21X mutation arose on the background of the rs41272114 splice variant. ConclusionsWe performed the largest epidemiological study on an LPA KIV-2 variant so far. Interestingly, R21X is located on the same haplotype as the splice mutation rs41272114, creating "double-null" LPA alleles that are inactivated by two independent mutations. The effect of the R21X nonsense mutation can thus not be discerned from the effect of rs41272114 splice site mutation. This emphasizes the importance of assessing the complex LD structure within LPA even for functional variants.

genetics↗