Reporting methodological issues of the mendelian randomization studies in health and medical research: a systematic review

Background Mendelian randomization (MR) studies using Genetic risk scores (GRS) as an instrumental variable (IV) have increasingly been used to control for unmeasured confounding in observational healthcare databases. However, proper reporting of methodological issues is sparse in these studies. We aimed to review published papers related to MR studies and identify reporting problems. Methods We conducted a systematic review using the clinical articles published between 2009 and 2019. We searched PubMed, Scopus, and Embase databases. We retrieved information from every MR study, including the tests performed to evaluate assumptions and the modelling approach used for estimation. Using our inclusion/exclusion criteria, finally, we identified 97 studies to conduct the review according to the PRISMA statement. Results Only 66 (68%) of the studies empirically verified the first assumption (Relevance assumption), and 40 (41.2%) studies reported the appropriate tests (e.g., R2, F-test) to investigate the association. A total of 35.1% clearly stated and discussed theoretical justifications for the second and third assumptions. 30.9% of the studies used a two-stage least square, and 11.3% used the Wald estimator method for estimating IV. Also, 44.3% of the studies conducted a sensitivity analysis to illuminate the robustness of estimates for violations of the untestable assumptions. Conclusions We found that incompleteness of the justification of the assumptions for the instrumental variable in MR studies was a common problem in our selected studies. This may misdirect the findings of the studies.

Skip hemilaminectomy for the treatment of holospinal epidural abscess: A single-center experience

Background: Holospinal epidural abscesses (HEAs) are rare with potentially devastating consequences. Urgent bony decompression and abscess evacuation with long-term antibiotic therapy are typically the treatment of choice. Methods: We reviewed cases of holospinal HEAs operated on between 2009 and 2018. Variables studied included preoperative laboratories, CT/MR studies plus clinical and radiographic follow-up for between 34 and 60 postoperative months. Results: We utilized skip hemilaminectomies to minimize the risks of segmental instability. Targeted antibiotic therapy was also started immediately and maintained for 6 postoperative weeks. MR/CT studies documented full radiographic and neurological recovery between 6 and 12-months later. Conclusion: HEAs may be treated utilizing multilevel skip hemilaminectomies to help maintain spinal stability while offering adequate abscess decompression/resolution.

Imaging evolution from “presyrinx” to syrinx in patient with spinal lipoma

Background: The evolution of syrinx formation has rarely been documented. Here, we report a patient whose “presyrinx” evolved on successive magnetic resonance (MR) images to a mature syrinx. Case Description: A patient had a lipoma and tethered cord at birth. At 3 weeks of age, he had undergone a partial removal of the lipoma and untethering of the spinal cord. At age 6, the thoracic MR images showed edema within the gray matter of the cord at the T7 level, consistent with a “presyrinx.” In addition, subsequent MR studies (i.e., at age 7) showed a small cavity in the right posterior horn of the cord accompanied by further expansion throughout the right-sided gray matter. Despite repeated cord untethering at age 7, the T7 parenchymal cord change evolved into a mature syrinx by age 10. Conclusion: An infant with a lipoma/tethered cord, despite two instances of cord detethering (i.e., ages 3 weeks and 7 years), showed continued MR evolution of a “presyrinx” to a mature syrinx by age 10.

Development of a Proton-Frequency-Transparent Birdcage Radiofrequency Coil for In Vivo 13C MRS/MRSI Study in a 3.0 T MRI System

A proton-frequency-transparent (PFT) birdcage RF coil that contains carbon-proton switching circuits (CPSCs) is presented to acquire 13C MR signals, which, in turn, enable 1H imaging with existing 1H RF coils without being affected by a transparent 13C birdcage RF coil. CPSCs were installed in the PFT 13C birdcage RF coil to cut the RF coil circuits during 1H MR imaging. Finite-difference time-domain (FDTD) electromagnetic (EM) simulations were performed to verify the performance of the proposed CPSCs. The performance of the PFT 13C birdcage RF coil with CPSCs was verified via phantom and in vivo MR studies. In the phantom MR studies, 1H MR images and 13C MR spectra were acquired and compared with each other using the 13C birdcage RF coil with and without the CPSCs. For the in vivo MR studies, hyperpolarized 13C cardiac MRS and MRSI of swine were performed. The proposed PFT 13C birdcage RF coil with CPSCs led to a percent image uniformity (PIU) reduction of 1.53% in the proton MR images when compared with the case without it. FDTD EM simulations revealed PIU reduction of 0.06% under the same conditions as the phantom MR studies. Furthermore, an SNR reduction of 5.5% was observed at 13C MR spectra of corn-oil phantom using the PFT 13C birdcage RF coil with CPSCs compared with that of the 13C birdcage RF coil without CPSCs. Utilizing the PFT 13C birdcage RF coil, 13C-enriched compounds were successfully acquired via in vivo hyperpolarized 13C MRS/MRSI experiments. In conclusion, the applicability and utility of the proposed 16-leg low-pass PFT 13C birdcage RF coil with CPSCs were verified via 1H MR imaging and hyperpolarized 13C MRS/MRSI studies using a 3.0 T MRI system.

Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies

Background Obesity is a worldwide epidemic that has been associated with a plurality of diseases in observational studies. The aim of this study was to summarize the evidence from Mendelian randomization (MR) studies of the association between body mass index (BMI) and chronic diseases. Methods PubMed and Embase were searched for MR studies on adult BMI in relation to major chronic diseases, including diabetes mellitus; diseases of the circulatory, respiratory, digestive, musculoskeletal, and nervous systems; and neoplasms. A meta-analysis was performed for each disease by using results from published MR studies and corresponding de novo analyses based on summary-level genetic data from the FinnGen consortium (n = 218,792 individuals). Results In a meta-analysis of results from published MR studies and de novo analyses of the FinnGen consortium, genetically predicted higher BMI was associated with increased risk of type 2 diabetes mellitus, 14 circulatory disease outcomes, asthma, chronic obstructive pulmonary disease, five digestive system diseases, three musculoskeletal system diseases, and multiple sclerosis as well as cancers of the digestive system (six cancer sites), uterus, kidney, and bladder. In contrast, genetically predicted higher adult BMI was associated with a decreased risk of Dupuytren’s disease, osteoporosis, and breast, prostate, and non-melanoma cancer, and not associated with Alzheimer’s disease, amyotrophic lateral sclerosis, or Parkinson’s disease. Conclusions The totality of the evidence from MR studies supports a causal role of excess adiposity in a plurality of chronic diseases. Hence, continued efforts to reduce the prevalence of overweight and obesity are a major public health goal.

Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures

Selection bias is increasingly acknowledged as a limitation of Mendelian randomization (MR). However, few methods exist to assess this issue. We focus on two plausible causal structures relevant to MR studies and illustrate the data-generating process underlying selection bias via simulation studies. We conceptualize the use of control exposures to validate MR estimates derived from selected samples by detecting potential selection bias and reproducing the exposure–outcome association of primary interest based on subject matter knowledge. We discuss the criteria for choosing the control exposures. We apply the proposal in an MR study investigating the potential effect of higher transferrin with stroke (including ischemic and cardioembolic stroke) using transferrin saturation and iron status as control exposures. Theoretically, selection bias affects associations of genetic instruments with the outcome in selected samples, violating the exclusion-restriction assumption and distorting MR estimates. Our applied example showing inconsistent effects of genetically predicted higher transferrin and higher transferrin saturation on stroke suggests the potential selection bias. Furthermore, the expected associations of genetically predicted higher iron status on stroke and longevity indicate no systematic selection bias. The routine use of control exposures in MR studies provides a valuable tool to validate estimated causal effects. Like the applied example, an antagonist, decoy, or exposure with similar biological activity as the exposure of primary interest, which has the same potential selection bias sources as the exposure–outcome association, is suggested as the control exposure. An additional or a validated control exposure with a well-established association with the outcome is also recommended to explore possible systematic selection bias.

Genetic effect modification of cis-acting C-reactive protein variants in cardiometabolic disease status

Mendelian randomization (MR) studies carried out among patients with a particular health condition should establish the genetic instrument influences the exposure in that subgroup, however this is normally investigated in the general population. Here, we investigated whether the genetic associations of four cis-acting C-reactive protein (CRP) variants differed between participants with and without three cardiometabolic conditions: obesity, type 2 diabetes, and cardiovascular disease. Associations of cis-genetic variants with CRP differed between obese and non-obese individuals. A multivariable analysis suggested strong independent associations of the gene-by-body mass index (BMI) interaction on CRP (P<1.18×10−8 for the CRP variants). Applying MR, we observed strong causal effect of BMI on CRP (P=2.14×10−65). In summary, our study indicates that genetic associations with CRP differ across disease sub-groups, with evidence to suggest that BMI is an effect modifier. MR studies of disease progression should report on the genetic instrument-exposure association in the disease subgroup under investigation.

Alcohol consumption in relation to cardiovascular diseases and mortality: a systematic review of Mendelian randomization studies

The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.

Review of Mendelian Randomization Studies on Ovarian Cancer

Ovarian cancer (OC) is one of the deadliest gynecological cancers worldwide. Previous observational epidemiological studies have revealed associations between modifiable environmental risk factors and OC risk. However, these studies are prone to confounding, measurement error, and reverse causation, undermining robust causal inference. Mendelian randomization (MR) analysis has been established as a reliable method to investigate the causal relationship between risk factors and diseases using genetic variants to proxy modifiable exposures. Over recent years, MR analysis in OC research has received extensive attention, providing valuable insights into the etiology of OC as well as holding promise for identifying potential therapeutic interventions. This review provides a comprehensive overview of the key principles and assumptions of MR analysis. Published MR studies focusing on the causality between different risk factors and OC risk are summarized, along with comprehensive analysis of the method and its future applications. The results of MR studies on OC showed that higher BMI and height, earlier age at menarche, endometriosis, schizophrenia, and higher circulating β-carotene and circulating zinc levels are associated with an increased risk of OC. In contrast, polycystic ovary syndrome; vitiligo; higher circulating vitamin D, magnesium, and testosterone levels; and HMG-CoA reductase inhibition are associated with a reduced risk of OC. MR analysis presents a2 valuable approach to understanding the causality between different risk factors and OC after full consideration of its inherent assumptions and limitations.