Using Mendelian Randomization to Decipher Mechanisms of Bone Disease

Purpose of Review

This review summarizes the basic principles of Mendelian randomization (MR) and provides evidence for the causal effect of multiple modifiable factors on bone outcomes.

Recent Findings

Several studies using MR approach have provided support for the causal effect of obesity on bone mineral density (BMD). Strikingly, studies have failed to prove a causal association between elevated 25(OH) D concentrations and higher BMD in community-dwelling individuals.

Summary

The MR approach has been successfully used to evaluate multiple factors related to bone mineral density variation and/or fracture risk. The MR approach avoids some of the classical observational study limitations and provides more robust causal evidence, ensuring bigger success of the clinical trials. The selection of interventions based on genetic evidence could have a substantial impact on clinical practice.

     

Influence of Visceral Obesity for Postoperative Pulmonary Complications After Pancreaticoduodenectomy

Background  

We conduct this study to determine whether postoperative complications, including postoperative pulmonary complications (PPCs), are associated with BMI and visceral fat area (VFA) after pancreaticoduodenectomy.     

Association of Sleep Traits and Heel Bone Mineral Density: Observational and Mendelian Randomization Studies

Observational studies have suggested that sleep and circadian disturbances are potentially modifiable risk factors for low bone mineral density (BMD), but the causal relationship is unclear. This study aimed to (i) replicate the findings by examining observational association of sleep traits with low estimated BMD); (ii) examine whether these associations were causal by using Mendelian randomization (MR) analyses; and (iii) investigate potential modulation effects of sex and menopause. A total of 398,137 White British subjects (aged 39 to 73 years) with valid BMD estimated by quantitative ultrasound of the heel (eBMD) at baseline were included. Linear regression analyses and inverse-variance weighted method were used as main methods for observational and one-sample MR analyses, respectively, to investigate the associations between self-reported sleep traits (sleep duration, chronotype, daytime sleepiness, and insomnia) and low eBMD. Furthermore, sensitivity analyses were performed in subgroups based on sex and menopause in both observational and MR analyses. In observational analyses, short/long sleep, insomnia, and definite eveningness were associated with low eBMD (short sleep: β = −0.045, effect in standard deviation change of rank-based inverse normally transformed eBMD; long sleep: β = −0.028; sometimes insomnia: β = −0.012; usually insomnia: β = −0.021; definite eveningness: β = −0.047), whereas definite morningness was associated with decreased risk of low eBMD (β = 0.011). Subgroup analyses suggested associations of short/long sleep and definite eveningness with low eBMD among men, short sleep with low eBMD among premenopausal women, and short sleep, eveningness, and daytime sleepiness among postmenopausal women. In bidirectional MR analyses, there was no causal relationship between sleep traits and eBMD in either overall sample or subgroup analyses. In summary, although observational analysis showed a robust association of low eBMD with sleep duration, chronotype, and insomnia, there was no evidence of causal relationship as suggested by MR analysis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Association Between Postoperative Complications and Clinical Cancer Outcomes

Introduction

The treatment for a majority of solid organ tumors is surgical resection; 10–20 % of patients suffer a perioperative complication. Perioperative complications may contribute to cancer recurrence. This study examined the relationship between postoperative complications and risk-adjusted patient overall survival.

Methods

Data from 2003 to 2009 were linked from our clinical cancer registry, the National Surgery Quality Improvement Project (NSQIP), and medical records. Patients who had tumor extirpation for cure were included. The NSQIP was used to identify complications. Patients with a complication were matched to patients without a complication. χ ² tests and Cox proportional hazard regression models were used.

Results

A total of 415 patients were included for survival analysis. The hazard ratio (HR) for mortality associated with having a complication was 2.17. The HR for mortality after 200 days postoperatively was 2.47. Infectious complications were associated with the highest association with increased mortality (HR = 3.56). Noninfectious complications were not associated with an increased risk of mortality.

Conclusions

This study investigated the relationship of surgical infectious complications in cancer patients with long-term survival for patients who had a number of different types of cancer. After taking into account the site, histology, and stage of the cancer, we found that patients with infectious complications had earlier death.     

Causal Associations of Anthropometric Measurements With Fracture Risk and Bone Mineral Density: A Mendelian Randomization Study

Uncovering additional causal clinical traits and exposure variables is important when studying osteoporosis mechanisms and for the prevention of osteoporosis. Until recently, the causal relationship between anthropometric measurements and osteoporosis had not been fully revealed. In the present study, we utilized several state-of-the-art Mendelian randomization (MR) methods to investigate whether height, body mass index (BMI), waist-to-hip ratio (WHR), hip circumference (HC), and waist circumference (WC) are causally associated with two major characteristics of osteoporosis, bone mineral density (BMD) and fractures. Genomewide significant (p ≤ 5 × 10⁻⁸) single-nucleotide polymorphisms (SNPs) associated with the five anthropometric variables were obtained from previous large-scale genomewide association studies (GWAS) and were utilized as instrumental variables. Summary-level data of estimated bone mineral density (eBMD) and fractures were obtained from a large-scale UK Biobank GWAS. Of the MR methods utilized, the inverse-variance weighted method was the primary method used for analysis, and the weighted-median, MR-Egger, mode-based estimate, and MR pleiotropy residual sum and outlier methods were utilized for sensitivity analyses. The results of the present study indicated that each increase in height equal to a single standard deviation (SD) was associated with a 9.9% increase in risk of fracture (odds ratio [OR] = 1.099; 95% confidence interval [CI] 1.067–1.133; p = 8.793 × 10⁻¹⁰) and a 0.080 SD decrease of estimated bone mineral density (95% CI −0.106–(−0.054); p = 2.322 × 10⁻⁹). We also found that BMI was causally associated with eBMD (beta = 0.129, 95% CI 0.065–0.194; p = 8.113 × 10⁻⁵) but not associated with fracture. The WHR adjusted for BMI, HC adjusted for BMI, and WC adjusted for BMI were not found to be related to fracture occurrence or eBMD. In conclusion, the present study provided genetic evidence for certain causal relationships between anthropometric measurements and bone mineral density or fracture risk. © 2021 American Society for Bone and Mineral Research (ASBMR).     

高危慢性阻塞性肺病病人的围手术期处理

探讨高危慢阻肺（ＣＯＰＤ）病人的围手术期处理,方法：择期进行上腹部和胸腔内手术病人１６例,均患有严重的慢性肺,术前评估围手术期有高度发生呼吸系统并发症的危险。术前准备包括戒烟、预防和控制感染,支气管扩张和呼吸功能锻炼６例病人术前进行无创正压压气（ＮＰＰＶ）训练,手术在硬膜外阻滞复合全身麻醉下完成。术后施行硬膜外镇杂１胸部理疗扩张支气管和氧疗。部分病人间断采用ＮＰＰＶ进行呼吸支持。结果：１６例病人术     

Type 2 Diabetes Is Causally Associated With Reduced Serum Osteocalcin: A Genomewide Association and Mendelian Randomization Study

Recent advances indicate that bone and energy metabolism are closely related. However, little direct evidence on causality has been provided in humans. We aimed to assess the association of three bone-related biomarkers—25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and osteocalcin (OCN)—with several metabolic phenotypes and investigate any causal relevance to the associations using a Mendelian randomization (MR) study. Serum 25OHD, PTH, and total OCN were measured at baseline in 5169 eligible Chinese participants in Changfeng study. Partial correlation and bivariate GREML analysis were used to estimate phenotypic and genetic correlations, respectively. Multiple linear regression and logistic regression were used to assess linear associations. Genomewide association analysis (GWAS) was performed. Bidirectional two-sample MR analyses were conducted to examine causal relationships between OCN and body mass index (BMI), diastolic blood pressure (DBP), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), glycated hemoglobin A1c (HbA1c), and type 2 diabetes (T2DM), using our GWAS result of OCN and GWAS statistics from Biobank Japan project (BBJ) and the largest meta-analysis of T2DM GWAS in East Asian population. Circulating OCN was significantly associated with higher DBP and HDL-C and decreased TG, blood glucose level, insulin resistance, liver fat content, bone mineral density, BMI, and a favorable body fat distribution pattern. GWAS identified one novel serum PTH locus and two novel serum OCN loci, explaining 0.81% and 1.98% of variances of PTH and OCN levels, respectively. MR analysis suggested a causal effect of T2DM on lower circulating OCN concentration (causal effect: −0.03; −0.05 to −0.01; p = 0.006 for T2DM_BBJ and −0.03; −0.05 to −0.01; p = 0.001 for T2DM_EAS). These findings indicate that T2DM might impact bone remodeling and provide a resource for understanding complex relationships between osteocalcin and metabolic (and related) traits in humans. © 2021 American Society for Bone and Mineral Research (ASBMR).     

克罗恩病手术后并发症影响因素的分析

目的:探讨克罗恩病手术后并发症及其影响素.方法:对行手术治疗的45例克罗恩病患者的临床资料进行回顾性研究,logistic分析术后并发症的影响素.结果:12例出现术后并发症,7例患者发现一种以上并发症,肠梗阻9例、吻合口瘘5例、切口感染5例.根据logistic多素回归分析得出术前营养状态、皮质激素的使用、吻合方式,可以影响术后并发症的发生率.结论:术前营养不良、使用皮质激素、非侧侧吻合方式是术后并发症发生率显著增加的影响素.认识这些影响素有助减少术后并发症的发生率.     

Obesity and Postoperative Complications Following Ankle Arthrodesis: A Propensity Score Matched Analysis

Obese patients undergoing orthopedic procedure have been reported to have higher rates of postoperative complications, but the published associations have numerous confounders. This study aims to evaluate the independent effect of obesity on postoperative complications and hospital utilization following ankle arthrodesis. A database review of a Medicare database was performed on patients less than 85 years old who underwent ankle arthrodesis between 2005 and 2014. Patient cohorts were defined using International Classification of Diseases-9 coding for body mass index (BMI)—obese (30-40 kg/m²), and morbidly obese (>40 kg/m²). Normal BMI patients were defined as those without the respect codes for obesity (30-40 kg/m²), morbidly obese (>40 kg/m²), or underweight (<19 kg/m²). All groups were propensity score matched by demographics and comorbidities. Outcomes of interest included 90-day major and minor medical complications, and hospital burden. Morbid obesity was associated with an increased risk of acute kidney injury (4.4% vs 2.4%, OR 1.94, 95% CI 1.37-2.74, p < .001), urinary tract infection (5.2% vs 3.2%, OR 1.66, 95% CI 1.21-2.25, p = .001), readmission (13.6% vs 10.8%, OR 1.33, 95% CI 1.10-1.61, p = .003), and overall minor complications (16.0% vs 11.8%, OR 1.44, 95% CI 1.19-1.74, p < .001) compared to normal BMI patients, and an increased risk for acute kidney injury (4.4% vs 1.9%, OR 2.25, 95% CI 1.32-3.97, p = .003) compared to obese patients. Obesity was not associated with increased medical complications (p > .05). While morbid obesity was associated with an increase in the postoperative complications, obesity was not associated with any increase in postoperative complications following ankle arthrodesis.     

Risk Factors for Mortality and Postoperative Complications After Gastrointestinal Surgery

Background Predictors of a poor surgical outcome are numerous, of which some are well-defined. We aimed to assess risk factors predictive of poor surgical outcome across different gastrointestinal operations related to the patient, the disease, the treatment, and the organization of care. Methods Data from 5,255 unselected patients undergoing open gastrointestinal surgery from 1995 through 1998 was prospectively recorded in a clinical database and validated. The database embraced variables related to patient history, preoperative clinical condition, operative findings and complexity, and the surgeon’s training. Variables predictive of mortality and complications occurring within 30 days after surgery were assessed by multiple logistic regression analysis. Results After elective operation, the 30-day mortality was 2.8% and major complications occurred in 11.5% of the patients. The corresponding figures in emergency surgery were 13.8% and 30.1%. Independent of elective or emergency surgery, dependent functional status, and type of operation were associated with postoperative mortality. Comorbidity, type of operation, blood loss, and reoperation were predictors of complications regardless of elective or emergency operation. In elective surgery, predictors of poor surgical outcome were high age, comorbidity, malignancy, and the surgeons training, whereas abnormal vital signs values and peritonitis were predictors of poor outcome after emergency surgery. Conclusion Premorbid factors, characteristics of the disease, the patients’ preoperative condition, operative factors, and the surgeon’s training are all associated with surgical outcome across different gastrointestinal operations and should be assessed when auditing surgical outcome.     

A Genetic "Obesity Risk Index" for Patients With Morbid Obesity

Background:The influence of genetics on obesity is well established. Adoption studies and twin studies suggest that about 80% of the obesity risk is genetic. We designed a tool to predict outcomes of treatments in patients with sporadic or familial obesity. Methods:Two factors best correlate with multifactorial genetic risk: 1) familial history and 2) age of onset. 147 morbidly obese adults self- or physician-referred for possible surgery for morbid obesity (age 17-66y, BMI 35-82) were studied. Six elements were selected to measure the genetic influence on patients' weight: 3 personal weight milestones (weight at age 10, 20 and 30), and 3 family history factors (parents'weight, siblings' weight and second degree relatives' weight. These 6 elements of personal and family history information were collected prospectively on 35 obese patients and a feasible scoring system devised, with 0 points signifying no genetic component and 100 points suggesting the maximal possible genetic risk for obesity. Prospective data were then collected on 147 consecutive patients seen in consultation for possible bariatric surgery,to provide this "obesity risk index" (ORI). Results: The final scoring system for the ORI assigned 50 possible points for personal weight milestones and 50 possible points for family history factors. At age 10, patients receive 10 or 20 points for being 2 or 3 SD above the mean BMI for age, respectively. At age 20, 10 or 20 points are received for BMI > 30 or 40, respectively. At age 30, 5 or 10 points are received for BMI > 35 or 50, respectively. 0 to 28 points are awarded for parental obesity, with 7 or 14 points for each parent with BMI > 30 or 40, respectively. The mean BMI of all siblings was calculated, with 6 or 12 points received for mean BMI greater than 30 or 40, respectively.Two points are awarded for each second degree relative with BMI>35, to a maximum of 10 points. The mean (±SEM) score for our first 114 patients was 32 ± 2 (range 0 to 87).The median score was 28. 13% of patients had scores <10; conversely, 13% scored points on all 6 elements. Conclusion: An ORI has been devised to quantify the genetic contribution to an individual's weight. Using this scoring system, we found that about 85% of patients who are candidates for bariatric surgery have elements in their history to suggest a genetic risk for morbid obesity. About 15% have extremely strong genetic ORIs.     

Risk Factor Analysis of Postoperative Complications After Robotic Rectal Cancer Surgery

Background  

The robotic system has been adopted as the new modality for minimally invasive surgery for rectal cancer. However, analysis of risk factors for complications after robotic rectal cancer surgery (RRS) has been limited. This study aimed to identify the risk factors for complications after RRS.     

Respiratory Complications of Obesity

Obesity, well known as a cardiovascular risk factor, can also lead to significant respiratory complications. The respiratory changes associated with obesity extend from a simple change in respiratory function, with no effect on gas exchange, to the more serious condition of hypercapnic respiratory failure, characteristic of obesity hypoventilation syndrome. More recently, it has been reported that there is an increased prevalence of asthma which is probably multifactorial in origin, but in which inflammation may play an important role. Hypoventilation in the obese subject is the result of complex interactions that involve changes in the ventilatory mechanics and anomalies in breathing control. Two other conditions (COPD and sleep apneahypopnea syndrome [SAHS], often present in obese patients, can trigger or aggravate it. The prevalence of hypoventilation in the obese is under-estimated and the diagnosis is usually established during an exacerbation, or when the patient is studied due to suspicion of SAHS. Ventilatory management of these patients, ventilatory management of these patients includes either CPAP or NIV. The choice of one or another will depend on the underlying clinical condition and whether or not there is another comorbidity. Both NIV and CPAP have demonstrated their effectiveness, not only in the control of gas exchange, but also in improving the quality of life and survival of these patients     

Association of Hypoalbuminemia on the First Postoperative Day and Complications Following Esophagectomy

Objective Changes in serum albumin may reflect systemic immunoinflammation and hypermetabolism in response to insults such as trauma and sepsis. Esophagectomy is associated with a major metabolic stress, and the aim of this study was to determine if the absolute albumin level on the first postoperative day was of value in predicting in-hospital complications. Methods A retrospective study of 200 patients undergoing esophagectomy for malignant disease at St. James Hospital between 1999 and 2005 was performed. Patients who had pre and postoperative (days 1, 3, and 7) serum albumin levels measured were included in the study. Patients were subdivided into three postoperative albumin categories <20 g/l, 20–25 g/l, >25 g/l. Logistic regression analysis was performed to calculate the odds of morbidity and mortality according to the day 1 albumin level. Results Patients with an albumin of less than 20 g/l on the first postoperative day were twice as likely to develop postoperative complications than those with an albumin of greater than 20 g/l (54 vs 28% respectively, p < 0.011). Correspondingly, these patients also had a significantly higher rate of Adult Respiratory Distress Syndrome (22 vs 5%, p < 0.001), respiratory failure (27 vs 8%, p < 0.01) and in-hospital mortality (27 vs 6% (p < 0.001). On multivariate logistic regression analysis, day 1 albumin level was independently related to postoperative complications (odds ratios, 0.89: 95%; confidence intervals, 0.83–0.96; p < 0.005). In addition, albumin <20 g/l on the first postoperative day was associated with the need for further surgery and a return to ICU. Conclusion Serum albumin concentration on the first postoperative day is a better predictor of surgical outcome than many other preoperative risk factors. It is a low cost test that may be used as a prognostic tool to detect the risk of adverse surgical outcomes.     

Clinicopathologic Characteristics of Elderly with Gastric Cancer,and the Risk Factors of Postoperative Complications

Purpose: In China, gastric cancer (GC), which is one of the most common malignant tumors, has an increasing incidence in elderly population due to aging process. Since a considerable number of elderly patients with GC accepting surgical treatments developed postoperative complications, it is necessary to evaluate risk factors for postoperative complications. Materials and methods: In the present study, the clinicopathologic characteristics of 3,024 elderly patients (aged ≥65 years) with GC, who underwent surgery between 1996 and 2006, were examined and contributing factors for postoperative complications were analyzed. A total of 2,915 non-elderly patients (aged <65 years) with GC during the same period were enrolled as a control group. Clinicopathologic characteristics of non-elderly patients were investigated and compared with elderly group. Results: As to clinicopathologic characteristics, significant differences were detected in terms of location of primary lesions between elderly patients and non-elderly patients (p <.05), whereas no statistical difference was observed in other characteristics between two groups (p >.05). Surgical property and method in elderly patients were similar to that in non-elderly patients (p >.05). Regression analysis showed that diabetes, chronic pulmonary disease, preoperative anemia, preoperative hypoalbuminemia, combined organ excision, and blood transfusion were independent factors for complications in elderly patients (p <.05), with some differences from non-elderly group. Conclusions: Elderly group with GC had distinctive clinicopathologic characteristics. Surgery remains principal treatment for elderly, and proper preoperative measures are required to decrease postoperative complications.     

Pilonidal Sinus Disease: Risk Factors for Postoperative Complications and Recurrence

The aim of this study is to analyze the risk factors for complications and recurrence in pilonidal sinus disease. The prospective study consisted of 144 patients with pilonidal sinus disease who were operated on at Dicle University Medical Faculty, Department of General Surgery, between February 2008 and December 2010. Patients receiving the Limberg flap totaled 106 (73.6%), while 38 (26.4%) had primary closure. Postoperative complications developed in 42 subjects (29.2%), and recurrence occurred in 19 (13.2%). The Limberg flap method was statistically considered as a risk factor for postoperative complications (P  =  0.039). Regarding recurrence, family tendency (P  =  0.011), sinus number (P  =  0.005), cavity diameter (P  =  0.002), and primary closure (P  =  0.001) were found to be risk factors. Postoperative complication rate is higher in the Limberg flap method than primary closure method. The risk of recurrence is related to family tendency, sinus number, cavity diameter and anesthesia type and is also higher in primary closure.     

Identification and Validation of Risk Factors for Postoperative Infectious Complications Following Hepatectomy

Summary

Postoperative infectious complications (PICs) are associated with significant morbidity after abdominal surgery. Using multivariate analysis of data from a prospective database, our study focused on the risk factors for PICs and the prevention of these complications after hepatectomy, with the goal of improving outcomes and reducing the length of hospital stays.

Background

PICs following surgery are associated with significant morbidity, increase the length of hospital stays, and have a negative impact on long-term oncological outcome. The aim of this study was to determine the risk factors for PICs following partial hepatectomy and to validate these results with an external database.

Methods

Between January 2006 and December 2009, 555 patients underwent elective partial hepatectomy. We prospectively collected and retrospectively analyzed demographic data, pathological variables, associated pathological conditions, and preoperative, intraoperative, and postoperative variables. The dependent variables studied were the occurrence of PICs, defined as development of one or more of the following conditions: pneumonia, sepsis, Central line-associated bloodstream infection, urinary tract infection, wound infection, and infected intra-abdominal fluid collection. PICs were devised in medical (PIMCs) and surgical (PISCs) complications. The incidence of PICs and validation of the predictive score were determined using an external prospective database of 342 patients.

Results

The multivariate analysis identified three independent risk factors for PICs: the presence of a nasogastric tube (OR?=?1.8), blood transfusion (OR?=?1.9), and diabetes (OR?=?2.4). The multivariate analysis identified only one independent risk factor for PISCs: an associated portal venous resection (OR?=?5.5). The multivariate analysis identified four independent risk factors for PIMCs: presence of a biliary drainage (OR?=?1.9), blood transfusion (OR?=?2.1), diabetes (OR?=?2.9), and presence of atrial fibrillation (OR?=?3.6). According to the three predictive factors, the observed rates of PICs ranged from 18.8 % to 77.8 % and ranged from 24.2 % to 100 % in the external database. Predicted and observed risks of PICs were not statistically different.

Conclusions

The correction of modifiable risk factors among the identified factors could reduce the incidence of PICs and, as a consequence, improve patient outcomes and reduce the length of hospital stays.     

Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study

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