Reflecting on “A Statistician in Medicine” in 2020

In this commentary, we revisit Sir Austin Bradford Hill's seminal Alfred Watson Memorial Lecture in 1962 through the eyes of two practicing biostatisticians of the current era. We summarize some eternal takeaway messages from Hill's lecture regarding observations and experiments translated through the modern lexicon of causal inference. Finally, we pose a series of questions that we would have liked to pose to Sir Austin Bradford Hill if he were to deliver the lecture in 2020.     

Next generation sequencing for neurological diseases: New hope or new hype?

Over the past year huge advances have been made in our ability to determine the genetic aetiology of many neurological diseases through the utilisation of next generation sequencing platforms. This technology is, on a daily basis, providing new breakthroughs in neurological disease. The aim of this article is to clearly describe the technological platforms, methods of data analysis, established breakthroughs, and potential future clinical and research applications of this innovative and exciting technique which has relevance to all those working within clinical neuroscience.     

Computerized physical activity training for persons with severe mental illness - experiences from a communal supported housing project

Purpose: To study the effectiveness of Exergames in communal psychiatry for persons with severe mental illness, a randomized cluster study was performed. The hypothesis was to increase physical activity habits to improve somatic health. To identify factors promoting or impeding the use of the Exergames.

Methods: Assessments of BMI, blood pressure, physical fitness, SF36, GAF and social interactions were studied at baseline and 10 months. An integrated methods design using content analysis of focus group interviews was integrated with a statistical analysis. Forty-three persons were randomized to the intervention and 30 to the control group. The qualitative interviews included 18 users, 11 staffs and one technical assistant.

Results: There were no significant between-group changes in physical activity behaviours or somatic health parameters after 10 months. Only 5% of the intervention group made systematic use of the intervention. Technological difficulties and staff attitudes were found to be barriers. The Exergames were perceived as technically complicated. The staff did not see playing TV games as important and negative attitudes were found.

Conclusions: Exergames was not a successful intervention to increase physical activity behaviours in persons with severe mental illness in the community. Exergames and motivation for physical activity in this group is problematic.

• Implications for rehabilitation

• There are difficulties to change passive physical activity habits for persons with severe mental illness, living in sheltered housing conditions in the community due to negative symptoms with depression, low motivation and bad self -confidence.

• An exergame intervention was not successful in this group of persons. No somatic health benefits were found.

• Simple physical activities and offering different choices meeting different user needs should be offered.

• Ensuring user and staff engagement, good technical knowledge and good monitoring is a need for a successful intervention, if Exergames are offered as an alternative physical activity.

     

Allometric body shape indices,type 2 diabetes and kidney function: A two-sample Mendelian randomization study

Aim

To examine the association between body mass index (BMI)-independent allometric body shape indices and kidney function.

Materials and methods

We performed a two-sample Mendelian randomization (MR) analysis, using summary statistics from UK Biobank, CKDGen and DIAGRAM. BMI-independent allometric body shape indices were: A Body Shape Index (ABSI), Waist-Hip Index (WHI) and Hip Index (HI). Kidney function outcomes were: urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate and blood urea nitrogen. Furthermore, we investigated type 2 diabetes (T2D) as a potential mediator on the pathway to albuminuria. The main analysis was inverse variance-weighted random-effects MR in participants of European ancestry. We also performed several sensitivity MR analyses.

Results

A 1-standard deviation (SD) increase in genetically predicted ABSI and WHI levels was associated with higher UACR (β = 0.039 [95% confidence interval: 0.016, 0.063] log [UACR], P = 0.001 for ABSI, and β = 0.028 [0.012, 0.044] log [UACR], P = 6 x 10⁻⁴ for WHI) in women, but not in men. Meanwhile, a 1-SD increase in genetically predicted HI was associated with lower UACR in women (β = −0.021 [−0.041, 0.000] log [UACR], P = 0.05) and in men (β = −0.026 [−0.058, 0.005] log [UACR], P = 0.10). Corresponding estimates in individuals with diabetes were substantially augmented. Risk of T2D increased for genetically high ABSI and WHI in women (P < 6 x 10⁻¹⁹) only, but decreased for genetically high HI in both sexes (P < 9 x 10⁻³). No other associations were observed.

Conclusions

Genetically high HI was associated with decreased risk of albuminuria, mediated through decreased T2D risk in both sexes. Opposite associations applied to genetically high ABSI and WHI in women only.     

The effects of blood pressure and antihypertensive drugs on heart failure: A Mendelian randomization study

Background and aimsHeart failure (HF) is often triggered by hypertension and can benefit from antihypertensive treatment. We aimed to investigate whether pulse pressure (PP) could independently raise the risk of HF beyond systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as explore the potential mechanisms of antihypertensives in HF prevention.Methods and resultsWe generated genetic proxies for SBP, DBP, PP, and five drug classes based on a massive genome-wide association study. We applied two-sample Mendelian randomization (MR) using summary statistics derived from European individuals and conducted summary data-based MR (SMR) with gene expression data. In univariate analysis, PP showed an obvious association with HF risk (OR, 1.24 per 10 mm Hg increment; 95% CI, 1.16 to 1.32), which was largely attenuated in multivariable analysis when adjusted for SBP (0.89; 0.77 to 1.04). A significant decrease in HF risk was obtained with genetically proxied β-blockers (equivalent to a 10 mm Hg reduction in SBP, 0.71; 0.62 to 0.82) and calcium channel blockers (0.71; 0.65 to 0.78), but not with genetically proxied angiotensin-converting enzyme inhibitors (0.69; 0.40 to 1.19) and thiazide diuretics (0.80; 0.47 to 1.37). Additionally, the enrichment of expression for the KCNH2 gene, a target gene of β-blockers, in blood vessels and nerves was significantly associated with HF risk.ConclusionOur findings suggest that PP may not be an independent risk factor for HF. β-blockers and calcium channel blockers have a protective effect against HF, which at least partly depends on their blood pressure-lowering effect.     

Flow cytometry-based diagnosis of primary immunodeficiency diseases

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs.Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost.     

Assessing causal relationships using genetic proxies for exposures: an introduction to Mendelian randomization

Background and aims

Studying the consequences of addictive behaviours is challenging, with understanding causal relationships from observational data being particularly difficult. For example, people who smoke or drink excessively are often systematically different from those who do not, are less likely to participate in research and may misreport their behaviours when they do. Furthermore, the direction of causation between an addictive behaviour and outcome may be unclear. Mendelian randomization (MR) offers potential solutions to these problems.

Methods

We describe MR's principles and the criteria under which it is valid. We identify challenges and potential solutions in its application (illustrated using two applied examples) and describe methodological extensions in its application.

Results

MR is subject to certain assumptions, and requires the availability of appropriate genetic data, large sample sizes and careful design and conduct. However, it has already been applied successfully to the addiction literature. The relationship between alcohol consumption (proxied by a variant in the ADH1B gene) and cardiovascular risk has been investigated, finding that alcohol consumption increases risk, with no evidence of a cardioprotective effect at moderate consumption levels. In addition, heaviness of smoking (proxied by a variant in the CHRNA5‐A3‐B4 gene cluster) and risk of depression and schizophrenia have been investigated, with no evidence of a causal effect of smoking on depression but some evidence of a causal effect on schizophrenia.

Conclusions

Mendelian randomization analyses are already producing robust evidence for addiction‐related practice and policy. As genetic variants associated with addictive behaviours are identified, the potential for Mendelian randomization analyses will grow. Methodological developments are also increasing its applicability.     

Cholesteryl Ester Transfer Protein Inhibition for Preventing Cardiovascular Events: JACC Review Topic of the Week

Cholesteryl ester transfer protein (CETP) facilitates exchange of triglycerides and cholesteryl ester between high-density lipoprotein (HDL) and apolipoprotein B100–containing lipoproteins. Evidence from genetic studies that variants in the CETP gene were associated with higher blood HDL cholesterol, lower low-density lipoprotein cholesterol, and lower risk of coronary heart disease suggested that pharmacological inhibition of CETP may be beneficial. To date, 4 CETP inhibitors have entered phase 3 cardiovascular outcome trials. Torcetrapib was withdrawn due to unanticipated off-target effects that increased risk of death, and major trials of dalcetrapib and evacetrapib were terminated early for futility. In the 30,000-patient REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, anacetrapib doubled HDL cholesterol, reduced non-HDL cholesterol by 17 mg/dl (0.44 mmol/l), and reduced major vascular events by 9% over 4 years, but anaceptrapib was found to accumulate in adipose tissue, and regulatory approval is not being sought. Therefore, despite considerable initial promise, CETP inhibition provides insufficient cardiovascular benefit for routine use.