Are Mendelian randomization investigations immune from bias due to reverse causation?
Stephen Burgess, Sonja A Swanson & Jeremy A Labrecque
21 February 2021
Mendelian randomization uses genetic variants as instrumental variables to make causal inferences about the effect of a risk factor on an outcome. If a genetic variant satisfies the instrumental variable assumptions for the given risk factor and outcome, then an association between the genetic variant and the outcome implies the risk factor affects the outcome in some individuals at some point in the life-course.
Combining the instrumental variable assumptions with further assumptions and precise specification of the outcome (including specifying a time period for the outcome) allows valid testing of a more specific causal hypothesis and/or valid estimation of global or local, and point or period average causal effects.
In this short manuscript, the researchers discuss three ways in which Mendelian randomization analyses may be susceptible to bias due to reverse causation. They conclude that while the analyses offer some protection against biases, they are not totally immune from the phenomenon; and that researchers should consider carefully whether their findings could be explained by genetic variants having a primary association with the outcome, and how previous versions of an outcome can impact the stated risk factor.
Publication: Journal of Neuroscience
Rong Ye, Frank H. Hezemans, Claire O’Callaghan, Kamen A. Tsvetanov, Catarina Rua, P. Simon Jones, Negin Holland, Maura Malpetti, Alexander G. Murley, Roger A. Barker, Caroline H. Williams-Gray, Trevor W. Robbins, Luca Passamonti and James B. Rowe
5 September 2023
Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system.
Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson’s syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetisation-transfer-weighted imaging of the LC. Parameters of ‘race models’ of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer non-decision times, and more lapses of attention.
The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioural modelling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioural changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimisation of noradrenergic treatment is likely to benefit from stratification according to LC integrity.View publication
Publication: Journal of Internal Medicine
Youngwon Kim, Haeyoon Jang, Mengyao Wang, Qiaoxin Shi, Tessa Strain, Stephen J Sharp, Shiu Lun Au Yeung, Shan Luo, Simon Griffin, Nicholas J. Wareham, Katrien Wijndaele, Soren Brage
23 August 2023
Excess sedentary time (ST) is recognized as an important modifiable risk factor for coronary heart disease (CHD). However, whether the associations of genetic susceptibility with CHD incidence can be modified by replacing wearable-device-measured ST with physical activity (PA) is unknown.View publication
Publication: Molecular Psychiatry
Dr Leonidas Chouliaras, Professor John T. O’Brien
22 August 2023
Early and accurate diagnosis of dementia subtype is critical to improving clinical care and developing better treatments. Structural and molecular imaging has contributed to a better understanding of the pathophysiology of neurodegenerative dementias and is increasingly being adopted into clinical practice for early and accurate diagnosis.
In this review we summarise the contribution imaging has made with particular focus on multimodal magnetic resonance imaging (MRI) and positron emission tomography imaging (PET). Structural MRI is widely used in clinical practice and can help exclude reversible causes of memory problems but has relatively low sensitivity for the early and differential diagnosis of dementia subtypes.
F-fluorodeoxyglucose PET has high sensitivity and specificity for AD and FTD, while PET with ligands for amyloid and tau can improve the differential diagnosis of AD and non-AD dementias, including recognition at prodromal stages. Dopaminergic imaging can assist with the diagnosis of LBD. The lack of a validated tracer for α-synuclein or TAR DNA-binding protein 43 (TDP-43) imaging remain notable gaps, though work is ongoing.
Emerging PET tracers such as C-UCB-J for synaptic imaging may be sensitive early markers but overall larger longitudinal multi-centre cross diagnostic imaging studies are needed.View publication
Publication: Cell Reports Medicine
Ruth Hanssen, Chiara Auwerx, Maarja Jõeloo, Sadaf Farooqi, Alexandre Reymond, Katherine Lawler
15 August 2023
New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2–3 [BP2–3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10−10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10−6). We conclude that people with 16p11.2 BP2–3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.View publication
Publication: Nature Immunology
Jing Hua Zhao, David Stacey, Niclas Eriksson, Erin Macdonald-Dunlop, Asa K Hedman et al
18 July 2023
Aberrant inflammatory responses play a role in pathogenesis of many diseases, including autoimmune conditions, cardiovascular diseases and cancers. In this study of genetic influences on inflammation-related proteins, an international team conducted a genome-wide association study of 91 plasma proteins in ~15,000 participants within the SCALLOP Consortium.
Having identified 180 gene-protein associations, they integrated with gene expression and disease genetics to provide insights into disease aetiology, implicating FGF5 in hypertension and cardiovascular disease, and lymphotoxin-α in multiple sclerosis.
The team identified both shared and distinct effects of specific proteins across immune mediated diseases, including directionally discordant functions for CD40 in rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease, and a role for CXCL5 in the aetiology of ulcerative colitis UC but not Crohns disease.
These results provide a powerful resource to understand the role of chronic inflammation in a wide range of diseases and facilitate future drug target prioritisation.View publication
Publication: Innovation in Aging
Chen S, Zhang H, Underwood BR, Wang D, Chen X, Cardinal RN
22 May 2023
We looked at survey data from 2000-2018 about people aged over 65, with cognitive impairment, and living alone in the United States. We examined their need for support with activities of daily living, and the extent to which such support was provided. We examined trends over time, including trends by gender and by ethnicity.View publication
Publication: International Journal Geriatric Psychiatry
Anne D. Kershenbaum, Annabel C. Price, Rudolf N. Cardinal, Shanquan Chen, James M. Fitzgerald, Jonathan Lewis, Sinéad Moylett, John T. O’Brien
19 May 2023
Survival is shorter in Lewy body dementia (LBD, referring to both Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB)) compared with Alzheimer’s disease (AD), but the reasons for this difference are not well established.
Researchers identified cohorts of patients with dementia (male and female AD, PDD, and DLB dementia groups) referred into mental health services and linked to National Health Service (NHS) Hospital Episode Statistics and the Office for National Statistics to identify death dates and proximal cause of death. Among patients with DLB and PDD compared to AD ,those with PDD, especially males with PDD, had the highest hazard ratio for death. Aspiration pneumonia and nervous system causes of death accounted for a significant proportion of the excess deaths in the male PDD group compared to the male AD group. Compared with AD, hazard ratios for nervous system causes of death were significantly elevated in all LBD groups. A range of cause‐of‐death categories were significantly more frequent across the LBD groups, with aspiration pneumonia ,genitourinary causes and other respiratory causes elevated in more than one groupView publication
Publication: Nature Medicine
Agatha A. van der Klaauw, Emily C. Horner, Pehuén Pereyra-Gerber, Utkarsh Agrawal, William S. Foster, Sarah Spencer, Bensi Vergese, Miriam Smith, Elana Henning, Isobel D. Ramsay, Jack A. Smith, Stephane M. Guillaume, Hayley J. Sharpe, Iain M. Hay, Sam Thompson, Silvia Innocentin, Lucy H. Booth, Chris Robertson, Colin McCowan, Steven Kerr, Thomas E. Mulroney, Martin J. O’Reilly, Thevinya P. Gurugama, Lihinya P. Gurugama, Maria A. Rust, Alex Ferreira, Soraya Ebrahimi, Lourdes Ceron-Gutierrez, Jacopo Scotucci, Barbara Kronsteiner, Susanna J. Dunachie, Paul Klenerman, PITCH Consortium, Adrian J. Park, Francesco Rubino, Abigail A. Lamikanra, Hannah Stark, Nathalie Kingston, Lise Estcourt, Heli Harvala, David J. Roberts, Rainer Doffinger, Michelle A. Linterman, Nicholas J. Matheson, Aziz Sheikh, I. Sadaf Farooqi & James E. D. Thaventhiran
11 May 2023
Clinical trials have shown that COVID-19 vaccines are highly effective at reducing symptoms, hospitalisation and deaths caused by the virus, including for people with obesity. Previous studies have suggested that antibody levels may be lower in vaccinated people who have obesity and that they may remain at higher risk of severe disease than vaccinated people with normal weight. The reasons for this have, however, remained unclear. Read the news story.View publication
Publication: New England Journal of Medicine
Peter J. Hutchinson, Hadie Adams, Midhun Mohan, Bhagavatula I. Devi, Christopher Uff, Shumaila Hasan, Harry Mee, Mark H. Wilson, Deepak K. Gupta, M.Ch, Diederik Bulters, Ardalan Zolnourian, Catherine J. McMahon, Matthew G. Stovell, Yahia Z. Al-Tamimi, Manoj K. Tewari, Manjul Tripathi, Simon Thomson, Edoardo Viaroli, Antonio Belli, Andrew T. King, Adel E. Helmy, Ivan S. Timofeev, Sarah Pyne,Dhaval P. Shukla, Dhananjaya I. Bhat, Andrew R. Maas, Franco Servadei, Geoffrey T. Manley,Garry Barton, Carole Turner, David K. Menon, Barbara Gregson, and Angelos G. Kolias,
23 April 2023
A new trial has found – where possible – surgeons should replace the removed section of the skull following surgery to treat a form of brain bleed. Researchers say the approach will save patients undergoing skull reconstruction further down the line. Read the full story.View publication
Publication: BMC Medical Informatics and Decision Making
Cardinal RN, Moore A, Burchell M, Lewis JR
5 May 2023
Researchers developed a new way to link information between two organisations (e.g. an NHS organisation and a government education department) for research, without direct identifiers (such as names or dates of birth) being used during the linkage process itself.View publication
Publication: Journal of Alzheimer’s Disease
Chen S, Cardinal RN, Gräf S, O’Brien JT, Underwood BR
28 January 2023
We examined longer-term mortality in patients with dementia and SARS-CoV-2 infection. We found an increased mortality in patients with dementia beyond the acute phase of illness. We identified several investigation results associated with increased mortality, and increased mortality in patients prescribed antipsychotics or benzodiazepines.View publication
Publication: Frontiers in Psychiatry
Hannah LA, Walsh CM, Perez J, Jopling L, Cardinal RN, Cameron R
16 February 2023
Economic evidence for interventions in treatment-resistant depression is underdeveloped, particularly so for service-level interventions. Where evidence does exist, it is hampered by inconsistency in study design, methodological quality, and availability of high quality long-term outcomes evidence. This review identifies a number of key considerations and challenges for the design of future economic evaluations. Recommendations for research and suggestions for good practice are made.View publication
Maura Malpetti, Thomas E. Cope, Duncan Street, P. Simon Jones, Frank H. Hezemans, Elijah Mak, Kamen A. Tsvetanov, Timothy Rittman, W. Richard Bevan-Jones, Karalyn Patterson, Luca Passamonti, Tim D. Fryer, Young T. Hong, Franklin I. Aigbirhio, John T. O’Brien and James B. Rowe
08 March 2023
Brain scans like PET enable the visualisation and quantification of brain inflammation, which is an important and common pathological feature in dementia. Using PET we found that high levels of inflammation in frontal brain regions in people with frontotemporal dementia is associated with faster decline in their thinking performance over time. Our results highlight the potential for immunomodulatory treatment strategies in frontotemporal dementia.View publication
Maria Herrero-Zazo, Tomas Fitzgerald, Vince Taylor, Helen Street, Afzal N. Chaudhry, John R. Bradley, Ewan Birney, Victoria L. Keevil
20 January 2023
- Time-series blood test & vital sign data from older inpatients were presented to HMM (Hidden Markov Models)
- Hidden clinically interpretable states were extracted, linked with diagnoses and death
- States modeled inpatient trajectories, differentiating risk from admission-discharge
- The clinical interpretation of HMM states helped explain how ML models organise data
Publication: Nature Nanotechnology
Filip Bošković, Jinbo Zhu, Ran Tivony, Alexander Ohmann, Kaikai Chen, Mohammed F. Alawami, Milan Đorđević, Niklas Ermann, Joana Pereira Dias, Michael Fairhead, Mark Howarth, Stephen Baker, Ulrich F. Keyser
16 January 2023
Respiratory infections are the major cause of death from infectious disease worldwide. Multiplexed diagnostic approaches are essential as many respiratory viruses have indistinguishable symptoms.
We created self-assembled DNA nanobait that can simultaneously identify multiple short RNA targets. The nanobait approach relies on specific target selection via toehold-mediated strand displacement and rapid read-out via nanopore sensing. Here, we show this platform can concurrently identify several common respiratory viruses, detecting a panel of short targets of viral nucleic acids from multiple viruses.
Our nanobait can be easily reprogrammed to discriminate viral variants, as we demonstrated for several key SARS-CoV-2 variants with single-nucleotide resolution. Lastly, we show that nanobait discriminates
between samples extracted from oropharyngeal swabs from negative and positive SARS-CoV-2 patients
Our system allows for multiplexed identification of native RNA molecules, providing a new scalable approach for diagnostics of multiple respiratory viruses in a single assay.View publication
Publication: Nature Medicine
Aideen B. Daly, Charlotte K. Boughton, Munachiso Nwokolo, Sara Hartnell, Malgorzata E. Wilinska, Alina Cezar, Mark L. Evans & Roman Hovorka
12 January 2023
Cambridge scientists have successfully trialled an artificial pancreas for use by patients living with type 2 diabetes. The device – powered by an algorithm developed at the University of Cambridge – doubled the amount of time patients were in the target range for glucose and halved the time spent experiencing high glucose levels. Read the full news story.View publication
Publication: British Journal of Psychiatry
Noham Wolpe, Shanquan Chen, Brian Kirkpatrick, Peter B. Jones, Christopher Jenkins, Rudolf N. Cardinal and Emilio Fernandez-Egea
10 January 2023
In a cohort of 187 people with schizophrenia treated with clozapine, we examined the relationship between clozapine, sedation, and aspects of symptoms: motivation/pleasure, and emotional expressivity. Clozapine was associated with increased sedation (a known side effect), and this sedation worsened motivation/pleasure; however, there was also a separate effect through which clozapine was directly associated with improved motivation/pleasure. These results highlight the important of addressing sedative side-effects of antipsychotic medications to improve quality of life.
Publication: PLoS Medicine
Shanquan Chen, Annabel C Price, Rudolf N Cardinal, Sinéad Moylett, Anne D Kershenbaum, James Fitzgerald, Christoph Mueller, Robert Stewart, John T O’Brien
6 December 2022
In an observational study of people who had dementia with Lewy bodies, use of cholinesterase inhibitors (a symptomatic treatment) was associated with shorter duration of hospital admissions and decreased risk of mortality.View publication
Dimitra Zannidi, Pinal S. Patel, Eleni Leventea, Jessica Paciepnik, Frances Dobson, Caroline Heyes, Robert J. B. Goudie, Linda M. Oude Griep, Jacobus Preller, and Lynsey N. Spillman,
8 October 2022
Previous research has shown that people hospitalised with COVID-19 are at risk of weight loss and malnutrition. This study looked at patients who experienced weight loss of 10% or more during their hospital admission to Cambridge University Hospitals NHS with COVID-19 during the first wave of the pandemic. Weight loss of 10% or more is considered a large amount to lose as it increases the chance of someone becoming more poorly and not surviving. Therefore, preventing weight loss may help patients to survive and recover. The study looked at risk factors for weight loss to help better recognise the patients that need more support to prevent weight loss.View publication
Publication: European Heart Journal
Paddy C Dempsey, Alex V Rowlands, Tessa Strain, Francesco Zaccardi, Nathan Dawkins, Cameron Razieh, Melanie J Davies, Kamlesh K Khunti, Charlotte L Edwardson, Katrien Wijndaele, Soren Brage, Tom Yates
27 October 2022
Increasing physical activity of any intensity is beneficial for health, but new research published in the European Heart Journal shows that there is a greater reduction in cardiovascular disease risk when more of that activity is of at least moderate intensity.View publication