Guidance on review type selection for health technology assessments: key factors and considerations for deciding when to conduct a de novo systematic review, an update of a systematic review, or an overview of systematic reviews.

BACKGROUND: A systematic review (SR) helps us make sense of a body of research while minimizing bias and is routinely conducted to evaluate intervention effects in a health technology assessment (HTA). In addition to the traditional de novo SR, which combines the results of multiple primary studies, there are alternative review types that use systematic methods and leverage existing SRs, namely updates of SRs and overviews of SRs. This paper shares guidance that can be used to select the most appropriate review type to conduct when evaluating intervention effects in an HTA, with a goal to leverage existing SRs and reduce research waste where possible. PROCESS: We identified key factors and considerations that can inform the process of deciding to conduct one review type over the others to answer a research question and organized them into guidance comprising a summary and a corresponding flowchart. This work consisted of three steps. First, a guidance document was drafted by methodologists from two Canadian HTA agencies based on their experience. Next, the draft guidance was supplemented with a literature review. Lastly, broader feedback from HTA researchers across Canada was sought and incorporated into the final guidance. INSIGHTS: Nine key factors and six considerations were identified to help reviewers select the most appropriate review type to conduct. These fell into one of two categories: the evidentiary needs of the planned review (i.e., to understand the scope, objective, and analytic approach required for the review) and the state of the existing literature (i.e., to know the available literature in terms of its relevance, quality, comprehensiveness, currency, and findings). The accompanying flowchart, which can be used as a decision tool, demonstrates the interdependency between many of the key factors and considerations and aims to balance the potential benefits and challenges of leveraging existing SRs instead of primary study reports. CONCLUSIONS: Selecting the most appropriate review type to conduct when evaluating intervention effects in an HTA requires a myriad of factors to be considered. We hope this guidance adds clarity to the many competing considerations when deciding which review type to conduct and facilitates that decision-making process.

Cost-effectiveness analysis of a reduction in diagnostic imaging in degenerative spinal disorders.

BACKGROUND: Advanced imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) are highly sensitive, but often non-specific, diagnostic tools. Despite this, CT and MRI are overutilized in degenerative spinal disorder diagnosis. From the perspective of the Ministry of Health, we evaluated against usual care the cost-effectiveness of a hypothetical triage program for non-emergent spinal disorders that reduces unnecessary imaging uses. METHODS: Diagnostic and surgical data were prospectively collected on 2,046 outpatients who received consultation with the senior surgical author at Toronto Western Hospital, University Health Network, between September 2005 and April 2008. Using these data, we modelled an evidence-based diagnostic triage program wherein spine-focused clinical assessments and plain X-ray imaging would be applied prior to CT and MRI. Incremental costs were the incurred expenses from additional consultations and plain X-rays less the cost savings from the eliminated CT and MRI scans, expressed in 2009 Canadian dollars. Outcomes were expressed as the number of surgical candidates identified per MRI used in diagnosis, reflecting the efficiency of diagnostic imaging. RESULTS: The triage program incurred $109,720 from additional consultations and plain X-rays and saved $2,117,697 from eliminated CT and MRI scans, resulting in net cost savings of $2,007,977 for the 31 months of the study period, or $777,282 per year. In usual care, 0.328~0.418 surgical candidates were identified per MRI whereas in the triage program, 0.736~0.885 surgical candidates were identified per MRI, resulting in over a twofold improvement in MRI efficiency. The triage program was therefore dominating. Applying to high-volume spine surgeons in Ontario, we estimated that the implementation of the triage program would save the province $24,234,929 per year. INTERPRETATION: Based on the assumptions made in our modelling, eliminating unnecessary imaging in spinal disorder diagnosis can save healthcare significant resources.

The long and the short of SAD-1 kinase.

The Ser/Thr SAD kinases are evolutionarily conserved, critical regulators of neural development. Exciting findings in recent years have significantly advanced our understanding of the mechanism through which SAD kinases regulate neural development. Mammalian SAD-A and SAD-B, activated by a master kinase LKB1, regulate microtubule dynamics and polarize neurons. In C. elegans, the sad-1 gene encodes two isoforms, namely the long and the short, which exhibit overlapping and yet distinct functions in neuronal polarity and synaptic organization. Surprisingly, our most recent findings in C. elegans revealed a SAD-1-independent LKB1 activity in neuronal polarity. We also found that the long SAD-1 isoform directly interacts with a STRADalpha pseudokinase, STRD-1, to regulate neuronal polarity and synaptic organization. We elaborate here a working model of SAD-1 in which the two isoforms dimer/oligomerize to form a functional complex, and STRD-1 clusters and localizes the SAD-1 complex to synapses. While the mechanistic difference between the vertebrate and invertebrate SAD kinases may be puzzling, a recent discovery of the functionally distinct SAD-B isoforms predicts that the difference likely arises from our incomplete understanding of the SAD kinase mechanism and may eventually be reconciled as the revelation continues.

C. elegans STRADalpha and SAD cooperatively regulate neuronal polarity and synaptic organization.

Neurons are polarized cells with morphologically and functionally distinct axons and dendrites. The SAD kinases are crucial for establishing the axon-dendrite identity across species. Previous studies suggest that a tumour suppressor kinase, LKB1, in the presence of a pseudokinase, STRADalpha, initiates axonal differentiation and growth through activating the SAD kinases in vertebrate neurons. STRADalpha was implicated in the localization, stabilization and activation of LKB1 in various cell culture studies. Its in vivo functions, however, have not been examined. In our present study, we analyzed the neuronal phenotypes of the first loss-of-function mutants for STRADalpha and examined their genetic interactions with LKB1 and SAD in C. elegans. Unexpectedly, only the C. elegans STRADalpha, STRD-1, functions exclusively through the SAD kinase, SAD-1, to regulate neuronal polarity and synaptic organization. Moreover, STRD-1 tightly associates with SAD-1 to coordinate its synaptic localizations. By contrast, the C. elegans LKB1, PAR-4, also functions in an additional genetic pathway independently of SAD-1 and STRD-1 to regulate neuronal polarity. We propose that STRD-1 establishes neuronal polarity and organizes synaptic proteins in a complex with the SAD-1 kinase. Our findings suggest that instead of a single, linear genetic pathway, STRADalpha and LKB1 regulate neuronal development through multiple effectors that are shared in some cellular contexts but distinct in others.

A chemical-genetic strategy reveals distinct temporal requirements for SAD-1 kinase in neuronal polarization and synapse formation.

BACKGROUND: Neurons assemble into a functional network through a sequence of developmental processes including neuronal polarization and synapse formation. In Caenorhabditis elegans, the serine/threonine SAD-1 kinase is essential for proper neuronal polarity and synaptic organization. To determine if SAD-1 activity regulates the establishment or maintenance of these neuronal structures, we examined its temporal requirements using a chemical-genetic method that allows for selective and reversible inactivation of its kinase activity in vivo. RESULTS: We generated a PP1 analog-sensitive variant of SAD-1. Through temporal inhibition of SAD-1 kinase activity we show that its activity is required for the establishment of both neuronal polarity and synaptic organization. However, while SAD-1 activity is needed strictly when neurons are polarizing, the temporal requirement for SAD-1 is less stringent in synaptic organization, which can also be re-established during maintenance. CONCLUSION: This study reports the first temporal analysis of a neural kinase activity using the chemical-genetic system. It reveals that neuronal polarity and synaptic organization have distinct temporal requirements for SAD-1.

Protons as intercellular messengers.

Muscle contractions are driven by neurotransmitters released at neuromuscular junctions. In this issue, Beg et al. (2008) report that protons, in the absence of neurotransmitters and neurons, can stimulate muscle contractions involved in the defecation cycle of the worm Caenorhabditis elegans. Their results identify protons as a new intercellular messenger and suggest that proton-mediated intercellular communication may be a widespread phenomenon.