LOS PEORES ATAQUES SUFRIDOS EN EL SIGLO XX

Three different study designs were included in the review: RCTs, prospective longitudinal cohort studies and case-control studies. These methods were

included as each can provide unique and mutually exclusive information regarding the question of whether long-term physical activity is safe for older adults with knee pain. Together their evidence can be triangulated to counter individual method limitations. There are, however, some challenges associated with

including all three study designs, including maintaining consistent inclusion criteria across different study designs, synthesising varying safety outcomes (for example, mean treatment effects seen in RCTs and odds ratios seen in prospective cohorts) and consistently assessing study risk of bias across different designs.

Randomised controlled trials (RCTs)

RCTs can give safety outcome information, including adverse events, from specific physical activity interventions in controlled experimental conditions. RCTs are thought of as the “gold standard” design for testing the comparable effectiveness of interventions as they are considered to have the least risk of bias (Sackett et al, 2000; Akobeng, 2005; Zhang et al, 2010; Jewell, 2011). For example,

randomisation of participants aims to equalise both known and unknown confounding variables between groups which helps eliminate selection bias (Sackett et al, 2000; Kunz et al, 2007; Jewell, 2011). A confounder is a third

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variable (not the outcome or exposure variable of interest) that distorts the relationship between the exposure and the outcome (Fletcher et al, 2012) (see chapter 7, section 7.3.5 for a causal diagram explanation of confounding). In the case of RCTs the exposure of interest is the physical activity intervention and the outcome a safety domain related measure. Selection bias can occur if there are systematic differences between baseline characteristics of the groups that are being compared which are associated with outcome (Higgins & Green, 2009).

Non-randomised trials were hence excluded as they are at increased risk of such bias.

However, there are limitations associated with RCTs. RCT participants with knee pain who meet the inclusion criteria and provide consent to participate in a RCT testing physical activity interventions may be systematically different from the general population of older adults with knee pain. This may therefore limit the generalisability of findings from RCTs. In addition, few RCTs are conducted over a period of several years due to cost implications and the challenge of loss to follow-up at the longer-term time-points. This has implications for long-term safety outcomes such as progression of structural OA detected using imaging such as radiographs, which have a greater responsiveness in periods over two years (Reichmann et al, 2011). Finally, it could be considered unethical to carry out a long-term trial that was showing physical activity to be unsafe (Fletcher et al, 2012). Hence, for the purposes of the current systematic review of long-term physical activity safety other study designs were also included to help overcome the limitations of the RCT design.

53 Prospective longitudinal cohort studies

Prospective longitudinal cohort studies were included in the review as they give longitudinal safety information from observed samples, thus overcoming the potential limited generalisability of RCTs and are well suited to questions of

prognosis (Mallen et al, 2006). They involve a baseline sample of older adults with knee pain, exposed to varying physical activity types and intensities, being

observed over a long period of time for safety related outcomes whilst also

adjusting for other known confounders. They hence allow the calculation of odds ratios of safety outcomes based on physical activity exposures. They permit large numbers of individuals to be observed, often over a period of years, in a pragmatic manner (Fletcher et al, 2012). Hence, they may have a better chance than RCTs of recording rare or long-term safety outcomes such as TKR (Higgins & Green, 2009). However, the disadvantage of these observational studies is the

extraneous differences between groups exposed and not exposed to physical activity (Fletcher et al, 2012), since it is only possible to adjust for known or

hypothesised confounding factors on safety outcomes. Confounding is particularly problematic in older adults with knee pain attributable to OA, since there are

uncertainties and methodological challenges regarding prognostic factors for OA radiographic and clinical symptom progression (Zhang et al, 2010; Chapple et al, 2011; Neogi & Zhang, 2013; Bastick et al, 2015a, 2015b) and there may be unknown unadjusted extraneous prognostic variables that bias results (Zhang et al, 2010; Szklo & Nieto, 2014).

Retrospective cohort studies involve analysing observational data or medical records after both exposure and outcome have already occurred to calculate post-hoc risk ratios (Hennekens & Buring, 1987; Szklo & Nieto, 2014). This type of

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study design was not included in this review as it is less likely to gather sufficient baseline information, relevant confounders or detailed physical activity exposure (Fletcher et al, 2012; Szklo & Nieto, 2014). It is hence at increased risk of unknown and unadjusted confounding. In addition, retrospective cohort studies are usually taken from “survival” populations with available data to look back at, rather than the “true” cohort of all older adults with knee pain which may limit their generalisability (Fletcher et al, 2012). For example, individuals who are deceased or who did not access healthcare are all likely to be underrepresented in such analyses. Cross-sectional studies involve data collection at a single point of time (Sim & Wright, 2000) and were also excluded from this review as they are unable to give a temporal relationship between physical activity exposure and safety outcomes. Cross-sectional studies are hence at risk of temporal bias, where inference about cause and effect may be erroneous, as it is not possible to tell whether the exposure (physical activity level) or safety outcome came first and in which order they influence each other (Szklo & Nieto, 2014).

Case-control studies

Case-control studies were included in the review. These studies usually select participants on the basis of whether or not they have a particular disease event under study (Fletcher et al, 2012). For example, subjects are either “cases”

having undergone a TKR (due to knee pain or OA progression) or “controls” who are otherwise similar people who have not undergone TKR. Cases and controls can then be compared to estimate the odds of individuals becoming cases based on certain risk factor exposures (e.g. type or dose of physical activity undertaken).

The advantages of case-control studies are that they allow the study of specific outcomes without the need for a very large cohort or a long follow-up period

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(Hennekens & Buring, 1987). Confounding can be reduced by matching the cases and controls for other key prognostic variables (e.g. age and gender), stratification or post-hoc statistical adjustment controlling for the effect of the confounders within multivariable mathematical models (Szklo & Nieto, 2014). The

disadvantages of these studies are that they are relatively hard to set up in terms of finding appropriate matched controls and they are prone to recall bias issues (Fletcher et al, 2012). Recall bias is a systematic error that is caused by

differences in the accuracy or completeness of the recollections by study

participants regarding events or experiences from the past (Last, 2000; Fletcher et al, 2012). For example, some participants may have difficulty remembering the exact levels and types of physical activity carried out in the past or may tend to report higher levels of physical activity for social desirability (Motl et al, 2005).