Biomarkers for Disease Progression in Parkinson's Disease
Biomarkers for Disease Progression in Parkinson's Disease
Following the development of a review protocol equivalent to the methodology described below, literature searches were conducted in the databases MEDLINE (1950 to August 2010) and Embase (1980 to August 2010), using the OVID search interface. Five separate search strategies, developed by an experienced information scientist, were run in each database. The first four were based on free-text words identified through background reading of relevant review articles. These searches included potential blood, urine or cerebrospinal fluid (CSF), imaging and neurophysiological biomarkers. A fifth search using generic terms for biomarkers based on index headings was also run in both databases. For details of the search strategy please see Additional file 1.
The searches were limited to human studies. Only English language articles were included, due to lack of resources for translation. Reference lists of included articles and relevant review articles were checked to identify any studies which the electronic search may have missed.
The electronic search strategy was validated by hand searching five years of the two journals from which most of the included articles came: Movement Disorders (2002–2006) and Journal of the Neurological Sciences (1992–1996). The number of relevant and irrelevant articles identified by hand searching and by the electronic search, was used to calculate the sensitivity and specificity for the electronic search strategy.
A single reviewer examined abstracts retrieved by the electronic search to identify articles meriting review in full. Full length articles were then reviewed before data were extracted from relevant papers. In both stages the inclusion and exclusion criteria detailed below were applied.
Only studies of participants with idiopathic Parkinson's disease diagnosed by formal criteria, or clearly described clinical means (the presence of at least two out of four of the cardinal clinical signs of PD and an attempt to exclude atypical syndromes), were included. No restriction was made on the grounds of participant's age, disease duration, or drug treatment.
Studies which investigated the efficacy of using a biomarker, including (but not restricted to) imaging, blood tests, tests of CSF and neurophysiological tests, to investigate disease progression in Parkinson's disease were included. To qualify for inclusion there must have been an attempt to examine for an association between the biomarker and a clinical measure of disease progression. Acceptable measures included measures of motor or cognitive impairment, disability, handicap, quality of life, and duration of survival.
Only studies exploring associations between a biomarker and the total score from a clinical rating scale, rather than its subsections, were included. The subsections of most clinical measures would never be acceptable outcome measures for neuroprotective trials and, therefore, developing surrogate biomarkers for these was felt not to be relevant. The exception was the Unified Parkinson's disease rating scale (UPDRS), where studies examining for relationships to its main constituent parts were included. Studies only investigated the relationship between a biomarker and individual symptoms (e.g. bradykinesia or rigidity), or olfactory function were excluded for similar reasons.
Only studies examining for associations between putative biomarkers and global measures of cognition (e.g. Mini-mental state examination (MMSE), Cambridge cognitive examination (CAMCOG)), rather than individual neuropsychological tests, were included. It is unlikely that improvement in a single neuropsychological test would be a suitable outcome measure for a neuroprotective trial. As depression in PD is not linked to overall disease progression and may be commoner at the time of diagnosis, studies only investigating the relationship between a biomarker and depression were excluded.
Studies examining the relationship between a biomarker and treatment status, the presence or severity of complications related to therapy, or duration of illness were excluded. Studies of static predictive biomarkers (e.g. genetic markers) which try to anticipate the future rate of disease progression were excluded. A useful biomarker for clinical trials needs to be dynamic - changing with disease progression. Therefore, these studies were not relevant.
As we aimed to produce a comprehensive review and detect any evidence of the utility of a putative biomarker, we set no study quality threshold. We, therefore, included small cross-sectional studies, in which an association between a biomarker and clinical measures of disease progression were analysed at a single time point across groups of patients with different disease severities.
Study methods and results were extracted by a single reviewer, and for accuracy this was performed twice. Data were extracted using a data extraction sheet (Additional file 2) relating to the following: (1) study design including restrictiveness of criteria for entry into the study; (2) setting; (3) study population, including number of participants, gender ratio, disease duration at baseline, baseline measures of disease severity and baseline treatment status; (4) specific biomarkers investigated; (5) statistical analyses performed; (6) results of statistical analyses of the associations between the biomarkers and clinical measures of disease severity and how completely these results were reported; (7) analysis of the effect of drug treatment on the biomarker; (8) economic analysis of using the biomarker; (9) measures of suitability and acceptability of the test to patients.
The restrictiveness of the inclusion and exclusion criteria applied in each study was graded as: none, explicit statement that only criteria to exclude atypical parkinsonian syndromes were applied; mild, ≤ 3 criteria applied (except those described under moderate); moderate, 4–5 criteria applied or evidence of an attempt to limit by age, gender, cognitive state, disease stage, drug therapy for PD (e.g. all de-novo); severe, ≥ 6 criteria applied; not detailed, no mention of whether criteria were applied.
No validated tool to measure the quality of studies investigating surrogate biomarkers as outcome measures exists. An attempt was, therefore, made to assess study quality using an adapted quality questionnaire, illustrated in Table 1, based on the assay methods and study design sections of the Reporting recommendations for tumor MARKer prognostic studies (REMARK) reporting recommendations for prognostic tumour markers. This measure of study quality was also used to assess whether there was any bias in terms of the quality of studies included.
Given the likelihood that included studies would examine the relationship of multiple different putative biomarkers with multiple different clinical measures of disease severity, we were aware that any data synthesis would be qualitative in nature.
Methods
Following the development of a review protocol equivalent to the methodology described below, literature searches were conducted in the databases MEDLINE (1950 to August 2010) and Embase (1980 to August 2010), using the OVID search interface. Five separate search strategies, developed by an experienced information scientist, were run in each database. The first four were based on free-text words identified through background reading of relevant review articles. These searches included potential blood, urine or cerebrospinal fluid (CSF), imaging and neurophysiological biomarkers. A fifth search using generic terms for biomarkers based on index headings was also run in both databases. For details of the search strategy please see Additional file 1.
The searches were limited to human studies. Only English language articles were included, due to lack of resources for translation. Reference lists of included articles and relevant review articles were checked to identify any studies which the electronic search may have missed.
Validation of the Electronic Search Strategy
The electronic search strategy was validated by hand searching five years of the two journals from which most of the included articles came: Movement Disorders (2002–2006) and Journal of the Neurological Sciences (1992–1996). The number of relevant and irrelevant articles identified by hand searching and by the electronic search, was used to calculate the sensitivity and specificity for the electronic search strategy.
Study Selection
A single reviewer examined abstracts retrieved by the electronic search to identify articles meriting review in full. Full length articles were then reviewed before data were extracted from relevant papers. In both stages the inclusion and exclusion criteria detailed below were applied.
Only studies of participants with idiopathic Parkinson's disease diagnosed by formal criteria, or clearly described clinical means (the presence of at least two out of four of the cardinal clinical signs of PD and an attempt to exclude atypical syndromes), were included. No restriction was made on the grounds of participant's age, disease duration, or drug treatment.
Studies which investigated the efficacy of using a biomarker, including (but not restricted to) imaging, blood tests, tests of CSF and neurophysiological tests, to investigate disease progression in Parkinson's disease were included. To qualify for inclusion there must have been an attempt to examine for an association between the biomarker and a clinical measure of disease progression. Acceptable measures included measures of motor or cognitive impairment, disability, handicap, quality of life, and duration of survival.
Only studies exploring associations between a biomarker and the total score from a clinical rating scale, rather than its subsections, were included. The subsections of most clinical measures would never be acceptable outcome measures for neuroprotective trials and, therefore, developing surrogate biomarkers for these was felt not to be relevant. The exception was the Unified Parkinson's disease rating scale (UPDRS), where studies examining for relationships to its main constituent parts were included. Studies only investigated the relationship between a biomarker and individual symptoms (e.g. bradykinesia or rigidity), or olfactory function were excluded for similar reasons.
Only studies examining for associations between putative biomarkers and global measures of cognition (e.g. Mini-mental state examination (MMSE), Cambridge cognitive examination (CAMCOG)), rather than individual neuropsychological tests, were included. It is unlikely that improvement in a single neuropsychological test would be a suitable outcome measure for a neuroprotective trial. As depression in PD is not linked to overall disease progression and may be commoner at the time of diagnosis, studies only investigating the relationship between a biomarker and depression were excluded.
Studies examining the relationship between a biomarker and treatment status, the presence or severity of complications related to therapy, or duration of illness were excluded. Studies of static predictive biomarkers (e.g. genetic markers) which try to anticipate the future rate of disease progression were excluded. A useful biomarker for clinical trials needs to be dynamic - changing with disease progression. Therefore, these studies were not relevant.
As we aimed to produce a comprehensive review and detect any evidence of the utility of a putative biomarker, we set no study quality threshold. We, therefore, included small cross-sectional studies, in which an association between a biomarker and clinical measures of disease progression were analysed at a single time point across groups of patients with different disease severities.
Data Extraction
Study methods and results were extracted by a single reviewer, and for accuracy this was performed twice. Data were extracted using a data extraction sheet (Additional file 2) relating to the following: (1) study design including restrictiveness of criteria for entry into the study; (2) setting; (3) study population, including number of participants, gender ratio, disease duration at baseline, baseline measures of disease severity and baseline treatment status; (4) specific biomarkers investigated; (5) statistical analyses performed; (6) results of statistical analyses of the associations between the biomarkers and clinical measures of disease severity and how completely these results were reported; (7) analysis of the effect of drug treatment on the biomarker; (8) economic analysis of using the biomarker; (9) measures of suitability and acceptability of the test to patients.
The restrictiveness of the inclusion and exclusion criteria applied in each study was graded as: none, explicit statement that only criteria to exclude atypical parkinsonian syndromes were applied; mild, ≤ 3 criteria applied (except those described under moderate); moderate, 4–5 criteria applied or evidence of an attempt to limit by age, gender, cognitive state, disease stage, drug therapy for PD (e.g. all de-novo); severe, ≥ 6 criteria applied; not detailed, no mention of whether criteria were applied.
Methodological Quality
No validated tool to measure the quality of studies investigating surrogate biomarkers as outcome measures exists. An attempt was, therefore, made to assess study quality using an adapted quality questionnaire, illustrated in Table 1, based on the assay methods and study design sections of the Reporting recommendations for tumor MARKer prognostic studies (REMARK) reporting recommendations for prognostic tumour markers. This measure of study quality was also used to assess whether there was any bias in terms of the quality of studies included.
Data Synthesis
Given the likelihood that included studies would examine the relationship of multiple different putative biomarkers with multiple different clinical measures of disease severity, we were aware that any data synthesis would be qualitative in nature.
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