Kristina Lindsley

Cruciferous vegetable consumption and lung cancer risk: a systematic review.

Background: Cruciferous vegetables, rich in isothiocyanates, may protect against lung cancer. Glutathione S-transferases are important in metabolizing isothiocyanates; hence, variants in GST genes may modify the association between cruciferous vegetable intake and lung cancer. We carried out a systematic review to characterize the association between cruciferous vegetable intake and lung cancer risk, with an emphasis on the potential interaction between cruciferous vegetables and GSTM1 and GSTT1 gene variants. Methods: A search of the epidemiologic literature through December 2007 was conducted using 15 bibliographic databases without language restrictions. Thirty studies on the association between lung cancer and either total cruciferous vegetable consumption (6 cohort and 12 case-control studies) or specific cruciferous vegetables (1 cohort and 11 case-control studies) were included. Results: The risk for lung cancer among those in the highest category of total cruciferous vegetable intake was 22% lower in case-control studies [random-effects pooled odds ratio, 0.78; 95% confidence interval (95% CI), 0.70-0.88] and 17% lower in cohort studies (pooled relative risk, 0.83; 95% CI, 0.62-1.08) compared with those in the lowest category of intake. The strongest inverse association of total cruciferous vegetable intake with lung cancer risk was seen among individuals with GSTM1 and GSTT1 double null genotypes (odds ratio, 0.41; 95% CI, 0.26-0.65; P for interaction = 0.01). Conclusions: Epidemiologic evidence suggests that cruciferous vegetable intake may be weakly and inversely associated with lung cancer risk. Because of a gene-diet interaction, the strongest inverse association was among those with homozygous deletion for GSTM1 and GSTT1. (Cancer Epidemiol Biomarkers Prev 2009;18(1):184–95)

Treatment of Sjögren's syndrome-associated dry eye an evidence-based review.

BACKGROUND Outcomes-based review of reported treatment options for patients with dry eye secondary to Sjögrens syndrome (SS). CLINICAL RELEVANCE Dry eye affects many individuals worldwide. Significant proportion of patients with dry eye has underlying SS, a progressive autoimmune condition. The few suggested guidelines for the treatment of dry eye are mostly based on severity of symptoms and/or clinical findings rather than on outcomes analysis, and do not differentiate SS from other causes of dry eye. METHODS AND LITERATURE REVIEW: A search strategy was developed to identify prospective, interventional studies of treatments for SS-associated dry eye from electronic databases. Eligible references were restricted to English-language articles published after 1975. These sources were augmented by hand searches of reference lists from accessed articles. Study selection, data extraction, and grading of evidence were completed independently by ≥4 review authors. RESULTS The searches identified 3559 references as of August 10, 2010. After duplicate review of the titles and abstracts, 245 full-text papers were assessed, 62 of which were relevant for inclusion in the review. CONCLUSIONS In the current literature on SS-associated dry eye, there is a paucity of rigorous clinical trials to support therapy recommendations. Nonetheless, the recommended treatments include topical lubricants, topical anti-inflammatory therapy, and tear-conserving strategies. The efficacy of oral secretagogues seems greater in the treatment of oral dryness than ocular dryness. Although oral hydroxychloroquine is commonly prescribed to patients with SS to alleviate fatigue and arthralgias, the literature lacks strong evidence for the efficacy of this treatment for dry eye.

Comparative Effectiveness of First-Line Medications for Primary Open-Angle Glaucoma: A Systematic Review and Network Meta-analysis.

TOPIC Primary open-angle glaucoma (POAG) is a highly prevalent condition worldwide and the most common cause of irreversible sight loss. The objective is to assess the comparative effectiveness of first-line medical treatments in patients with POAG or ocular hypertension through a systematic review and network meta-analysis, and to provide relative rankings of these treatments. CLINICAL RELEVANCE Treatment for POAG currently relies completely on lowering the intraocular pressure (IOP). Although topical drops, lasers, and surgeries can be considered in the initial treatment of glaucoma, most patients elect to start treatment with eye drops. METHODS We included randomized controlled trials (RCTs) that compared a single active topical medication with no treatment/placebo or another single topical medication. We searched CENTRAL, MEDLINE, EMBASE, and the Food and Drug Administrations website. Two individuals independently assessed trial eligibility, abstracted data, and assessed the risk of bias. We performed Bayesian network meta-analyses. RESULTS We included 114 RCTs with data from 20 275 participants. The overall risk of bias of the included trials is mixed. The mean reductions (95% credible intervals) in IOP in millimeters of mercury at 3 months ordered from the most to least effective drugs were as follows: bimatoprost 5.61 (4.94; 6.29), latanoprost 4.85 (4.24; 5.46), travoprost 4.83 (4.12; 5.54), levobunolol 4.51 (3.85; 5.24), tafluprost 4.37 (2.94; 5.83), timolol 3.70 (3.16; 4.24), brimonidine 3.59 (2.89; 4.29), carteolol 3.44 (2.42; 4.46), levobetaxolol 2.56 (1.52; 3.62), apraclonidine 2.52 (0.94; 4.11), dorzolamide 2.49 (1.85; 3.13), brinzolamide 2.42 (1.62; 3.23), betaxolol 2.24 (1.59; 2.88), and unoprostone 1.91 (1.15; 2.67). CONCLUSIONS All active first-line drugs are effective compared with placebo in reducing IOP at 3 months. Bimatoprost, latanoprost, and travoprost are among the most efficacious drugs, although the within-class differences were small and may not be clinically meaningful. All factors, including adverse effects, patient preferences, and cost, should be considered in selecting a drug for a given patient.

Boston Type 1 Keratoprosthesis versus Repeat Donor Keratoplasty for Corneal Graft Failure: A Systematic Review and Meta-analysis.

PURPOSE To compare repeat penetrating keratoplasty (PK) with Boston type I keratoprosthesis (KPro) implantation for full-thickness donor corneal graft failure. DESIGN Previous donor graft failure is a common indication for both PK and KPro implantation. Selection of the surgical procedure is entirely dependent on the surgeon because there are no studies available for guidance. Therefore, a systematic review was undertaken to examine vision, device retention, graft clarity, and postoperative glaucoma and infection outcomes after repeat PK versus KPro implantation. METHODS Articles with data regarding repeat PK published between 1990 and 2014 were identified in PubMed, EMBASE, the Latin American and Caribbean Health Sciences Literature Database, and the Cochrane Central Register of Controlled Trials and were reviewed. Results were compared with a retrospective review of consecutive, nonrandomized, longitudinal case series of KPro implantations performed at 5 tertiary care centers in the United States. Visual acuity at 2 years was the primary outcome measure. The proportion of clear grafts in the repeat PK group, device retention in the KPro group, and the development of postoperative glaucoma and infection were secondary outcome measures. RESULTS The search strategy identified 17 128 articles in the PK analysis. After screening, 26 studies (21 case series and 5 cohort studies) were included in the review. Pooled analysis of the 26 unique studies demonstrated a 42% (95% confidence interval [CI], 30%-56%) likelihood of maintaining 20/200 or better at 2 years after repeat PK, compared with an 80% (95% CI, 68%-88%) probability with KPro implantation. The probability of maintaining a clear graft at 5 years was 47% (95% CI, 40%-54%) after repeat PK, whereas the probability of retention of the KPro at 5 years was 75% (95% CI, 64%-84%). The rate of progression of glaucoma at 3 years was 25% (95% CI, 10%-44%) after repeat PK and 30% in the KPro cohort. CONCLUSIONS These results demonstrate favorable outcomes of KPro surgery for donor corneal graft failure with a greater likelihood of maintaining visual improvement without higher risk of postoperative glaucoma compared with repeat donor PK.

Interventions for Age-Related Macular Degeneration: Are Practice Guidelines Based on Systematic Reviews?

PURPOSE Are existing systematic reviews of interventions for age-related macular degeneration incorporated into clinical practice guidelines? DESIGN High-quality systematic reviews should be used to underpin evidence-based clinical practice guidelines and clinical care. We examined the reliability of systematic reviews of interventions for age-related macular degeneration (AMD) and described the main findings of reliable reviews in relation to clinical practice guidelines. METHODS Eligible publications were systematic reviews of the effectiveness of treatment interventions for AMD. We searched a database of systematic reviews in eyes and vision without language or date restrictions; the database was up to date as of May 6, 2014. Two authors independently screened records for eligibility and abstracted and assessed the characteristics and methods of each review. We classified reviews as reliable when they reported eligibility criteria, comprehensive searches, methodologic quality of included studies, appropriate statistical methods for meta-analysis, and conclusions based on results. We mapped treatment recommendations from the American Academy of Ophthalmology (AAO) Preferred Practice Patterns (PPPs) for AMD to systematic reviews and citations of reliable systematic reviews to support each treatment recommendation. RESULTS Of 1570 systematic reviews in our database, 47 met inclusion criteria; most targeted neovascular AMD and investigated anti-vascular endothelial growth factor (VEGF) interventions, dietary supplements, or photodynamic therapy. We classified 33 (70%) reviews as reliable. The quality of reporting varied, with criteria for reliable reporting met more often by Cochrane reviews and reviews whose authors disclosed conflicts of interest. Anti-VEGF agents and photodynamic therapy were the only interventions identified as effective by reliable reviews. Of 35 treatment recommendations extracted from the PPPs, 15 could have been supported with reliable systematic reviews; however, only 1 recommendation cited a reliable intervention systematic review. No reliable systematic review was identified for 20 treatment recommendations, highlighting areas of evidence gaps. CONCLUSIONS For AMD, reliable systematic reviews exist for many treatment recommendations in the AAO PPPs and should be cited to support these recommendations. We also identified areas where no high-level evidence exists. Mapping clinical practice guidelines to existing systematic reviews is one way to highlight areas where evidence generation or evidence synthesis is either available or needed.

Comparison of clinical trial and systematic review outcomes for the 4 most prevalent eye diseases

Importance Suboptimal overlap in outcomes reported in clinical trials and systematic reviews compromises efforts to compare and summarize results across these studies. Objectives To examine the most frequent outcomes used in trials and reviews of the 4 most prevalent eye diseases (age-related macular degeneration [AMD], cataract, diabetic retinopathy [DR], and glaucoma) and the overlap between outcomes in the reviews and the trials included in the reviews. Design, Setting, and Participants This cross-sectional study examined all Cochrane reviews that addressed AMD, cataract, DR, and glaucoma; were published as of July 20, 2016; and included at least 1 trial and the trials included in the reviews. For each disease, a pair of clinical experts independently classified all outcomes and resolved discrepancies. Outcomes (outcome domains) were then compared separately for each disease. Main Outcomes and Measures Proportion of review outcomes also reported in trials and vice versa. Results This study included 56 reviews that comprised 414 trials. Although the median number of outcomes per trial and per review was the same (n = 5) for each disease, the trials included a greater number of outcomes overall than did the reviews, ranging from 2.9 times greater (89 vs 30 outcomes for glaucoma) to 4.9 times greater (107 vs 22 outcomes for AMD). Most review outcomes, ranging from 14 of 19 outcomes (73.7%) (for DR) to 27 of 29 outcomes (93.1%) (for cataract), were also reported in the trials. For trial outcomes, however, the proportion also named in reviews was low, ranging from 19 of 107 outcomes (17.8%) (for AMD) to 24 of 89 outcomes (27.0%) (for glaucoma). Only 1 outcome (visual acuity) was consistently reported in greater than half the trials and greater than half the reviews. Conclusions and Relevance Although most review outcomes were reported in the trials, most trial outcomes were not reported in the reviews. The current analysis focused on outcome domains, which might underestimate the problem of inconsistent outcomes. Other important elements of an outcome (ie, specific measurement, specific metric, method of aggregation, and time points) might have differed even though the domains overlapped. Inconsistency in trial outcomes may impede research synthesis and indicates the need for disease-specific core outcome sets in ophthalmology.

Evaluation of Clinical Questions and Patient-Important Outcomes Associated With the Treatment of Age-Related Macular Degeneration

Importance Identifying and prioritizing unanswered clinical questions may help to best allocate limited resources for research associated with the treatment of age-related macular degeneration (AMD). Objective To identify and prioritize clinical questions and outcomes for research associated with the treatment of AMD through engagement with professional and patient stakeholders. Design, Setting, and Participants Multiple cross-sectional survey questions were used in a modified Delphi process for panel members of US and international organizations, the American Academy of Ophthalmology (AAO) Retina/Vitreous Panel (n=7), health care professionals from the American Society of Retinal Specialists (ASRS) (n=90), Atlantic Coast Retina Conference (ACRC) and Macula 2017 meeting (n=34); and patients from MD (Macular Degeneration) Support (n=46). Data were collected from January 20, 2015, to January 9, 2017. Main Outcomes and Measures The prioritizing of clinical questions and patient-important outcomes for AMD. Results Seventy clinical questions were derived from the AAO Preferred Practice Patterns for AMD and suggestions by the AAO Retina/Vitreous Panel. The AAO Retina/Vitreous Panel assessed all 70 clinical questions and rated 17 of 70 questions (24%) as highly important. Health care professionals assessed the 17 highly important clinical questions and rated 12 of 17 questions (71%) as high priority for research to answer; 9 of 12 high-priority clinical questions were associated with aspects of anti–vascular endothelial growth factor agents. Patients assessed the 17 highly important clinical questions and rated all as high priority. Additionally, patients identified 6 of 33 outcomes (18%) as most important to them (choroidal neovascularization, development of advanced AMD, retinal hemorrhage, gain of vision, slowing vision loss, and serious ocular events). Conclusions and Relevance Input from 4 stakeholder groups suggests good agreement on which 12 priority clinical questions can be used to underpin research related to the treatment of AMD. The 6 most important outcomes identified by patients were balanced between intended effects of AMD treatment (eg, slowing vision loss) and adverse events. Consideration of these patient-important outcomes may help to guide clinical care and future areas of research.

Missed opportunity from randomised controlled trials of medical interventions for open-angle glaucoma

Purpose To evaluate the extent to which intraocular pressure and visual field have been reported as outcomes in randomised controlled trials (also referred to as ‘trials’) of medical treatments for open-angle glaucoma. Methods We identified published reports of trials in a systematic review of medical interventions for open-angle glaucoma our group conducted. We assessed whether intraocular pressure and visual field were reported as trial outcomes and classified them to be either completely or incompletely reported for meta-analysis. We also collected data on the length of time patients were followed and source of funding for the trial. Results As of March 2014, we identified 401 trials that had enrolled 76 861 participants. Eighty per cent of 401 trials provided complete information on intraocular pressure and 11% of the 401 trials provided complete information on visual field. Only a minority of trials followed patients for at least 1 year. About half of all reports in our study stated that receiving funding from the industry. Conclusions Although the vast majority of trials provided sufficient data for meta-analysis of the effect of medical management of open-angle glaucoma on intraocular pressure, relatively few provided data for analysing the effect on visual field. We considered this as missed opportunity because the data were not available for evidence synthesis. Investigators have an obligation to patients and providers to determine the comparative effectiveness of glaucoma interventions in terms of patient-important outcomes and not to waste data that could have been collected in trials.

Outcome measures in health research: from assessing validity to outcome reporting

Clinical research seeks to find answers to questions regarding the diagnosis and prognosis of disease, as well as treatment effects, including safety, and treatment monitoring. Health events that either occur, or do not, are a common type of outcome, which can be recorded as dichotomous or count data; examples of these include death and myocardial infarction. Other outcomes are surrogates or predictors of health events, such as glycated haemoglobin for diabetic microangiopathic complications. Interest in Patient-Reported Outcome Measures (PROMs) is growing, such as in using questionnaires to investigate general, or diseasespecific, disability. PROMs generally assess self-reported symptom status, physical function, mental health, social function, and well-being [1]. They aim to directly measure an individual’s subjectively perceived health; hence they often are more variable than biological factors, and larger sample sizes are required to study them. The brief examples presented above highlight the variability in how health outcomes can be measured, such as investigator or patient-reported; objective or subjective; dichotomous, continuous, or counted data. To add further complexity, the responses to questions used to collect PROMs often are ordered categories, e.g. from‘‘not at all’’ to ‘‘totally’’, which are then used to generate sum scores.WhenPROMsare used in health economics models, they are associated with generic health-state values, such as utility values that range from 0—absence of health or death—to 1—perfect health. The aim of this article is to present a basic understanding on outcome measure characteristics, from the perspective of clinicians and researchers (also see summary in Table 1).

Outcome measures in trials: the systematic reviewer's point of view.

A previous article of this Journal section has summarised the desirable properties of outcome measures used in health research, particularly in randomised controlled trials (RCTs) [1]. This is the second article of this series, focussing on the dimensions and aspects that a systematic reviewer has to consider for each included study, as they can modify the confidence we have on the overall estimates and quality of evidence. Systematic reviews are the result of a complex process, with a foundation of formulating a proper question, with an accurate definition of the Population, Intervention, Comparator and Outcome (PICO), a comprehensive data search, objective selection and data extraction and critical evaluation of primary studies. Systematic reviews should define in advance the objectives, search strategy, eligibility criteria, data collection procedures and data analysis, including statistical synthesis, and grading the quality of evidence. The PICO places the review question in its specific research context, isolating a relevant and well-defined question that has been identified as being relevant to patients, physicians or health care providers, and clinical practice guideline developers. Among the PICO elements, choosing the Outcomes relates to how best to answer the research question, and also requires planning how the outcomes should be analysed and reported (Table 1). Among the many possible properties of outcome measures, key ones are: validity, the outcome is actually measuring what was intended; reliability, the outcome is reproducibly measured, e.g. by different assessors; responsiveness, outcome values vary when the underlying target condition worsens or improves; above all, it must be clinically important, for example an event which is relevant to patients or is a predictor of their future health [1]. When a trial is planned, a primary outcome should be pre-specified and used to calculate the study sample size. Secondary outcomes are important to confirm the results obtained for the primary outcome, or to explore other health dimensions or to measure important biomarkers. Statistical methods to be used for analyses should also be pre-specified, as well as any cutoffs or subgroups adopted. When authors report results in the final manuscript, they should present not only positive results, but rather all the results for specified outcomes, including those not statistically significant.