***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Leber congenital amaurosis ( LCA ) is a group of autosomal recessive blinding retinal diseases that are incurable . One molecular form is caused by mutations in the RPE65 ( retinal pigment epithelium-specific 65-kDa ) gene . A recombinant adeno-associated virus serotype 2 ( rAAV2 ) vector , altered to carry the human RPE65 gene ( rAAV2-CBSB-hRPE65 ) , restored vision in animal models with RPE65 deficiency . A clinical trial was design ed to assess the safety of rAAV2-CBSB-hRPE65 in subjects with RPE65-LCA . Three young adults ( ages 21 - 24 years ) with RPE65-LCA received a uniocular subretinal injection of 5.96 x 10(10 ) vector genomes in 150 microl and were studied with follow-up examinations for 90 days . Ocular safety , the primary outcome , was assessed by clinical eye examination . Visual function was measured by visual acuity and dark-adapted full-field sensitivity testing ( FST ) ; central retinal structure was monitored by optical coherence tomography ( OCT ) . Neither vector-related serious adverse events nor systemic toxicities were detected . Visual acuity was not significantly different from baseline ; one patient showed retinal thinning at the fovea by OCT . All patients self-reported increased visual sensitivity in the study eye compared with their control eye , especially noticeable under reduced ambient light conditions . The dark-adapted FST results were compared between baseline and 30 - 90 days after treatment . For study eyes , sensitivity increases from mean baseline were highly significant ( p < 0.001 ) ; whereas , for control eyes , sensitivity changes were not significant ( p = 0.99 ) . Comparisons are drawn between the present work and two other studies of ocular gene therapy for RPE65-LCA that were carried out contemporaneously and reported Leber 's congenital amaurosis ( LCA ) is a group of inherited blinding diseases with onset during childhood . One form of the disease , LCA2 , is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene ( RPE65 ) . We investigated the safety of subretinal delivery of a recombinant adeno-associated virus ( AAV ) carrying RPE65 complementary DNA ( cDNA ) ( Clinical Trials.gov number , NCT00516477 [ Clinical Trials.gov ] ) . Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2 . Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity . In one patient , an asymptomatic macular hole developed , and although the occurrence was considered to be an adverse event , the patient had some return of retinal function . Although the follow-up was very short and normal vision was not achieved , this study provides the basis for further gene therapy studies in patients with LCA OBJECTIVE To determine the safety and efficacy of subretinal gene therapy in the RPE65 form of Leber congenital amaurosis using recombinant adeno-associated virus 2 ( rAAV2 ) carrying the RPE65 gene . DESIGN Open-label , dose-escalation phase I study of 15 patients ( range , 11 - 30 years of age ) evaluated after subretinal injection of the rAAV2- RPE65 vector into the worse-functioning eye . Five cohorts represented 4 dose levels and 2 different injection strategies . MAIN OUTCOME MEASURES Primary outcomes were systemic and ocular safety . Secondary outcomes assayed visual function with dark-adapted full-field sensitivity testing and visual acuity with Early Treatment Diabetic Retinopathy Study charts . Further assays included immune responses to the vector , static visual fields , pupillometry , mobility performance , and optical coherence tomography . RESULTS No systemic toxicity was detected ; ocular adverse events were related to surgery . Visual function improved in all patients to different degrees ; improvements were localized to treated areas . Cone and rod sensitivities increased significantly in the study eyes but not in the control eyes . Minor acuity improvements were recorded in many study and control eyes . Major acuity improvements occurred in study eyes with the lowest entry acuities and parafoveal fixation loci treated with subretinal injections . Other patients with better foveal structure lost retinal thickness and acuity after subfoveal injections . CONCLUSIONS Gene therapy for Leber congenital amaurosis caused by RPE65 mutations is sufficiently safe and substantially efficacious in the extrafoveal retina . There is no benefit and some risk in treating the fovea . No evidence of age-dependent effects was found . Our results point to specific treatment strategies for subsequent phases . APPLICATION TO CLINICAL PRACTICE Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00481546 PURPOSE To provide an initial assessment of the safety of a recombinant adeno-associated virus vector expressing RPE65 ( rAAV2-CB-hRPE65 ) in adults and children with retinal degeneration caused by RPE65 mutations . DESIGN Nonr and omized , multicenter clinical trial . PARTICIPANTS Eight adults and 4 children , 6 to 39 years of age , with Leber congenital amaurosis ( LCA ) or severe early-childhood-onset retinal degeneration ( SECORD ) . METHODS Patients received a subretinal injection of rAAV2-CB-hRPE65 in the poorer-seeing eye , at either of 2 dose levels , and were followed up for 2 years after treatment . MAIN OUTCOME MEASURES The primary safety measures were ocular and nonocular adverse events . Exploratory efficacy measures included changes in best-corrected visual acuity ( BCVA ) , static perimetry central 30 ° visual field hill of vision ( V30 ) and total visual field hill of vision ( VTOT ) , kinetic perimetry visual field area , and responses to a quality -of-life question naire . RESULTS All patients tolerated subretinal injections and there were no treatment-related serious adverse events . Common adverse events were those associated with the surgical procedure and included subconjunctival hemorrhage in 8 patients and ocular hyperemia in 5 patients . In the treated eye , BCVA increased in 5 patients , V30 increased in 6 patients , VTOT increased in 5 patients , and kinetic visual field area improved in 3 patients . One subject showed a decrease in BCVA and 2 patients showed a decrease in kinetic visual field area . CONCLUSIONS Treatment with rAAV2-CB-hRPE65 was not associated with serious adverse events , and improvement in 1 or more measures of visual function was observed in 9 of 12 patients . The greatest improvements in visual acuity were observed in younger patients with better baseline visual acuity . Evaluation of more patients and a longer duration of follow-up will be needed to determine the rate of uncommon or rare side effects or safety concerns Early-onset , severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium-specific 65-kD protein ( RPE65 ) is associated with poor vision at birth and complete loss of vision in early adulthood . We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA ( cDNA ) under the control of a human RPE65 promoter . There were no serious adverse events . There was no clinical ly significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients . We detected no change in retinal responses on electroretinography . One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry . This patient also showed improvement in a subjective test of visual mobility . These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65 . ( Clinical Trials.gov number , NCT00643747 [ Clinical Trials.gov ] . ) A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its 
    Output:
    
Human gene therapy is a pioneering treatment option for RPE65-LCA .
Although its efficacy appears to be limited to less than 2 yrs after treatment , it carries the potential for further improvement and prolongation of efficacy