Clinical Trial of Lutein in Patients With Retinitis Pigmentosa Receiving Vitamin ALutein and Vitamin A in Retinitis Pigmentosa FREE

Retinitis pigmentosa has a prevalence of about 1:4000; an estimated 50 000 to 100 000 people are affected in the United States.¹ This condition is usually inherited by an autosomal dominant, autosomal recessive, or X-linked mode; almost half are isolates (ie, simplex cases) with no family history of this disease. Affected patients typically report night deficiency in adolescence and loss of midperipheral and then far peripheral field in adulthood with development of tunnel vision. Patients usually lose central vision after age 60 years. Clinical findings include elevated final dark adaptation thresholds, attenuated retinal vessels, intraretinal bone spicule pigment around the midperiphery in most cases, and reduced and delayed electroretinograms (ERGs). Histologic studies of autopsy eyes have shown that visual loss is due to degeneration of rod and cone photoreceptors.^{1 - 2}

In a randomized trial of vitamin A and vitamin E supplementation for adults with retinitis pigmentosa, we reported that the rate of progression is slowed, on average, among those taking 15 000 IU/d of vitamin A palmitate and appears to be hastened among those taking 400 IU/d of vitamin E.³ Subsequent to this vitamin A and E trial, we performed a risk factor analysis on those in the vitamin A group combining patients with all genetic types (n = 79) to see if rates of loss of retinal function were related to intake of specific foods and nutrients. We found that those taking vitamin A in the highest quintile of lutein intake (3.5-13 mg/d, roughly equivalent to as much as cup of cooked spinach per day) had a slower rate of decline in visual field area compared with those in the lower 4 quintiles (P = .05). A beneficial trend was also seen when relating 30-Hz ERG amplitude to quintile of lutein intake (P = .07). These findings suggested increased lutein intake further slowed disease progression among patients taking vitamin A.

Lutein is a carotenoid found in dark-green, leafy vegetables and, along with its isomer zeaxanthin, is the only carotenoid in the human retina.⁴ Lutein, being fat soluble, follows the same intestinal absorption path as dietary fat; it is packaged into triacylglycerol-rich chylomicrons⁵ and transported in the plasma by lipoproteins.⁶ The mechanism by which lutein is transported from the plasma to photoreceptors is unknown; there is evidence for the existence of a specific binding protein(s) in solubilized membranes derived from human retina.⁷ Although concentrated in and around the foveal depression in photoreceptor axons as macular pigment,^{8 - 9} lutein has also been found in rod outer segments throughout the human retina.^{10 - 13} Smoking and high alcohol intake have been associated with lower serum lutein and zeaxanthin levels.¹⁴ Lutein (as yellow macular pigment) is thought to screen the foveal cone photoreceptors from short-wavelength light to minimize chromatic aberration and enhance visual acuity.¹⁵ In rod outer segments, lutein may serve as an antioxidant to quench free radicals produced by high-energy short-wavelength illumination and thereby minimize light-induced retinal damage.^{16 - 17} There is no established dietary recommended intake for lutein; however, 6 mg/d has been associated with a reduced risk of cataracts and age-related macular degeneration.^{18 - 20} Most Americans only ingest 1 to 2 mg/d in their diet.^{21 - 24}

Our preliminary data showing a relationship between increased lutein intake and slowing of loss of visual function in adults with retinitis pigmentosa taking vitamin A as well as the known presence of lutein in photoreceptors, possibly serving as an antioxidant,^{10 - 11 ,16} provided the rationale for this randomized trial of the effect of lutein supplementation on visual function in adults with retinitis pigmentosa taking vitamin A.

We first conducted a randomized, controlled, double-masked phase 1/2 study from May 2000 through January 2001 to evaluate ocular and systemic safety as a function of lutein supplementation and to evaluate different doses of lutein supplementation in 41 patients (aged 18-56 years) with retinitis pigmentosa. After receiving a baseline ocular examination, patients were randomly assigned to placebo or 1 of 3 doses of lutein (3.3 mg/d, 6.6 mg/d, and 13 mg/d) and were examined after 2 and 4 months of supplementation; after stopping the supplement, they were reevaluated at 5 months (ie, 1-month washout). All patients were given 15 000 IU/d of vitamin A palmitate. In accord with a Data and Safety Monitoring Committee, we concluded that short-term lutein supplementation raises lutein in the serum and retina in adults with retinitis pigmentosa, the serum increase returns to baseline after 1 month of washout, that 12 mg/d of lutein is the minimum commercially available dose needed to achieve measurable elevations in both the serum and retina, lutein supplementation is not associated with a decrease in serum retinol level, and this supplement in the doses under study is safe for this population in the short-term.

In July 2003, we began a phase 3 trial to evaluate the effect of lutein supplementation on the course of retinitis pigmentosa. We screened patients for eligibility according to ocular, dietary, and medical criteria (Table 1). We performed a baseline examination on eligible patients within 8 weeks of the screening examination with the protocol used in the phase 1/2 study. At baseline, patients were randomly assigned to 1 of 2 groups: those receiving 1 tablet per day of 12 mg of lutein and those receiving a cornstarch control (supplied by Roche Vitamins, Inc, Parsippany, New Jersey, which became DSM Nutritional Products, Inc, Parsippany, in 2007). All were given vitamin A as 15 000 IU of retinyl palmitate (initially obtained from Akorn, Lake Forest, Illinois, July 2003-January 2005 and then from J. R. Carlson Laboratories, Inc, Arlington Heights, Illinois, February 2005-2009) and were instructed to take 1 study tablet and the vitamin A supplement daily with breakfast. Patients completed the Willett food frequency questionnaire²⁵ and a medical questionnaire at each visit with the aid of a clinical coordinator. They were also followed up annually over 4 years with blood tests and ocular examinations (Table 2). Serum lutein levels were monitored as a measure of compliance,²⁶ and serum retinol and retinyl ester levels²⁷ as well as serum liver function results were evaluated to detect any possible toxic effects of vitamin A. Change in macular pigment optical density (MPOD) as a measure of change in intraretinal lutein concentration was assessed in the fovea in 1 eye at each visit with heterochromatic flicker photometry.²⁸

We used the measurement of static perimetric sensitivities (ie, total point score) with the 30-2 program size V target in the Humphrey Field Analyzer (HFA) II (Carl Zeiss Meditech, Inc, Pleasanton, California) as the primary outcome measure. The size V target was used to minimize the number of locations with floor effects (ie, sensitivity ≤0 dB). The full-field 30-Hz cone ERG amplitude was studied as a secondary outcome measure among those with an amplitude of 0.68 μV or more pretreatment. Visual acuity (Early Treatment Diabetic Retinopathy Study),²⁹ the total point score to a size V target with the 60-4 program, and total point score to a size V target with the HFA 30-2 and 60-4 programs combined were also studied as secondary outcome measures. The FASTPAC test strategy was used to test both central (30-2) and midperipheral (60-4) visual fields in as short a time as possible.^{30 - 32}

We estimated that 240 patients were needed to provide sufficient power (ie, α = 0.05; β = 0.10) to observe a statistically significant difference between mean change in the lutein plus vitamin A and control plus vitamin A groups with respect to HFA 30-2 total point score over a 4-year interval. The project was approved by the institutional review boards of the Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, and the study conformed to the Declaration of Helsinki. All patients signed a consent form prior to the screening examination and, if eligible, prior to the baseline examination as well. A Data and Safety Monitoring Committee selected by the National Eye Institute approved the protocol and met with us annually to review the results for both patient safety and efficacy. The study was planned to allow 4 years of follow-up for each patient. The Lan-DeMets α-spending approach with an O’Brien-Fleming boundary with 5 looks was prespecified as the stopping-rule guideline.³³

The procedure for randomization took into account genetic type (dominant, recessive, X-linked, isolate, or undetermined [eg, adopted]) and serum level of lutein at the screening evaluation (ie, serum lutein level ≤6.4 or >6.4 μg/dL derived from analyses of serum lutein levels in our previous trial of docosahexaenoic acid supplementation)³⁴ ; therefore, there were 5 × 2 or 10 strata. All members of the staff in contact with the patients including the principal investigator (E.L.B.) were masked with respect to treatment group assignments. Only the data manager (C.W.D.) and the statistician (B.R.) had access to the code that listed group assignment. Each ocular examination was performed without review of previous records. Patients agreed not to know their group assignment.

Macular pigment optical density was measured by heterochromatic flicker photometry using a commercial tabletop instrument (Macular Metrics Corp, Rehoboth, Massachusetts)²⁸ in the eye with better visual acuity (or the right eye, if the 2 eyes were equal) after pupillary dilation to optimize sensitivity. For a given patient, the same eye was followed up at each visit. The standard task was for the patient to adjust the radiances of a 460-nm stimulus and an alternating 570-nm stimulus to achieve a brightness match by eliminating flicker within the central 1° where macular pigment absorbance is maximal and within a 2°-diameter field at a 5° eccentric location where macular pigment absorbance is sufficiently low to serve as a reference.³⁵ The adjusted radiance of the 460-nm stimulus minus that of the 570-nm stimulus for the central fovea minus the same difference for the reference location, expressed in base 10 logarithms, provided an estimate of MPOD. These stimuli were centered on a 6° background of 475 nm to desensitize rods and short wavelength–sensitive cones so that they would not contribute to the patient's judgment. Change in MPOD as measured by heterochromatic flicker photometry is regarded as a measure of uptake of lutein in the retina with lutein supplementation.³⁶

Ability to perform this standard task was not an eligibility criterion for enrollment. A majority of the patients could not perform the standard task throughout the trial, generally because they could not consistently visualize the entire 2° field in the parafoveal location. However, since MPOD was proportional to the log radiance difference measured by heterochromatic flicker photometry in the fovea alone in a subset of patients at baseline (r² = 0.54; P < .001), change in the latter value was used to estimate lutein uptake in the retina over follow-up in the entire cohort.

Outcome data for a given patient for each visit represented the test results from each eye or for a single eye if data for the other eye were not available. Visual field data (total point scores) were analyzed separately for the central field (30-2 program), midperipheral field (60-4 program), and 30-2 and 60-4 programs combined when both were available. Analyses of 30-Hz ERG data were limited to those who had an amplitude of 0.68 μV or more in at least 1 eye at baseline and data were censored when values declined to less than 0.34 μV. If an eye became pseudophakic after the baseline visit, data for that eye were analyzed only for those visits prior to cataract surgery. If the total point score for a visual field in an eye became zero, the visit at which the zero score was first obtained was included in the analyses and the total point scores for all subsequent visits for that eye were set to zero. Mean change from baseline was computed for each patient by eye. Slopes were calculated using data from all available eyes by treatment group. Comparisons by assigned treatment group were also performed within genetic type and within prespecified subgroups (eg, above and below the median level of visual field sensitivity) at baseline. Longitudinal regression analyses³⁷ were performed using PROC MIXED of SAS version 9.1.3.³⁸ Since the distribution of change for each HFA outcome measure was skewed and non normal, we also calculated the rate of change in visual field sensitivity using least squares regression for each eye of each patient, converted them to ranks, and used a nonparametric method (clustered Wilcoxon test) to compare the distribution of slopes in the lutein plus vitamin A group vs the control plus vitamin A group controlling for the correlation between the ranks of slopes for the 2 eyes within an individual.³⁹

Observational analyses were performed comparing rate of decline of HFA sensitivity over 4 years of follow-up with serum lutein level or change in MPOD using PROC MIXED. For this purpose, serum lutein level and change in MPOD were expressed as dichotomous variables defined by the highest vs the lower 3 quartiles. In addition, a restricted cubic spline analysis was performed^{40 - 41} to identify a threshold effect and a maximum effect of serum lutein level on change in HFA sensitivity.

Of the 240 randomized patients, 225 were followed up over 4 years. Of these patients, 215 had measurable (ie, greater than zero) central field sensitivities and 163 patients had measurable midperipheral field sensitivities in at least 1 eye in all 4 years of follow-up. The results will focus on these 2 consistent samples (ie, those with measurable sensitivities to the 30-2 program [n = 215] and those with measurable sensitivities to the 60-4 program [n = 163]). Patients were encouraged not to initiate new supplements. In October 2004, following publication of a trial of docosahexaenoic acid supplementation for retinitis pigmentosa,⁴² all patients were advised by letter to eat 1 to 2 three-oz servings per week of oily fish of which docosahexaenoic acid is a major constituent (eg, salmon, tuna, herring, mackerel, or sardines), if not already doing so. They were reminded at annual visits not only to take vitamin A and the study pill but also to eat oily fish and otherwise maintain their baseline dietary pattern.

From July 2003 through November 2004, we examined 412 patients from across the United States to identify 240 (1 per family) with retinitis pigmentosa who met the preset list of eligibility criteria (Table 1). Two hundred twenty-five of these patients completed all 4 annual follow-up visits by December 2008. Baseline characteristics of these 225 patients, shown in Table 3, reveal characteristics typical of retinitis pigmentosa, balance between groups, and evidence that many variables had skewed distributions. Ninety-two percent of eligible patients had intraretinal bone spicule pigmentation in the fundus midperiphery. Sixty-one percent had a posterior subcapsular cataract in at least 1 eye. Fifteen percent reported partial hearing loss. Seven percent were minorities.

At baseline, 52% of the 225 patients reported eating 1 to 2 servings of oily fish per week (49% in the lutein plus vitamin A group and 54% in the control plus vitamin A group). In response to our advice to eat oily fish between year 1 and year 2 of follow-up, 92% of these patients reported that they were following this instruction at year 4 (94% in the lutein plus vitamin A group and 90% in the control plus vitamin A group).

Capsule counts indicated that 92% of the lutein tablets, 93% of the control tablets, and 95% of the vitamin A tablets were consumed over all 4 years. Similar results were seen with returned monthly calendars. One patient in the control plus vitamin A group died in a motorcycle accident after year 3 of follow-up. Two patients in the lutein plus vitamin A group showed slight elevations of serum liver function levels (serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase) of unknown etiology at year 4 and stopped taking vitamin A and the study tablet as a precaution. No patient experienced a complete loss of vision in an eye over the course of this trial. Furthermore, there was no evidence of systemic illness or toxic effects attributable to the study tablet or vitamin A based on blood studies, serum liver function assessments, serum retinol and serum retinyl ester values, and responses to a symptom questionnaire.

At follow-up, mean serum lutein level (mean of all follow-up measures) was significantly higher in the lutein group compared with the control group (P < .001) (Figure 1); this difference was detectable by year 1 and maintained over 4 years. The lutein plus vitamin A group (n = 75) showed a significantly greater increase in MPOD over 4 years of follow-up compared with the control plus vitamin A group (n = 88) (P < .001). The mean (SD) annual rate of change in percentage of cataract area was 0.05 (0.03) in the lutein plus vitamin A group and 0.10 (0.03) in the control plus vitamin A group; these rates of change were not significantly different from one another. Serum retinol level increased slightly but comparably in both the lutein and control groups.

Table 4 shows no significant difference in the primary outcome measure of central visual field sensitivity with the 30-2 program for the randomized comparison between the lutein and control groups. However, Table 4 does show a significant difference (P = .05) in the secondary outcome measure of midperipheral visual field sensitivity with the 60-4 program; the lutein group lost, on average, 27 dB/y while the control group lost, on average, 34 dB/y. Comparisons of treatment groups stratified by initial median values did not reveal significant interactions according to baseline levels. Because rates of change of visual field sensitivity were skewed, particularly with the HFA 60-4 program (Figure 2), we performed additional analyses with the clustered Wilcoxon rank sum test for (1) the consistent samples and (2) the total available samples. Table 5 shows the results of these nonparametric analyses. Rates of change for the HFA 60-4 program showed a significant beneficial effect of lutein for both the consistent sample and the sample including all available data (P = .03 in each case).

Among the observational analyses (Table 6), the rate of HFA 60-4 sensitivity loss was significantly different (P = .01) among patients in the highest quartile of serum lutein level compared with those in the lower 3 quartiles. The mean rate of decline of HFA 60-4 sensitivity was 21 dB/y for those in the highest quartile of serum lutein level vs 33 dB/y in the lower 3 quartiles. Table 6 also shows that the rate of decline of HFA 60-4 sensitivity was significantly slower among those in the highest quartile of change in MPOD at all follow-up visits combined (ie, 18 dB/y) vs the rate among those in the lower 3 quartiles (ie, 34 dB/y) (P = .006). Similarly, those in the highest quartile of change in MPOD had a significantly slower rate of decline in central plus midperipheral field sensitivity combined (ie, 30-2 plus 60-4 program combined) vs those in the lower 3 quartiles (−62 dB/y for the highest quartile and −92 dB/y for the lower 3 quartiles; P = .005).

Figure 3 shows a spline regression of annual change in HFA 60-4 total point score by serum lutein level based on all patients. The fitted curve shows that the change in HFA 60-4 sensitivity starts to decrease (ie, disease progression is slowed) at a serum lutein level of 20 μg/dL and stops decreasing at 60 to 70 μg/dL.

No significant differences by treatment group assignment were observed for either the primary or secondary outcome measures within the dominant, recessive, X-linked, or isolate forms of retinitis pigmentosa or within category of baseline serum lutein level (data not shown).

The present trial among adults with retinitis pigmentosa showed no significant treatment effect on the course of retinal degeneration in central field sensitivity as monitored by the HFA 30-2 program (the primary outcome measure) or in the central macula as monitored by Early Treatment Diabetic Retinopathy Study acuity (a secondary outcome measure). The trial did, however, show a significant beneficial effect of 12 mg/d of lutein on preserving midperipheral visual field sensitivity as monitored by the HFA 60-4 program, a secondary outcome measure; the lutein plus vitamin A group lost on average 27 dB/y vs 34 dB/y in the control plus vitamin A group (Table 4). The effect of treatment was the same for patients with initial HFA sensitivities above and below the median, indicating that the observed benefit of lutein on slowing midperipheral field loss was not simply limited to those patients with milder disease who retained more sensitivity in this region. No effect of lutein could be detected with respect to preserving the full-field 30-Hz cone ERG (a secondary outcome measure); a possible explanation for the difference between the midperipheral HFA findings and the ERG results is that the latter is generated not only by central plus midperipheral cones but also by far peripheral cones. Since all the outcome measures were specified a priori and are correlated, no statistical adjustments for multiple comparisons were performed. The detectable benefit of lutein supplementation on preserving midperipheral function but not central function in retinitis pigmentosa may reflect an increased requirement for antioxidants in photoreceptor outer segments in a region of the retina where the photoreceptors are most impaired.

The effect of lutein on slowing midperipheral field decline was consistent with the observation that the annual rate of decline of midperipheral field sensitivity was significantly slower among those in the upper quartile of serum lutein level at follow-up vs those in the lower 3 quartiles. Most patients taking 12 mg/d of lutein had a serum lutein level more than 20 μg/dL, which was associated with a decrease in decline of HFA 60-4 sensitivity (Figure 3). Serum lutein levels more than 60 to 70 μg/dL were not associated with greater benefit. The finding that serum lutein levels vary widely among patients taking the same dose of lutein, described by others,⁴³ was also observed in this study (Figure 1). In addition, patients in the highest quartile of MPOD elevation at follow-up, as a measure of increase in intraretinal lutein level, had a significantly slower rate of decline not only of midperipheral field but also of central and midperipheral field combined compared with the rate among those in the lower 3 quartiles.

The randomized comparisons (Table 4 and Table 5) demonstrating a beneficial effect of lutein on slowing midperipheral field sensitivity loss, and the observational data that maximal slowing occurred among those with the highest serum lutein levels and greatest increase in MPOD (Table 6), provide evidence to support the use of 12-mg/d lutein supplementation among adults with typical retinitis pigmentosa also taking 15 000 IU/d of vitamin A palmitate and eating 1 to 2 servings of oily fish per week. No significant adverse effects were found with use of lutein with respect to both general health and lowering serum retinol level over the 4-year duration of this trial.

The short-term safety of lutein supplementation has been reported in 2 other studies of retinitis pigmentosa in which patients were given this supplement in higher doses for up to 6 months.^{35 ,44} However, some concern has been raised that long-term lutein supplementation is associated with an increased risk of lung cancer among smokers older than 50 years in the general population.⁴⁵ The present trial was conducted in current nonsmokers and therefore the recommendation for 12-mg/d lutein supplementation is limited to adult patients with typical retinitis pigmentosa who do not smoke. The long-term safety of lutein even in nonsmokers remains to be established. Because the highest serum lutein levels were not associated with greater benefit in this study (Figure 3) and because the long-term safety of higher-dose lutein supplementation is unknown, patients should not exceed 12 mg/d based on current knowledge.

Patients taking 15 000 IU/d of vitamin A palmitate, consuming 1 to 2 three-oz servings of oily fish per week, and taking 12 mg/d of lutein should be reminded to have a fasting serum vitamin A and liver function profile annually as a precaution. Women who are pregnant or planning to become pregnant should not take high-dose vitamin A supplements because of an increased risk of birth defects. Patients 49 years and older should monitor their bone health because of the slight (0.5%-1.0%) increased risk of hip fracture among patients taking long-term high-dose vitamin A supplementation.^{46 - 47}

The benefit of lutein supplementation on the long-term course of midperipheral visual field loss among patients also taking vitamin A and eating an oily fish diet can only be estimated. Based on the randomized comparison (Table 4), a patient aged 40 years would be expected to lose 27 dB/y of total point score, on average, in the lutein group vs 34 dB/y in the control group (ie, 7 dB/y saved) over the 4-year interval of this trial. Assuming 60 measurable test locations within the HFA 60-4 program and recognizing that 1 dB = 0.1 log₁₀ unit, we calculate that lutein supplementation saved, on average, 2.7% per test location per year of midperipheral field sensitivity (ie, 100 × [10^{(7 dB × 0.1/60)} − 1] = 2.7%) that is equivalent to 0.12 dB per test location per year (ie, 0.12 dB = 7 dB/60 test locations). With respect to change in serum lutein level (Table 6), we calculate a saving of 12 dB/y or 4.7% per year (ie, 100 × [10^{(12 dB × 0.1/60)} − 1] = 4.7%) that is equivalent to 0.2 dB per test location per year. With respect to change in MPOD, we calculate a saving of 16 dB/y or 6.3% per year (ie, 100 × [10^{(16 dB × 0.1/60)} − 1] = 6.3%) or 0.27 dB per test location per year. Therefore, depending on the analysis, the average yearly saving of midperipheral visual field sensitivity during the trial ranged from 2.7% to 6.3% per test location per year.

Over the longer-term, taking into account that a patient aged 40 years has, on average, 375 dB of midperipheral sensitivity based on total point scores (Table 3), the estimated benefit in preserving midperipheral field sensitivity based on the randomized comparison would be 3 additional years (ie, 375/27 = 14 vs 375/34 = 11), based on the serum lutein observational results would be 6 additional years (ie, 375/21 = 18 vs 375/33 = 12), and based on the MPOD observational results would be 10 additional years (ie, 375/18 = 21 vs 375/34 = 11). In the latter case, an average patient taking vitamin A who starts taking lutein at age 40 could expect to lose midperipheral field by age 61 (ie, 40 + 21), while a patient not taking lutein would be expected to lose midperipheral field by age 51 (ie, 40 + 11). Follow-up of patients taking lutein and vitamin A with an oily fish diet for at least 10 years would be needed to confirm these estimates with respect to preserving midperipheral visual field.

Correspondence: Eliot L. Berson, MD, Berman-Gund Laboratory, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 (linda_berard@meei.harvard.edu).

Submitted for Publication: December 3, 2009; final revision received January 15, 2010; accepted January 19, 2010.

Author Contributions: Dr Berson had full access to the data on completion of the study and takes responsibility for the integrity of the data and the accuracy of the data analyses.

Financial Disclosure: None.

Funding/Support: This research was supported by grant U10EY13945 from the National Eye Institute, Bethesda, Maryland, and in part by the Foundation Fighting Blindness, Owings Mills, Maryland.

Additional Contributions: We thank the study patients for participating in this research. Members of the Data and Safety Monitoring Committee for the current phase 3 trial were Janet Wittes, PhD (chair), Michael B. Gorin, MD, PhD, Susan Taylor Mayne, PhD, Cynthia S. McCarthy, DHCE, MA, Paul Sternberg, MD, Michael Wall, MD, and Maryann Redford, DDS, MPH (ad hoc). Members of the Data and Safety Monitoring Committee for the phase 1/2 study were Britain W. Nicholson, MD, (chair), Lawrence I. Rand, MD, Robert J. Glynn, PhD, and Donald Everett, MA (ad hoc). We thank Roche Pharmaceuticals and their successor DSM Pharmaceuticals (Parsippany, New Jersey) for providing the study pills. Marion McPhee, BEd, assisted with data analysis.