This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Clinical Trial Ceftriaxone in Subjects With ALS (NCT00349622), a randomized phase 3 study. The primary outcome is Survival.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00349622 |
| Phase | Phase 3 |
| Condition | Amyotrophic Lateral Sclerosis, ALS |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 513 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Massachusetts General Hospital |
| Results posted | Yes |
2. Clinical Question
The trial asked whether ceftriaxone treatment could affect survival in people with amyotrophic lateral sclerosis (ALS), compared with placebo. The primary outcome was time from randomization to death, tracheostomy or initiation of permanent assisted ventilation. The registry record also lists measures of vital capacity, upper- and lower-extremity muscle strength, and ALS-specific quality of life.
Population
People with amyotrophic lateral sclerosis. The record reports enrollment of 513 participants and gives no further participant characteristics in the posted outcome information.
Intervention
Ceftriaxone, with the arm description stating a daily dose of 4 grams. The study was double-masked; the description says the drug was administered intravenously.
Comparator
Placebo, described as an inactive pediatric multivitamin solution administered intravenously. Participants and study staff were masked to treatment assignment.
Primary question
How did the median time to death, tracheostomy or initiation of permanent assisted ventilation compare between the ceftriaxone and placebo groups?
The registry presents median survival and a confidence interval separately for each group. It does not report a hazard ratio or another sponsor-reported comparative estimate for this endpoint. The posted group medians are therefore descriptive results; they do not by themselves establish the size or statistical uncertainty of a treatment contrast.
3. Trial Design
This was a phase 3, randomized, double-masked, parallel-group study sponsored by Massachusetts General Hospital. The registry lists the study as completed, with a start date of 2006-07 and primary completion in 2012-11. Enrollment was 513. The record describes assignment to ceftriaxone or placebo, with two thirds assigned to ceftriaxone and one third to placebo.
The ceftriaxone arm description specifies 4 grams per day. It says ceftriaxone was administered intravenously. The placebo was described as pediatric multivitamin solution, also administered intravenously. Masking applied to participants and study staff; the registry does not give further details about how masking was maintained or assessed.
The primary outcome was a time-to-event measure. The event was the first of death, tracheostomy or initiation of permanent assisted ventilation. Follow-up was described as beginning at randomization and continuing until an event, with assessments at drug discontinuation and every 2 months thereafter for the life of the study. The timeframe description refers to the life of the study as 6 yrs.
Secondary measures listed in the registry include vital capacity, upper- and lower-extremity muscle strength measured with hand-held dynamometry, and ALS-specific quality of life. The listed secondary timeframes refer to repeated assessments every 12 weeks for one year. The registry record does not report further detail about the analysis population, handling of treatment discontinuation, or the statistical model used for these repeated measures.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Before assignment: Participants were randomly assigned to receive treatment with ceftriaxone or placebo for at least 12 months. Two thirds of participants received ceftriaxone and one third received placebo. This is a blinded study, so neither participants nor study staff knew which treatment a participant is receiving.
Overall Study
| Stage | Ceftriaxone | Placebo |
|---|---|---|
| STARTED | 340 | 173 |
| COMPLETED | 162 | 77 |
| NOT COMPLETED | 178 | 96 |
Reasons for not completing this period:
| Reason | Ceftriaxone | Placebo |
|---|---|---|
| Death | 168 | 86 |
| Lost to Follow-up | 5 | 1 |
| Withdrawal by Subject | 5 | 9 |
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | Ceftriaxone | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 340 | 173 | 513 | |
| Age, Continuous: Age at Screening | years | 55.6 (SD 10.4) | 54.8 (SD 10.3) | 55.4 (SD 10.4) |
| Sex: Female, Male: Female | Participants | 131 | 72 | 203 |
| Sex: Female, Male: Male | Participants | 209 | 101 | 310 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 17 | 6 | 23 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 320 | 165 | 485 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 3 | 2 | 5 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 2 | 0 | 2 |
| Race (NIH/OMB): Asian | Participants | 6 | 5 | 11 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 1 | 0 | 1 |
| Race (NIH/OMB): Black or African American | Participants | 8 | 3 | 11 |
| Race (NIH/OMB): White | Participants | 320 | 163 | 483 |
| Race (NIH/OMB): More than one race | Participants | 2 | 0 | 2 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 1 | 2 | 3 |
| Region of Enrollment: United States | participants | 293 | 151 | 444 |
| Region of Enrollment: Canada | participants | 47 | 22 | 69 |
| ALS Family History: Familial History of ALS | participants | 26 | 8 | 34 |
| ALS Family History: No Known Familial History of ALS | participants | 307 | 161 | 468 |
| ALS Family History: Unknown | participants | 7 | 4 | 11 |
| Site of Onset: Limb | participants | 257 | 137 | 394 |
| Site of Onset: Bulbar | participants | 75 | 35 | 110 |
| Site of Onset: Both | participants | 8 | 1 | 9 |
| Riluzole Use: On Riluzole | participants | 249 | 128 | 377 |
| Riluzole Use: Not on Riluzole | participants | 91 | 45 | 136 |
| Vital Capacity Percent Predicted | percent predicted based on age and heigh | 87.9 (SD 16.6) | 91.1 (SD 18.4) | 89.0 (SD 17.3) |
| Time to Screening: Years from Symptom Onset to Screening | years | 1.49 (SD 0.68) | 1.50 (SD 0.67) | 1.49 (SD 0.68) |
| Time to Screening: Years from Diagnosis to Screening | years | 0.56 (SD 0.49) | 0.58 (SD 0.49) | 0.57 (SD 0.49) |
| Time to Screening: Years from Symptom Onset to Diagnosis | years | 0.93 (SD 0.55) | 0.92 (SD 0.58) | 0.92 (SD 0.56) |
6. Primary Endpoint
The registry lists the primary outcome as Survival, measured over From date of randomization until date of death, tracheostomy, or the initiation of permanent assisted ventilation (PAV). This was assessed at time of each participant's drug discontinuation and every 2 months thereafter for the life of the study (6 yrs).
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | 95% Confidence Interval |
| Unit | days |
| Endpoint classification | Time-to-Event Analysis |
The primary endpoint, called survival in the registry, measures time from randomization until death, tracheostomy or initiation of permanent assisted ventilation. It is a composite time-to-event outcome: any one of those events counts as the endpoint. The record says that outcomes were assessed at drug discontinuation and every 2 months thereafter for the life of the study.
The registry reports the median time to the defined event for each group, along with a 95% confidence interval. A median is the time by which half of the observed group has experienced the event, under the survival analysis used to produce the estimate. It describes the middle of the event-time distribution rather than the experience of every participant. Participants whose event has not occurred by the end of observation can contribute information up to their last known follow-up; the registry does not report details of the estimation method or censoring rules.
Time-to-event outcomes are useful when the timing of an event matters and participants may have different lengths of follow-up. Combining death, tracheostomy and permanent assisted ventilation into one endpoint gives the trial a defined event for analysis, but it also means the median does not distinguish which component occurred. The registry does not report component-specific results or a sponsor-reported comparative estimate for the primary endpoint.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The reported median survival was 664 days in the ceftriaxone group, with a 95% confidence interval from 614 to 794 days. In the placebo group, the median was 581 days, with a 95% confidence interval from 521 to 672 days. These are group-level estimates for the registry’s composite endpoint: death, tracheostomy or initiation of permanent assisted ventilation.
The confidence intervals describe uncertainty around each group’s estimated median. They overlap, but the intervals for separate group medians are not a substitute for a confidence interval or test of the between-group contrast. The registry record does not report a hazard ratio, a comparative confidence interval, or a sponsor-reported test for survival. A conclusion about the statistical evidence for a difference in time to event cannot be drawn from the medians alone.
The posted secondary outcomes are continuous measures reported as means. Their group estimates describe changes over repeated assessments, and the unadjusted comparisons derived from the posted summaries are imprecise: each reported mean-difference confidence interval includes zero. The corresponding unadjusted p-values are 0.201 for vital capacity, 0.455 for upper-extremity muscle strength and 0.904 for ALS-specific quality of life. These are recalculations from the posted summary statistics, not sponsor-reported analyses. The registry record does not report a sponsor analysis for these outcomes.
Those secondary estimates should not be treated as definitive evidence for or against a treatment effect. Their uncertainty is substantial relative to the estimated contrasts, and the record does not report whether the comparisons were adjusted for other variables or for testing multiple outcomes. In particular, an unadjusted p-value does not account for the number of outcomes examined. The estimates and intervals are more informative when read together than when attention is focused only on whether an individual p-value crosses a conventional threshold.
The posted results do not establish why the group medians differ, whether any observed contrast is attributable to treatment, or how the result applies beyond the people enrolled in this trial. The primary outcome is a composite, and component-specific results are not reported in the registry record. Likewise, the record does not report enough analysis detail to assess the influence of missing observations, adherence or the analysis population. The evidence should therefore be read as registry-reported group summaries with important comparative and methodological details absent.
9. Statistical Methods Explained
Understanding these results requires separating the sponsor’s reported endpoint summaries from calculations that can be made from posted summary statistics. The distinction matters because a reconstructed comparison does not necessarily reproduce the trial’s planned analysis.
What does a median time-to-event estimate mean?
A time-to-event analysis considers both whether an event occurred and when it occurred. The registry defines the event as death, tracheostomy or initiation of permanent assisted ventilation, starting follow-up at randomization. The median is a point on the estimated event-time distribution: it marks the time by which half of that distribution has reached the event. It is not an average time, and it does not say that each participant experienced an event at approximately that time.
In studies with follow-up that ends before every participant experiences the event, time-to-event methods can retain information from participants who have not yet had an event. Such observations are generally treated as censored at the last time the participant is known to be event-free. That is a general description of survival analysis, not confirmation of the exact method used in this trial. The censoring rules, estimator and assumptions are not reported in the registry record.
How should the confidence intervals be read?
A confidence interval expresses statistical uncertainty around an estimate under the method used to calculate it. The primary endpoint’s intervals are reported separately for the two group medians. They indicate that the underlying medians are not known with perfect precision. They do not directly give the uncertainty for the difference between groups. A formal comparison would require a comparative estimate and its uncertainty, or an appropriate reported test; neither is reported for the primary endpoint.
Overlap between two separate confidence intervals is not itself a formal test of whether groups differ. Conversely, separate intervals should not be treated as if their endpoints directly define the interval for a difference. The registry’s primary results therefore support a description of each group’s estimated median and interval, but not a precise comparative statement about the treatment contrast.
What are the secondary comparisons?
For the continuous secondary outcomes, the posted group summaries include means and standard errors. A standard error describes the precision of an estimated mean, not the spread of individual participant values. The recalculated comparisons use the posted means and standard errors to form an unadjusted mean difference and confidence interval. They are simple comparisons based on summary statistics, rather than results from a model reported by the trial sponsor.
For vital capacity and upper-extremity strength, the displayed mean differences are positive; for ALS-specific quality of life, the displayed mean difference is negative. The reported confidence intervals for these recalculated differences include zero, indicating that the posted summaries are compatible with no mean difference as well as with differences in either direction at the interval’s stated level. The unadjusted p-values are 0.201, 0.455 and 0.904, respectively. These values do not incorporate any multiplicity adjustment, and the registry record does not report a sponsor-run analysis for these outcomes.
The registry describes repeated assessments every 12 weeks for one year. A comparison of means reconstructed from summaries may not capture the way repeated measurements were modeled, how incomplete follow-up was handled, or whether estimates were adjusted for baseline values. Those details are not reported in the registry record. The recalculated results should consequently be understood as descriptive statistical checks, not as replacements for a prespecified trial analysis.
What do the planning illustrations tell readers?
The sample-size illustrations are based on the observed effect and assume a two-sided significance level of 0.05, equal allocation between arms and a normal approximation. For continuous outcomes, the reported quantities are participants per arm for the stated power and assumed fraction of the observed effect. They illustrate how a hypothetical future study’s size changes when the effect to detect is made smaller or larger. They are not the trial’s design justification, and they are not observed power.
Observed effects can be imprecise, particularly when the estimated contrast is small or uncertain. Planning a future study directly from such an estimate can therefore produce an unstable target. The registry record does not report the original sample-size assumptions or justification. It also does not report interim analyses or the statistical plan used for the primary endpoint. The planning illustrations are useful as conditional scenarios, but they cannot fill in those missing protocol details.
What does over-dispersion mean in general?
For count outcomes, over-dispersion means that observed variability exceeds what a simple count model assumes. It can make standard errors too small and confidence intervals too narrow if the extra variability is ignored. This is a general statistical consideration, not a reported feature of the primary survival outcome or of the continuous outcomes in this trial. The registry record does not report a count-outcome analysis or a model addressing over-dispersion.
10. Multiplicity, Missing Data and Analysis Populations
The registry record does not report a multiplicity adjustment or a hierarchy for testing the primary and secondary outcomes. The secondary p-values calculated from posted means and standard errors are unadjusted. When multiple outcomes are examined, unadjusted testing can make isolated findings appear more compelling than they would under a plan that controls the overall risk of false-positive results. This does not mean that every unadjusted result is false; it means the results need to be interpreted in the context of the number and status of the analyses.
The registry record also does not report whether analyses were conducted according to intention to treat, per protocol, or another analysis population. It does not give the number of participants with available measurements at each time point, the reasons for missing data, or the methods used to handle missing observations. These omissions limit assessment of whether the posted summaries represent all randomized participants and whether incomplete follow-up could have influenced the estimates.
For the primary time-to-event endpoint, the registry gives a follow-up description but not the censoring rules, survival estimator, model, or sponsor-reported comparison. For the secondary measures, repeated assessments are described, but the statistical model and approach to within-participant correlation are not reported. The record does not state whether baseline values or other covariates were included in the sponsor’s analyses.
These details matter because analysis choices can affect estimates and their uncertainty. Without the statistical plan and analysis-population definitions, readers cannot verify which analyses were prespecified, how deviations were handled, or whether the posted results reflect the intended analysis. This is a limitation of the registry record, not evidence that any particular method was or was not used.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Ceftriaxone | 276 | 340 | 81.2% |
| Placebo | 125 | 173 | 72.3% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Ceftriaxone | 331 of 340 |
| Placebo | 153 of 173 |
Most frequent serious adverse event terms
| Event term | Organ system | Ceftriaxone | Placebo |
|---|---|---|---|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | 74 of 340 | 34 of 173 |
| Cholelithiasis | Hepatobiliary disorders | 28 of 340 | 0 of 173 |
| Infections with unknown ANC: Lung (pneumonia) | Infections and infestations | 13 of 340 | 12 of 173 |
| Thrombosis/thrombus/embolism | Vascular disorders | 20 of 340 | 4 of 173 |
| Line Infection | Infections and infestations | 3 of 340 | 9 of 173 |
| Renal/Genitourinary - Other | Renal and urinary disorders | 10 of 340 | 1 of 173 |
| PEG Placement (outpatient) | Surgical and medical procedures | 4 of 340 | 5 of 173 |
| Aspiration | Respiratory, thoracic and mediastinal disorders | 6 of 340 | 2 of 173 |
| Death not associated with CTCAE Term: Disease Progression NOS | General disorders | 4 of 340 | 4 of 173 |
| Pancreatitis | Gastrointestinal disorders | 7 of 340 | 0 of 173 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Ceftriaxone | Placebo |
|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | 152 of 340 | 41 of 173 |
| Cholelithiasis | Hepatobiliary disorders | 158 of 340 | 5 of 173 |
| Neurology - Other | Nervous system disorders | 97 of 340 | 52 of 173 |
| Catheter Exit Site Reaction | General disorders | 98 of 340 | 45 of 173 |
| Rash/desquamation | Skin and subcutaneous tissue disorders | 92 of 340 | 29 of 173 |
| Biliary Sludge | Hepatobiliary disorders | 100 of 340 | 12 of 173 |
| Constipation | Gastrointestinal disorders | 66 of 340 | 30 of 173 |
| Nausea | Gastrointestinal disorders | 64 of 340 | 28 of 173 |
| Pain: Abdomen NOS | General disorders | 75 of 340 | 16 of 173 |
| Pain: head/headache | Nervous system disorders | 53 of 340 | 32 of 173 |
Serious events with the highest arm-level rate: dyspnea (21.8%), cholelithiasis (8.2%), infections with unknown anc: lung (pneumonia) (6.9%), thrombosis/thrombus/embolism (5.9%), line infection (5.2%).
The registry reports serious adverse events affecting 276 participants in the ceftriaxone group and 125 in the placebo group. It reports other adverse events affecting 331 participants in the ceftriaxone group and 153 in the placebo group. The corresponding groups at risk are listed as 340 and 173, respectively. These counts describe participants recorded as affected; they do not indicate how many events each person experienced.
The serious-event terms listed most prominently include dyspnea at 21.8%, cholelithiasis at 8.2%, lung pneumonia among infections with unknown ANC at 6.9%, thrombosis/thrombus/embolism at 5.9%, line infection at 5.2%, and renal/genitourinary—other at 2.9%. The registry does not explain the denominator or calculation basis for these listed percentages, so they should not be interpreted as rates of all participants without further information.
These adverse-event summaries are descriptive. They do not establish that an event was caused by treatment, and the record does not report a comparative statistical analysis of safety. Death counts in the adverse-event summary are not reported in the registry record. Differences in the number affected should not be interpreted as adjusted risks or treatment effects.
12. What the Result Does, and Does Not, Mean
The registry reports a median time to the defined survival event of 664 days in the ceftriaxone group and 581 days in the placebo group. Each estimate has a 95% confidence interval, reflecting uncertainty around the group-specific median. These results describe the observed trial record for a composite endpoint that includes death, tracheostomy or initiation of permanent assisted ventilation.
The reported medians do not by themselves quantify a between-group effect. The registry does not report a hazard ratio, a comparative confidence interval, or a sponsor-reported test for survival. Separate group intervals cannot substitute for that missing comparison. The record also does not provide component-specific results, so the median cannot show which part of the composite endpoint contributed to the observed event times.
The secondary summaries likewise do not establish a definitive effect. Their recalculated unadjusted intervals include zero, and the record does not report sponsor analyses, multiplicity handling, or sufficient details about missing observations and analysis populations. A non-significant unadjusted result is not proof that groups have the same outcomes, just as a difference between group estimates is not proof that treatment caused it.
The results do not establish the mechanism behind any observed pattern or guarantee that outcomes would be similar in other populations or settings. The record identifies the trial population as people with ALS but does not provide detailed baseline characteristics in the posted outcome information. The appropriate reading is therefore bounded: these are registry-reported group estimates, with important information about formal comparisons and analysis methods not reported in the registry record.
13. Why This Trial Matters Statistically
This trial matters statistically because its primary outcome is a time-to-event measure with a clinically defined composite endpoint, while the registry reports only group-specific medians and confidence intervals. That distinction highlights a basic principle of comparative research: descriptive estimates in each arm are not the same as a direct estimate of the treatment contrast. Readers need the comparative estimate and its uncertainty to assess the precision of the between-group result.
The record also illustrates why endpoint definitions matter. Death, tracheostomy and initiation of permanent assisted ventilation are combined into one event definition. This creates a single time-to-event outcome, but it also means the reported median cannot indicate which component occurred or how the components contributed to the result. Component-specific results are not reported in the registry record.
There is also a useful distinction between sponsor analyses and recalculations from posted summaries. The secondary mean differences and their unadjusted p-values can help readers understand the summaries, but they are not a substitute for the trial’s planned statistical analysis. The registry does not report those sponsor analyses or the multiplicity approach. Sample-size illustrations based on observed effects are planning scenarios, not evidence of the trial’s power or a record of the original design assumptions.
Finally, safety counts, outcome estimates and missing analysis details belong to different parts of interpretation. A sound reading keeps each within its limits: describe what was recorded, distinguish uncertainty from absence of an effect, and avoid treating an unadjusted comparison as causal proof. The registry record supports that careful statistical reading, while leaving several important design and analysis questions unanswered.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The main trial-specific limitation is that the primary endpoint is reported as two medians with separate confidence intervals, without a sponsor-reported hazard ratio, comparative interval or test. This restricts direct assessment of the treatment contrast. The composite endpoint also combines death, tracheostomy and initiation of permanent assisted ventilation, and component-specific results are not reported in the registry record.
For the secondary measures, the posted group summaries do not include sponsor-reported comparisons. The recalculated mean differences are unadjusted and do not account for multiplicity. Although the registry describes repeated measurements, it does not report the model, handling of within-participant correlation, or whether the estimates account for baseline values. The numerical summary for lower-extremity muscle strength is not reported in the registry record.
The registry record does not report the original sample-size justification, interim analyses, full statistical plan, analysis-population definitions, missing-data methods, or time-to-event censoring details. It also does not provide detailed participant characteristics in the posted outcome information. These gaps limit evaluation of prespecification, representativeness, and possible effects of incomplete follow-up.
Safety reporting is also limited to counts and listed serious-event terms. The record does not report a comparative safety analysis, event attribution, or deaths in the adverse-event summary. The basis for the percentages attached to serious-event terms is not explained in the posted information. These limitations do not invalidate the reported summaries, but they constrain the conclusions that can be drawn from them.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Clinical Trial Ceftriaxone in Subjects With ALS — NCT00349622.
- Registry record last updated 2014-04-21; status last verified 2014-04.
- Results first posted 2014-04-01.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT00349622 is a completed phase 3 randomized, double-masked, parallel-group trial sponsored by Massachusetts General Hospital. It enrolled 513 participants and compared ceftriaxone with placebo in people with amyotrophic lateral sclerosis. The registry lists study start in 2006-07 and primary completion in 2012-11.
The primary outcome was median time from randomization to death, tracheostomy or initiation of permanent assisted ventilation. The reported medians were 664 days for ceftriaxone and 581 days for placebo, each with a 95% confidence interval. A sponsor-reported comparative survival estimate is not reported in the registry record.
Secondary measures include vital capacity, muscle strength and ALS-specific quality of life. Recalculated unadjusted comparisons from posted summaries are available for three measures; the registry does not report sponsor analyses or the multiplicity plan. Safety summaries report participants affected by serious and other adverse events, but do not provide a comparative safety analysis.