Medical progress: Cystinosis

This paper reviews adjusted methods of estimation of attributable risk (AR), that is methods that allow one to obtain estimates of AR while controlling for other factors. Estimability and basic principles of AR estimation are first considered and the rationale for adjusted AR estimators is discussed. Then, adjusted AR estimators are reviewed focusing on cross-sectional, cohort and case-control studies. Two inconsistent adjusted estimators are briefly commented upon. Next, adjusted estimators based on stratification, namely the weighted-sum and Mantel-Haenszel (MH) approaches, are reviewed and contrasted. It appears that the weighted-sum approach, which allows for full interaction between exposure and adjustment factors, can be affected by small-sample bias. By contrast, the MH approach, which rests on the assumption of no interaction between exposure and adjustment factors may be misleading if interaction between exposure and adjustment factors is present. Model-based adjusted estimators represent a more general and flexible approach that includes both stratification approaches as special cases and offers intermediate options. Bruzzi et al.'s and Greenland and Drescher's estimators are reviewed and contrasted. Finally, special problems of adjusted estimation are considered, namely estimation from case-cohort data, estimation for risk factors with multiple levels, for multiple risk factors, for recurrent events, estimation of the prevented and preventable fractions, and estimation of the generalized impact fraction. Comments on future directions are presented.

A review of adjusted estimators of attributable risk.

We have argued that the concept of attributable fraction requires separation into the concepts of excess fraction, etiologic fraction, and incidence-density fraction. These quantities do not necessarily approximate one another, and the etiologic fraction is not generally estimable without strong biologic assumptions. For these reasons, care is needed in deciding which (if any) of the concepts is appropriate for a particular application. It appears that the excess fraction (like incidence proportion) will be most relevant in situations that require only consideration of whether disease occurs by a particular time. In situations that require consideration of when disease occurs, direct measures of effect on incidence time may be as relevant as or more relevant than any attributable fraction. To avoid technical complications, we have not discussed additional problems of causal attribution that can arise when exposure has multiple levels or is sustained over time, and the estimation problems that can arise when considering case-control studies, competing risks, or differential censoring. For more detailed discussions of such problems and proposed solutions, see references 11-20.

Conceptual problems in the definition and interpretation of attributable fractions.

Background The lysosomal storage disease cystinosis results in renal failure at approximately 10 years of age. Although oral cysteamine therapy is recognized to preserve kidney function, the extent of renal benefit has not been determined. Methods Between 1960 and 1992, we determined 24-hour creatinine clearances in 76 children with cystinosis during 1081 admissions to the National Institutes of Health. Seventeen children were considered to have received adequate treatment with cysteamine, since they had depletion of cystine from leukocytes and began therapy before the age of 2 years; treatment lasted a mean of 7.1 years. Thirty-two children were considered to have received partial treatment, since they had poor compliance with therapy or began treatment after the age of 2; treatment lasted a mean of 4.5 years. Twenty-seven children were followed in the era before cysteamine therapy and thus never received cysteamine. Results Of the 27 children who never received cysteamine, 16 were followed at the Nation...

https://www.nejm.org/doi/pdf/10.1056/NEJM199304223281604

Improved Renal Function in Children with Cystinosis Treated with Cysteamine

The lysosomal catabolism of glycoproteins is part of the normal turnover of cellular constituents and the cellular homeostasis of glycosylation. Glycoproteins are delivered to lysosomes for catabolism either by endocytosis from outside the cell or by autophagy within the cell. Once inside the lysosome, glycoproteins are broken down by a combination of proteases and glycosidases, with the characteristic properties of soluble lysosomal hydrolases. The proteases consist of a mixture of endopeptidases and exopeptidases, which act in concert to produce a mixture of amino acids and dipeptides, which are transported across the lysosomal membrane into the cytosol by a combination of diffusion and carrier-mediated transport. Although the glycans of all mature glycoproteins are probably degraded in lysosomes, the breakdown of N-linked glycans has been studied most intensively. The catabolic pathways for high-mannose, hybrid, and complex glycans have been established. They are bidirectional with concurrent sequential removal of monosaccharides from the nonreducing end by exoglycosidases and proteolysis and digestion of the carbohydrate-polypeptide linkage at the reducing end. The process is initiated by the removal of any core and peripheral fucose, which is a prerequisite for the action of the peptide N-glycanase aspartylglucosaminidase, which hydrolyzes the glycan-peptide bond. This enzyme also requires free alpha carboxyl and amino groups on the asparagine residue, implying extensive prior proteolysis. The catabolism of O-linked glycans has not been studied so intensively, but many lysosomal glycosidases appear to act on the same linkages whether they are in N- or O-linked glycans, glycosaminoglycans, or glycolipids. The monosaccharides liberated during the breakdown of N- and O-linked glycans are transported across the lysosomal membrane into the cytosol by a combination of diffusion and carrier-mediated transport. Defects in these pathways lead to lysosomal storage diseases. The structures of some of the oligosaccharides that accumulate in these diseases are not digestion intermediates in the lysosomal catabolic pathways but correspond to intermediates in the biosynthetic pathway for N-linked glycans, suggesting another route of delivery of glycans to the lysosome. Incorrectly folded or glycosylated proteins that are rejected by the quality control mechanism are broken down in the ER and cytoplasm and the end product of the cytosolic degradation of N-glycans is delivered to the lysosomes. This route is enhanced in cells actively secreting glycoproteins or producing increased amounts of aberrant glycoproteins. Thus interaction between the lysosome and proteasome is important for the regulation of the biosynthesis and distribution of N-linked glycoproteins. Another example of the extralysosomal function of lysosomal enzymes is the release of lysosomal proteases into the cytosol to initiate the lysosomal pathway of apoptosis.

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Lysosomal metabolism of glycoproteins.

We treated 93 children with nephropathic cystinosis with oral cysteamine (mean dose, 51.3 mg per kilogram of body weight per day) for up to 73 months. This agent is known to be effective in depleting cells of cystine. In our study, the mean cystine depletion from leukocytes was 82 percent. A historical control group of 55 children received either ascorbic acid (27 children) or placebo (28). At age six, 2 of 17 controls had a serum creatinine level less than 1.0 mg per deciliter, as compared with 17 of 27 patients treated with cysteamine for at least one year (odds ratio, 12.8; 95 percent confidence interval, 2.1 to 33.9). At the end of the study, creatinine clearance was higher in the cysteamine group than in the control group (38.5 vs. 29.7 ml per minute per 1.73 m2; 95 percent confidence limits on the difference, 1.8 and 15.8), even though the cysteamine group was on average 1.4 years older than the control group. Cysteamine also improved growth; those in the cysteamine group between two and three years of age grew at 93 percent of the normal velocity, as compared with 54 percent in the control group. Fourteen percent of the patients could not tolerate the taste and smell of cysteamine. Concurrent controls treated in a blinded fashion with a placebo were not included in this study. With this limitation in mind, we conclude that oral cysteamine, by depleting cells of cystine, helps maintain renal glomerular function, improves growth, and constitutes the current treatment of choice for nephropathic cystinosis.

Cysteamine Therapy for Children with Nephropathic Cystinosis

In case-control studies, exposure to a risk factor often occurs at several levels, so the attributable risk at each level is of interest. In this paper, estimation for the 2 X 2 table (case-control status versus dichotomous exposure) and the 2 X k table (case-control status versus exposure at several levels) are reviewed along with an example. A method for finding confidence intervals for attributable risk in the 2 X k table is proposed, and its application to estimates adjusted across strata (the 2 X k X s case) is indicated. The results of a Monte Carlo study of the procedure demonstrate that the nominal and actual coverage probabilities agree satisfactorily for practical applications.

Daniel W. Denman

Papers

Cysteamine Therapy for Children with Nephropathic Cystinosis

Interval estimation of the attributable risk for multiple exposure levels in case-control studies.